incretins and Diabetes-Mellitus--Type-2

The increasing number of cases of diabetes mellitus (DM) and related diseases has become a global health concern. In this context, controlling blood glucose levels is critical to prevent and/or slow down the development of diabetes-related complications. Incretins, as gutderived hormones that trigger the post-meal secretion of insulin, are a well-known family of blood glucose modulators. Currently, incretin medications, including glucagon-like peptide-1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors, are extensively used to treat patients with type 2 diabetes mellitus (T2D). Several experimental and clinical studies illustrate that these metabolic hormones exert their antidiabetic effects through multiple molecular mechanisms. Accordingly, the current review aims to investigate key mechanisms and signaling pathways, such as the cAMP/PKA, Nrf2, PI3K/Akt, and AMPK pathways, associated with the antidiabetic effects of incretins. It also summarizes the outcomes of a group of clinical trials evaluating the incretins' antidiabetic potential in diabetic patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Phosphatidylinositol 3-Kinases

To describe recent advances in the understanding of how gut-derived hormones regulate bone homeostasis in humans with emphasis on pathophysiological and therapeutic perspectives in diabetes.. The gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is important for postprandial suppression of bone resorption. The other incretin hormone, glucagon-like peptide 1 (GLP-1), as well as the intestinotrophic glucagon-like peptide 2 (GLP-2) has been shown to suppress bone resorption in pharmacological concentrations, but the role of the endogenous hormones in bone homeostasis is uncertain. For ambiguous reasons, both patients with type 1 and type 2 diabetes have increased fracture risk. In diabetes, the suppressive effect of endogenous GIP on bone resorption seems preserved, while the effect of GLP-2 remains unexplored both pharmacologically and physiologically. GLP-1 receptor agonists, used for the treatment of type 2 diabetes and obesity, may reduce bone loss, but results are inconsistent. GIP is an important physiological suppressor of postprandial bone resorption, while GLP-1 and GLP-2 may also exert bone-preserving effects when used pharmacologically. A better understanding of the actions of these gut hormones on bone homeostasis in patients with diabetes may lead to new strategies for the prevention and treatment of skeletal frailty related to diabetes.

Topics: Bone Resorption; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Incretins

The prevalence of obesity is rising, creating an urgent need for efficacious therapies. Recent clinical trials show that tirzepatide, a dual agonist of receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), yields more weight loss than selective GLP-1 receptor (GLP-1R) agonists. Incretin receptors in the central nervous system (CNS) may contribute to these effects. Yet exactly how each receptor regulates body weight from within the CNS is not clearly understood. It remains especially unclear how GIP receptor (GIPR) signalling contributes to the effects of tirzepatide because both stimulation and inhibition of CNS GIPRs yield weight loss in preclinical models. We summarise current knowledge on CNS incretin receptor pharmacology to provide insight into the potential mechanisms of action of dual GIPR/GLP-1R agonists, with tirzepatide as the exemplar. In addition, we discuss recent developments in incretin-based dual- and tri-agonism for inducing weight loss in obese individuals.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Obesity; Weight Loss

Gastrointestinal hormones play an important role in the endocrine communication between the intestine, the pancreas, the liver and the brain. Glucagon-like peptide‑1 receptor agonists (GLP-1RA) are established therapeutic agents in the treatment of type‑2 diabetes. Multiple agonists acting as ligands on various gastrointestinal hormone receptors are a novel pharmacological development. In addition to glucagon-like peptide 1 (GLP-1), these multiple agonists also have glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptors as target structures for their pharmacological action. The multiple agonist action is designed to increase glycaemic effects as well as the effects on body weight. This article provides an overview of GLP-1RA and the multiple agonists. Among the dual agonists, the GIP/GLP-1-agonist tirzeptide has been approved for the treatment of type‑2 diabetes, and clinical studies with tirzepatide as a treatment for obesity are ongoing. The currently available data on studies with GLP-1/glucagon agonists and triple agonists are also summarized.. Gastrointestinale Hormone nehmen eine wichtige Rolle in der endokrinen Kommunikation zwischen Darm, Pankreas, Leber und Gehirn ein. Glucagon-like-peptide-1-Rezeptor-Agonisten (GLP-1RA) sind als Therapeutika bei Diabetes mellitus Typ 2 mittlerweile fest etabliert. Eine pharmakologische Weiterentwicklung sind die multiplen Agonisten, die als Liganden an mehreren Darmhormonrezeptoren fungieren. Zielstrukturen für die Wirkung sind hier neben „glucagon-like peptide 1“ (GLP-1) die Rezeptoren von „glucose-dependent insulinotropic polypeptide“ (GIP) und Glukagon. Durch die multiple Agonistenwirkung sollen glykämische Wirkungen und Effekte auf das Körpergewicht verstärkt werden. Der vorliegende Beitrag gibt eine Übersicht über GLP-1RA und die multiplen Agonisten. Unter den dualen Agonisten hat der GIP/GLP-1-Agonist Tirzepatid mittlerweile eine Zulassung zur Behandlung des Typ-2-Diabetes. Klinische Zulassungsstudien zum Einsatz von Tirzepatid bei Adipositas werden derzeit durchgeführt. Die aktuellen Daten aus Studien zu GLP-1/Glukagon-Agonisten und Dreifachagonisten werden hier ebenfalls zusammengefasst.

Topics: Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins

Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent insulinotropic polypeptide (GIP) have shown high glucose-lowering and weight-lowering efficacy when administered by once-weekly subcutaneous injection. These analogues herald an exciting new era in peptide-based therapy for type 2 diabetes (T2D) and obesity. Of note is the GLP-1R agonist semaglutide, available in oral and injectable formulations and in clinical trials combined with the long-acting amylin analogue, cagrilintide. Particularly high efficacy in both glucose- and weight lowering capacities has also been observed with the GLP-1R/GIP-R unimolecular dual agonist, tirzepatide. In addition, a number of long-acting unimolecular GLP-1R/GCGR dual agonist peptides and GLP-1R/GCGR/GIPR triagonist peptides have entered clinical trials. Other pharmacological approaches to chronic weight management include the human monoclonal antibody, bimagrumab which blocks activin type II receptors and is associated with growth of skeletal muscle, an antibody blocking activation of GIPR to which are conjugated GLP-1R peptide agonists (AMG-133), and the melanocortin-4 receptor agonist, setmelanotide for use in certain inherited obesity conditions. The high global demand for the GLP-1R agonists liraglutide and semaglutide as anti-obesity agents has led to shortage so that their use in T2D therapy is currently being prioritized.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Incretins; Obesity

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that stimulate insulin secretion from pancreatic β cells in response to food ingestion. Modified GLP-1 and GIP peptides are potent agonists for their incretin receptors, and some evidence shows that the dual GLP-1 and GIP receptor agonist tirzepatide is effective in promoting marked weight loss. GLP-1 receptor agonists signal in the CNS to suppress appetite, increase satiety, and thereby decrease calorie intake, but many other effects of incretin signalling have been recognised that are relevant to the treatment of non-alcoholic fatty liver disease (NAFLD). This Review provides an overview of the literature supporting the notion that endogenous incretins and incretin-receptor agonist treatments are important not only for decreasing risk of developing NAFLD, but also for treating NAFLD and NAFLD-related complications. We discuss incretin signalling and related incretin-receptor agonist treatments, mechanisms in key relevant tissues affecting liver disease, and clinical data from randomised controlled trials. Finally, we present future perspectives in this rapidly developing field of research and clinical medicine.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Non-alcoholic Fatty Liver Disease

Glucagon-like peptide-1 (GLP-1) receptor agonists currently occupy a privileged place in the management of type-2 diabetes (T2D). Dual glucose-dependent insulinotropic polypeptides (GIP/GLP-1) have been recently developed. Tirzepatide is the most advanced unimolecular dual GIP/GLP-1 receptor agonist to be used as once weekly subcutaneous injection in T2D and recently received approval by the European Medicines Agency. Because of the complementarity of action of the two incretins, tirzepatide showed better dose-dependent (5, 10 and 15mg) efficacy (greater reduction in HbA1c and body weight) than placebo, basal insulin or two GLP-1 analogues (dulaglutide and semaglutide) in the SURPASS program. Its cardiovascular protective effect is currently being assessed versus dulaglutide in the SURPASS-CVOT study. Finally, studies for the treatment of obesity (SURMOUNT program) and metabolic-associated fatty liver disease (MAFLD) are also ongoing. Gastrointestinal tolerance of tirzepatide appears comparable to that of GLP-1 analogues, except for higher incidence of diarrhea. Other original molecules have been built, including triple GIP/GLP-1/glucagon receptor agonists. The risk/benefit ratio will decide whether dual (or triple) receptor agonists should replace pure GLP-1 receptor agonists for the management of T2D in the near future, with a significant role in the pharmacotherapy of obesity.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Obesity

Glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). The GLP-1R cellular signaling mechanism relevant to insulin secretion and blood glucose regulation has been extensively studied. Numerous drugs targeting GLP-1R have entered clinical treatment. However, novel functional molecules with reduced side effects and enhanced therapeutic efficacy are still in high demand. In this review, we summarize the basis of GLP-1R cellular signaling, and how it is involved in the treatment of T2DM. We review the functional molecules of incretin therapy in various stages of clinical trials. We also outline the current strategies and emerging techniques that are furthering the development of novel therapeutic drugs for T2DM and other metabolic diseases.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Signal Transduction

Among the two incretins that strongly stimulate insulin secretion and are also involved in its physiological regulation in type 2 diabetes, glucagon-like peptide-1 (GLP1) has been the focus of interest for a long time, due to its retained - although reduced - secretagogue nature also in type 2 diabetes. Its receptor agonists were also included in the antidiabetic treatment toolkit. In the light of more recent studies, however, the "other" incretin, the glucose-dependent insulinotropic polypeptide (GIP) has also come into a different light. It turned out that by regulating glucagon and insulin production according to blood sugar levels, it acts as a bifunctional blood sugar stabilizing factor in type 2 diabetes as well. The article reviews new data on the physiology of GIP, its verifiable effects in type 2 diabetes and obesity, the so-called "twincretin" effect as well as the benefits of the double stimulation of the GIP and the GLP1 receptor. It describes the pharmacology of the first dual receptor agonist, tirzepatide, already incorporated in therapeutic recommendations, and the first clinical trials related to its use. In the light of the data so far, the molecule may open new horizons in the treatment of type 2 diabetes and obesity. Orv Hetil. 2023; 164(6): 210-218.. Az inzulinszekréciót erélyesen serkentő, élettani szabályozásában is részt vevő két inkretin közül a 2-es típusú diabetesben is megtartott – bár csökkent − secretagog természete folytán hosszú időn keresztül a glükagonszerű peptid-1 (GLP1) került az érdeklődés előterébe, kívülről bejuttatott receptoragonistái bekerültek az antidiabetikus kezelés eszköztárába is. Újabb vizsgálatok fényében a „másik” inkretin, a glükózdependens insulinotrop polipeptid (GIP) is más megvilágításba került. Kiderült, hogy a glükagon és az inzulintermelés vércukorszinthez igazodó szabályozásával bifunkcionális vércukor-stabilizáló tényezőként viselkedik 2-es típusú diabetesben is. A közlemény áttekinti a GIP élettanával kapcsolatos új adatokat, 2-es típusú diabetesben és elhízásban igazolható hatásait, a „twincretin” hatás, a GIP és a GLP1-receptor kettős stimulálásának előnyeit. Ismerteti az első, már terápiás ajánlásokban is megjelent duális receptoragonista, a tirzepatid farmakológiáját és az alkalmazásával kapcsolatos első klinikai vizsgálatokat. A molekula az eddigi adatok tükrében új távlatokat jelenthet a 2-es típusú diabetes és az elhízás kezelésében. Orv Hetil. 2023; 164(6): 210–218.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Obesity

To maintain normal glucose homeostasis after a meal, it is essential to secrete an adequate amount of insulin from pancreatic β-cells. However, if pancreatic β-cells solely depended on the blood glucose level for insulin secretion, a surge in blood glucose levels would be inevitable after the ingestion of a large amount of carbohydrates. To avoid a deluge of glucose in the bloodstream after a large carbohydrate- rich meal, enteroendocrine cells detect the amount of nutrient absorption from the gut lumen and secrete incretin hormones at scale. Since insulin secretion in response to incretin hormones occurs only in a hyperglycemic milieu, pancreatic β-cells can secrete a "Goldilocks" amount of insulin (i.e., not too much and not too little) to keep the blood glucose level in the normal range. In this regard, pancreatic β-cell sensitivity to glucose and incretin hormones is crucial for maintaining normal glucose homeostasis. In this Namgok lecture 2022, we review the effects of current anti-diabetic medications on pancreatic β-cell sensitivity to glucose and incretin hormones.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin

The incretin hormone glucagon-like peptide 1 (GLP-1) is a key component of the signaling mechanisms promoting glucose homeostasis. Clinical and experimental studies demonstrated that GLP-1 receptor agonists, including GLP-1 itself, have favorable effects on blood pressure and reduce the risk of major cardiovascular events, independently of their effect on glycemic control. GLP-1 receptors are present in the hypothalamus and brainstem, the carotid body, the vasculature, and the kidneys. These organs are involved in blood pressure regulation, have their function altered in hypertension, and are positively benefited by the treatment with GLP-1 receptor agonists. Here, we discuss the potential mechanisms whereby activation of GLP-1R signaling exerts blood pressure-lowering effects beyond glycemic control.

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and now tirzepatide, a dual GLP-1 RA/glucose-dependent insulinotropic polypeptide agonist, have numerous advantages in the treatment of type 2 diabetes and obesity, yet only 11% of patients with type 2 diabetes are prescribed a GLP-1 RA. This narrative review addresses the complexity and cost issues surrounding incretin mimetics to support clinicians.. This narrative review summarizes key trials on the differing effects of incretin mimetics on glycosylated hemoglobin and weight, provides a table with rationale for how to interchange among agents, and summarizes the key factors that guide drug selection beyond guidance from the American Diabetes Association. To support proposed dose interchanges, we preferentially selected high-quality, prospective randomized controlled trials with direct comparisons of agents and doses when available.. Tirzepatide produces the greatest reductions in glycosylated hemoglobin and weight, but its impact on cardiovascular events is still under investigation. Subcutaneous semaglutide and liraglutide are approved for weight loss specifically and are effective in the secondary prevention of cardiovascular disease. Although producing less weight loss, only dulaglutide has effectiveness in the primary and secondary prevention of cardiovascular disease. Semaglutide is the only orally available incretin mimetic; however, the oral formulation produces less weight loss versus its subcutaneous alternative and did not have cardioprotection in its outcomes trial. Although effective in controlling type 2 diabetes, exenatide extended release has the least impact on glycosylated hemoglobin and weight among commonly used agents, while not having cardioprotection. However, exenatide extended release may be preferred on some restrictive insurance formularies.. Although trials have not explicitly studied how to interchange among agents, interchanges can be guided by comparisons between agents' impact on glycosylated hemoglobin and weight. Efficient changes among agents can help clinicians optimize patient-centered care, particularly in the face of changing patient needs and preferences, insurance formularies, and drug shortages.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Prospective Studies; Weight Loss

Incretin hormones, principally glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1), potentiate meal-stimulated insulin secretion through direct (GIP + GLP-1) and indirect (GLP-1) actions on islet β-cells. GIP and GLP-1 also regulate glucagon secretion, through direct and indirect pathways. The incretin hormone receptors (GIPR and GLP-1R) are widely distributed beyond the pancreas, principally in the brain, cardiovascular and immune systems, gut and kidney, consistent with a broad array of extrapancreatic incretin actions. Notably, the glucoregulatory and anorectic activities of GIP and GLP-1 have supported development of incretin-based therapies for the treatment of type 2 diabetes and obesity. Here we review evolving concepts of incretin action, focusing predominantly on GLP-1, from discovery, to clinical proof of concept, to therapeutic outcomes. We identify established vs uncertain mechanisms of action, highlighting biology conserved across species, while illuminating areas of active investigation and uncertainty that require additional clarification.

Topics: Biology; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins

To provide an overview of the safety and efficacy, pharmacology, dosing, place in therapy, and clinical trials for tirzepatide, a novel glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist for treatment of type 2 diabetes.. Diabetes is a chronic disease state with a high burden on healthcare spending and patient quality of life. Incretin-influencing agents such as GLP-1 receptor agonists have gained favor as diabetes therapeutic options due to their impact on multiple glycemic factors as well as resulting weight loss and cardiovascular benefits. Tirzepatide was approved in 2022 for the management of type 2 diabetes and utilizes GLP-1 receptor agonism along with GIP agonism to simultaneously address 2 incretin pathways. Thus far, the SURPASS and SURMOUNT trials, for which findings have been published, have shown great efficacy of tirzepatide in glycosylated hemoglobin and weight reduction in multiple subgroup populations with and without diabetes. Tirzepatide has similar gastrointestinal adverse reactions and contraindications as traditional GLP-1 receptor agonists.. Tirzepatide is a novel agent on the market for type 2 diabetes management that offers targeting of a familiar pathway along with the new GIP pathway to address glycemic control in patients with diabetes. Tirzepatide is approved for use in patients with diabetes and may serve as a strong option for patients requiring improved glycemic and weight control.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Quality of Life

There are no drugs approved by regulatory agencies for the treatment of nonalcoholic fatty liver disease (NAFLD); incretin combination therapies are being developed for treatment of type 2 diabetes and research has moved to test their usefulness in NAFLD.. We reviewed the literature on the effectiveness of dual and triple peptides combining receptor agonists of the glucagon-like peptide 1, the glucose-dependent insulinotropic peptide, and glucagon to treat NAFLD and its associated metabolic diseases, and/or the cardiovascular risk intimately connected with the cluster of the metabolic syndrome. Other combination peptides involved the glucagon-like peptide 2 receptor, the fibroblast growth factor 21, the cholecystokinin receptor 2, and the amylin receptor.. Both dual and triple agonists are promising, based on animal, pharmacokinetic and proof-of concept studies, showing effectiveness both in the presence and the absence of diabetes on a few validated surrogate NAFLD biomarkers, but the majority of studies are still in progress. Considering the long natural history of NAFLD, final proof of their efficacy on primary clinical liver outcomes might be also derived from the analysis of large databases of National Healthcare Systems or Insurance companies, when used in diabetes for improving glycemic control, after careful propensity-score matching.

Topics: Animals; Biomarkers; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Non-alcoholic Fatty Liver Disease

Cognitive dysfunction, including mild cognitive impairment and dementia, is increasingly recognized as an important complication of type 2 diabetes mellitus. The aims of the preset study was to investigate the cognitive protection of incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, in patients with type 2 diabetes mellitus.. PubMed, EMBASE, Cochrane library, Web of Science and PsycINFO were searched from the inception through 17 January 2023 for randomized controlled trials and cohort studies on the association between incretin-based therapies and cognitive function. A total of 15 studies were finally included in our systematic review, and eight of which were incorporated into our meta-analysis.. Pooled results showed that the Mini-Mental State Examination score in incretin-based therapy groups was increased by 1.20 compared with the control group (weighted mean difference 1.20, 95% confidence interval 0.39-2.01). The results of eight studies assessed by the Newcastle Ottawa Quality Assessment Scale and the Cochrane Collaboration's tool, and the quality of the eight studies were at a relatively high level. Egger's regression did not show significant publication bias.. Current evidence shows that incretin-based therapies might be more effective, when compared with the other hypoglycemic drugs, for cognitive improvement in patients with type 2 diabetes mellitus.

Topics: Cognition; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Development of DKD increases risks for cardiovascular events and death. Glucagon-like peptide-1 (GLP-1) receptor agonist have demonstrated improved cardiovascular and kidney outcomes in large-scale clinical trials.. GLP-1 and dual GLP-1/glucose-depending insulinotropic polypeptide (GIP) receptor agonists have robust glucose-lowering efficacy with low risk of hypoglycemia even in advanced stages of DKD. Initially approved as antihyperglycemic therapies, these agents also reduce blood pressure and body weight. Cardiovascular outcome and glycemic lowering trials have reported decreased risks of development and progression of DKD and atherosclerotic cardiovascular events for GLP-1 receptor agonists. Kidney and cardiovascular protection is mediated partly, but not entirely, by lowering of glycemia, body weight, and blood pressure. Experimental data have identified modulation of the innate immune response as a biologically plausible mechanism underpinning kidney and cardiovascular effects.. An influx of incretin-based therapies has changed the landscape of DKD treatment. GLP-1 receptor agonist use is endorsed by all major guideline forming organizations. Ongoing clinical trials and mechanistic studies with GLP-1 and dual GLP-1/GIP receptor agonists will further define the roles and pathways for these agents in the treatment of DKD.

Topics: Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Renal Insufficiency, Chronic

Therapeutic strategies for neurodegenerative disorders have commonly targeted individual aspects of the disease pathogenesis to little success. Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by several pathological features. In AD and PD, there is an abnormal accumulation of toxic proteins, increased inflammation, decreased synaptic function, neuronal loss, increased astrocyte activation, and perhaps a state of insulin resistance. Epidemiological evidence has revealed a link between AD/PD and type 2 diabetes mellitus, with these disorders sharing some pathological commonalities. Such a link has opened up a promising avenue for repurposing antidiabetic agents in the treatment of neurodegenerative disorders. A successful therapeutic strategy for AD/PD would likely require a single or several agents which target the separate pathological processes in the disease. Targeting cerebral insulin signalling produces numerous neuroprotective effects in preclinical AD/PD brain models. Clinical trials have shown the promise of approved diabetic compounds in improving motor symptoms of PD and preventing neurodegenerative decline, with numerous further phase II trials and phase III trials underway in AD and PD populations. Alongside insulin signalling, targeting incretin receptors in the brain represents one of the most promising strategies for repurposing currently available agents for the treatment of AD/PD. Most notably, glucagon-like-peptide-1 (GLP-1) receptor agonists have displayed impressive clinical potential in preclinical and early clinical studies. In AD the GLP-1 receptor agonist, liraglutide, has been demonstrated to improve cerebral glucose metabolism and functional connectivity in small-scale pilot trials. Whilst in PD, the GLP-1 receptor agonist exenatide is effective in restoring motor function and cognition. Targeting brain incretin receptors reduces inflammation, inhibits apoptosis, prevents toxic protein aggregation, enhances long-term potentiation and autophagy as well as restores dysfunctional insulin signalling. Support is also increasing for the use of additional approved diabetic treatments, including intranasal insulin, metformin hydrochloride, peroxisome proliferator-activated nuclear receptor γ agonists, amylin analogs, and protein tyrosine phosphatase 1B inhibitors which are in the investigation for deployment in PD and AD treatment. As such, we provide a comprehensive review of

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Inflammation; Insulin; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease

Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease (CKD), leading end-stage renal disease. Thus, DKD is one of the most important diabetic complications. Incretin-based therapeutic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonizts and dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to elicit vasotropic actions, suggesting a potential for effecting reduction in DKD. Glucose-dependent insulinotropic polypeptide (GIP) is also classified as an incretin. However, the insulin action after GIP secretion is known to be drastically reduced in patients with type 2 diabetes. Therefore, GIP has been formally considered unsuitable as a treatment for type 2 diabetes in the past. This concept is changing as it has been reported that resistance to GIP can be reversed and its effect restored with improved glycemic control. The development of novel dual- or triple- receptor agonizts that can bind to the receptors, not only for GLP-1 but also to GIP and glucagon receptors, is intended to simultaneously address several metabolic pathways including protein, lipid, and carbohydrate metabolism. These led to the development of GIP receptor agonist-based drugs for type 2 diabetes. The possibility of combined GIP/GLP-1 receptor agonist was also explored. The novel dual GIP and GLP-1 receptor agonist tirzepatide has recently been launched (Mounjaro®, Lilly). We have revealed precise mechanisms of the renoprotective effect of GLP-1 receptor agonizts or DPP-4 inhibitors, while the long-term effect of tirzepatide will need to be determined and its potential effects on kidneys should be properly tested.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

The incretin hormones, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), have been shown to decrease bone resorption in humans. The aim of this review is to collate evidence and current advances in the research within the last year on the effect of incretins on skeletal health.. Preclinical studies show potential direct beneficial effects on bone by GLP-1 and GIP, however real world epidemiological data show no effects of GLP-1 receptor analogues on fracture risk. This may be due to the weight loss accompanied by GLP-1 treatment which may have detrimental effects on bone. GIP is shown to reduce bone resorption and increase bone formation. Further evidence suggests an additive effect of GIP and glucagon like peptide-2, which could affect bone by different mechanisms.. GIP and GLP-1 based therapies are more widespread used and may have potential beneficial effects on bone, possibly counterbalanced by weight loss. Long-term effects and side-effects of GIP or GIP/ GLP-2 co-administration remain to be elucidated, and longer term treatment trials are needed.

Topics: Bone Resorption; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Weight Loss

Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Incretins; Insulin; Weight Loss

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have demonstrated cardiovascular benefits in people with type 2 diabetes. However, socioeconomic disparities in their uptake may constrain the collective advantages offered by these medications to the broader population. In this review we examine the socioeconomic disparities in the utilisation of incretin-based therapies and discuss strategies to address these inequalities. Based on real-world evidence, the uptake of GLP-1 RAs is reduced in people who live in socioeconomically disadvantaged areas, have low income and education level, or belong to racial/ethnic minorities, even though these individuals have a greater burden of type 2 diabetes and cardiovascular disease. Contributing factors include suboptimal health insurance coverage, limited accessibility to incretin-based therapies, financial constraints, low health literacy and physician-patient barriers such as provider bias. Advocating for a reduction in the price of GLP-1 RAs is a pivotal initial step to enhance their affordability among lower socioeconomic groups and improve their value-for-money from a societal perspective. By implementing cost-effective strategies, healthcare systems can amplify the societal benefits of incretin-based therapies, alongside measures that include maximising treatment benefits in specific subpopulations while minimising harms in vulnerable individuals, increasing accessibility, enhancing health literacy and overcoming physician-patient barriers. A collaborative approach between governments, pharmaceutical companies, healthcare providers and people with diabetes is necessary for the effective implementation of these strategies to enhance the overall societal benefits of incretin-based therapies.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Socioeconomic Factors

In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Non-alcoholic Fatty Liver Disease; Obesity

Major cardiovascular outcome trials and real-life observations have proven that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), regardless of structural GLP-1 homology, exert clinically relevant cardiovascular protection. GLP-1RAs provide cardioprotective benefits through glycaemic and non-glycaemic effects, including improved insulin secretion and action, body-weight loss, blood-pressure lowering and improved lipid profile, as well as via direct effects on the heart and vasculature. These actions are likely combined with anti-inflammatory and antioxidant properties that translate into robust and consistent reductions in atherothrombotic events, particularly in people with type 2 diabetes and established atherosclerotic CVD. GLP-1RAs may also have an impact on obesity and chronic kidney disease, conditions for which cardiovascular risk-reducing options are limited. The available evidence has prompted professional and medical societies to recommend GLP-1RAs for mitigation of the cardiovascular risk in people with type 2 diabetes. This review summarises the clinical evidence for cardiovascular protection with use of GLP-1RAs and the main mechanisms underlying this effect. Moreover, it looks into how the availability of upcoming dual and triple incretin receptor agonists might expand the possibility for cardiovascular protection in people with type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins

Incretin-based therapies, in particular glucagon-like peptide-1 (GLP-1) receptor agonists, have been evaluated in other forms of diabetes, but randomised controlled trials are mainly limited to people living with type 1 diabetes. In this review we present the evidence issuing from these trials and discuss their clinical implications as well as the difficulties in interpreting the data. In type 1 diabetes, the addition of GLP-1 receptor agonists to intensive insulin therapy lowers weight and required insulin doses compared with placebo, but the effects on glucose control (HbA

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin

Diabetes is a serious health issue that causes a progressive dysregulation of carbohydrate metabolism due to insufficient insulin hormone, leading to consistently high blood glucose levels. According to the epidemiological data, the prevalence of diabetes has been increasing globally, affecting millions of individuals. It is a long-term condition that increases the risk of various diseases caused by damage to small and large blood vessels. There are two main subtypes of diabetes: type 1 and type 2, with type 2 being the most prevalent. Genetic and molecular studies have identified several genetic variants and metabolic pathways that contribute to the development and progression of diabetes. Current treatments include gene therapy, stem cell therapy, statin therapy, and other drugs. Moreover, recent advancements in therapeutics have also focused on developing novel drugs targeting these pathways, including incretin mimetics, SGLT2 inhibitors, and GLP-1 receptor agonists, which have shown promising results in improving glycemic control and reducing the risk of complications. However, these treatments are often expensive, inaccessible to patients in underdeveloped countries, and can have severe side effects. Peptides, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are being explored as a potential therapy for diabetes. These peptides are postprandial glucose-dependent pancreatic beta-cell insulin secretagogues and have received much attention as a possible treatment option. Despite these advances, diabetes remains a major health challenge, and further research is needed to develop effective treatments and prevent its complications. This review covers various aspects of diabetes, including epidemiology, genetic and molecular basis, and recent advancements in therapeutics including herbal and synthetic peptides.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Peptides

Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Islets of Langerhans; Receptors, Glucagon

Obesity and its comorbidities, including type 2 diabetes mellitus, cardiovascular disease, heart failure and non-alcoholic liver disease are a major health and economic burden with steadily increasing numbers worldwide. The need for effective pharmacological treatment options is strong, but, until recently, only few drugs have proven sufficient efficacy and safety. This article provides a comprehensive overview of obesity and its comorbidities, with a special focus on organ-specific pathomechanisms. Bariatric surgery as the so far most-effective therapeutic strategy, current pharmacological treatment options and future treatment strategies will be discussed. An increasing knowledge about the gut-brain axis and especially the identification and physiology of incretins unfolds a high number of potential drug candidates with impressive weight-reducing potential. Future multi-modal therapeutic concepts in obesity treatment may surpass the effectivity of bariatric surgery not only with regard to weight loss, but also to associated comorbidities.

Topics: Bariatric Surgery; Comorbidity; Diabetes Mellitus, Type 2; Humans; Incretins; Obesity; Weight Loss

Recent studies show that Alzheimer's disease (AD) has many common links with conditions associated with insulin resistance, including neuroinflammation, impaired insulin signaling, oxidative stress, mitochondrial dysfunction and metabolic syndrome. The authors conducted an electronic search for publications in the PubMed/MEDLINE and Google Scholar databases using the keywords "amyloid beta", "Alzheimer type-3-diabetes", "intranasal insulin", "metformin", "type 2 diabetes mellitus", "incretins" and "PPARy agonists». A systematic literature search was conducted among studies published between 2005 and 2022. The authors used the following inclusion criteria: 1) Subjects who received therapy for AD and/or DM2, if the expected result concerned the risk of cognitive decline or the development of dementia; 2) The age of the study participants is > 50 years; 3) The type of studies included in this review were randomized clinical trials, population-based observational studies or case-control studies, prospective cohort studies, as well as reviews and meta-analyses; 4) The included articles were written in English. In recent years, there has been considerable interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in AD. Human studies involving patients with mild cognitive impairment and Alzheimer's disease have shown that the administration of certain antidiabetic drugs, such as intranasal insulin, metformin, incretins and thiazolidinediones, can improve cognitive function and memory. The purpose of this study is to evaluate the effectiveness of antidiabetic drugs in the treatment of AD. According to the results of the study, metformin, intranasal insulin, thiazolidinediones and incretins showed a positive effect both in humans and in animal models. Recent studies show that thiazolidinediones can activate pathways in the brain that are regulated by IGF-1; however, rosiglitazone may pose a significant risk of side effects. The results of clinical studies on the use of metformin in AD are limited and contradictory.

Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Middle Aged; Observational Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Thiazolidinediones

The increasing burden of diabetic kidney disease (DKD) has led to the discovery of novel therapies.. This review aims to summarize the results of recent clinical trials that test the efficacy of potential therapies for DKD.. A systematized narrative review was performed utilizing the PubMed, Embase (Ovid), CINAHL, and Cochrane databases (January 2010 to January 2021). The included trials assessed the efficacy of specific medications using renal endpoints in adult participants with type 1 or 2 diabetes.. Fifty-three trials were identified. Large, multinational, and high-powered trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrated improved renal outcomes, even in patients with established DKD. Trials examining incretin-related therapies also showed some improvement in renal outcomes. Additionally, mineralocorticoid receptor antagonists exhibited potential with multiple improved renal outcomes in large trials, including those involving participants with established DKD. Atrasentan, baricitinib, ASP8232, PF-04634817, CCX140-B, atorvastatin, fenofibrate, probucol, doxycycline, vitamin D, omega-3 fatty acids, silymarin, turmeric, total glucosides of paeony, and tripterygium wilfordii Hook F extract were all associated with some improved renal endpoints but need further exploration. While bardoxolone methyl was associated with a decrease in albuminuria, high rates of cardiovascular adverse effects curtailed further exploration into this agent. Selonsertib, allopurinol, praliciguat, palosuran, benfotiamine, and diacerein were not associated with improved renal outcomes.. Trials have yielded promising results in the search for new therapies to manage DKD. SGLT2 inhibitors and incretin-related therapies have demonstrated benefit and were associated with improved cardiovascular outcomes. Mineralocorticoid receptor antagonists are another class of agents with increasing evidence of benefits.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Incretins; Prognosis; Sodium-Glucose Transporter 2 Inhibitors

In the incretin system, Glucagon-like peptide-1 (GLP-1) is a hormone that inhibits the release of glucagon and regulates glucose-dependent insulin secretion. In type 2 diabetes, correcting the impaired incretin system using GLP-1 agonist is a well-defined therapeutic strategy.. This review article aims to discuss the mechanism of action, key regulatory events, clinical trials for glycaemic control, and comparative analysis of semaglutide with the second-line antidiabetic drugs.. Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist with enhanced glycaemic control in diabetes patients. In 2019, USFDA approved the first oral GLP-1 receptor agonist, semaglutide, to be administered as a once-daily tablet. Further, recent studies highlight the ability of semaglutide to improve Glycemic control in obese patients with a reduction in body weight. Still, in clinical practice, in the type 2 DM treatment paradigm, the impact of oral semaglutide remains unidentified. This review article discusses the mechanism of action, pharmacodynamics, key regulatory events, and clinical trials regarding glycaemic control.. The review highlights the comparative analysis of semaglutide with the existing second- line drugs for the management of type 2 diabetes mellitus by stressing its benefits and adverse events.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incretins

Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single-targeting agents have limited efficacy. Proglucagon-derived peptides, glucagon, and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP-1/GIP and GLP-1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP-1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity

The therapeutic arsenal for treating type 2 diabetes mellitus (T2DM) has been enriched recently with the inclusion of type 1 glucagon-like peptide (GLP-1). GLP-1 receptor agonists (RA) secondarily reduce appetite, decrease gastric emptying, and reduce body weight. This effect has been used to treat overweight/obesity, especially with comorbidities associated with T2DM. However, the first formulations and adverse effects gradually gave way to new formulations with fewer unpleasant effects and a more extended period of action (weekly subcutaneous administration and even oral administration), which improved the acceptance and adherence to the treatment. Therefore, titration of GLP-1RA should be done gradually. Furthermore, when side effects are consistent and intolerable after weeks/months of titration, a lower dose or a combination of antidiabetic therapies should be implemented, avoiding treatment interruption. The effort to produce increasingly powerful molecules with fewer side effects is the driving force behind the pharmaceutical industry. The unimolecular dual agonism GLP-1RA plus glucagon receptor agonism (GRA) represents an updated pharmacological indication for controlling blood glucose levels in treating T2DM and its comorbidities, showing better effects with less adverse impact than mono GLP-1RA. There are currently different proposals in this way by different laboratories. Nevertheless, the experimental results are promising and show that soon, we will have the contribution of new drugs for the treatment of T2DM.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Obesity

The long-acting glucagon-like peptide-1 receptor (GLP1R) agonist, semaglutide and the unimolecular glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP1R dual-agonist, tirzepatide have been successfully introduced as therapeutic options for patients with Type-2 diabetes (T2DM) and obesity. Proglucagon-derived peptides from phylogenetically ancient fish act as naturally occurring dual agonists at the GLP1R and the glucagon receptor (GCGR) with lamprey GLP-1 and paddlefish glucagon being the most potent and effective in stimulating insulin release from BRIN-BD11 clonal β-cells. These peptides were also the most effective in lowering blood glucose and elevating plasma insulin concentrations when administered intraperitoneally to overnight-fasted mice together with a glucose load. Zebrafish GIP acts as a dual agonist at the GIPR and GLP1R receptors. Studies with the high fat-fed mouse, an animal model with obesity, impaired glucose-tolerance and insulin-resistance, have shown that twice-daily administration of the long-acting analogs [D-Ala

Topics: Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Eating; Fish Proteins; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Obesity; Proglucagon

Incretin-based therapy leads to glycemic control in a glucose-dependent manner with a low risk of hypoglycemia, making it appealing for use in the hospital. The aim of this systematic review was to assess the benefits of incretin-based therapy in patients with type 2 diabetes hospitalized outside of the intensive care unit. We searched for studies published up to August 2021 in the PubMed and Scopus databases. Clinical trials comparing incretin-based therapy (alone or in combination with insulin) versus an insulin regimen were selected. The results of the included studies showed that incretin-based therapy showed mean blood glucose values, a percentage of records within the therapeutic target, and a percentage of treatment failure similar to insulin management, particularly in patients with mild to moderate hyperglycemia. Furthermore, incretin-based treatment was associated with a lower total insulin dose and a lower incidence of hypoglycemia. In conclusion, incretin-based therapy achieved glycemic control similar to insulin treatment in patients with type 2 diabetes hospitalized outside the intensive care unit and has the advantages of reducing the insulin requirement and a lower risk of hypoglycemia.

Topics: Diabetes Mellitus, Type 2; Glycemic Control; Humans; Hypoglycemic Agents; Incretins; Insulin

Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of β-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a 'chemical excitant' that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word 'incretin' to describe the phenomena. Incretins include GIP and GLP-1. The 'enteroinsular axis' is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin-Secreting Cells

As the worldwide prevalence of diabetes and obesity continues to rise, so does the risk of debilitating cardiovascular complications. Given the significant association between diabetes and cardiovascular risk, the actions of glucose-lowering therapies within the cardiovascular system must be clearly defined. Incretin hormones, including GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide), are gut hormones secreted in response to nutrient intake that maintain glycemic control by regulating insulin and glucagon release. GLP-1 receptor agonists (GLP-1Ras) and dipeptidyl peptidase 4 inhibitors (DPP-4is) represent two drug classes used for the treatment of type 2 diabetes mellitus (T2DM) that improve glucose regulation through stimulating the actions of gut-derived incretin hormones or inhibiting their degradation, respectively. Despite both classes acting to potentiate the incretin response, the potential cardioprotective benefits afforded by GLP-1Ras have not been recapitulated in cardiovascular outcome trials (CVOTs) evaluating DPP-4is. This review provides insights through discussion of clinical and preclinical studies to illuminate the physiological mechanisms that may underlie and reconcile observations from GLP-1Ra and DPP-4i CVOTs. Furthermore, critical knowledge gaps and areas for further investigation will be emphasized to guide future studies and, ultimately, facilitate improved clinical management of cardiovascular disease in T2DM.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome

Since the first use of insulin 100 years ago, there have been marked improvements in diabetes therapy including, but not limited to, the development of oral antidiabetic agents (OADs), incretin mimetics and insulin analogues. Still, there are substantial shortcomings in diabetes therapy: the blood-glucose lowering effect of OADs is often limited, incretin mimetics often induce gastrointestinal side effects and insulins still induce hypoglycaemia and weight gain in many patients.This review evaluates on-going developments of antidiabetic drugs for their potential for future therapy focussing on injectable therapies. Recent data from dual agonists, in particular tirzepatide, a combination of GIP- and GLP-1 receptor agonists, show unprecedented reductions in HbA1c, body weight and cardiovascular risk factors. Once-weekly administrations of incretin mimetics open up the potential of a combination with once-weekly insulins that have been shown to have low peak-to-trough fluctuations. Eventually, it might be feasible to administer incretins and insulins (combinations) orally. While this has already been achieved for incretins, there are still some challenges for the oral application of insulin. Nevertheless, many promising data of novel antidiabetic drugs clearly indicate that therapy of people with diabetes will become easier, safer and more efficacious in the next years.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Pharmaceutical Preparations

This systematic review investigated the efficacy of a meal sequence, the carbohydrate-later meal pattern (CL), on type 2 diabetes mellitus (T2DM).. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov until April 2020 to perform meta-analyses using random-effects models. Primary outcomes were hemoglobin A1c (HbA1c) and quality of life. Secondary outcomes were plasma concentrations of glucose, insulin and incretin 120 min after a meal, and any adverse outcomes. The revised Cochrane risk-of-bias tool and Grading of Recommendations, Assessment, Development, and Evaluation approach were used to assess the quality of individual studies and the body of evidence, respectively. The present study was registered in the UMIN Clinical Trials Registry.. We included 230 participants in eight trials, including both trials that examined long-term changes (more than 2 months and less than 2 years) and short-term changes (in 2-hour postprandial values). CL resulted in a slight to no difference in HbA1c (mean difference (MD), -0.21% in the intervention group; 95% CI -0.44% to+0.03%), plasma glucose (MD,+4.94 mg/dL; 95% CI -8.34 mg/dL to +18.22 mg/dL), plasma insulin (MD, -3.63 μIU/mL; 95% CI -11.88 μIU/mL to +4.61 μIU/mL), plasma GLP-1 (MD, +0.43 pmol/L; 95% CI -0.69 pmol/L to +1.56 pmol/L), and plasma GIP (MD, -2.02 pmol/L; 95% CI -12.34 pmol/L to +8.31 pmol/L). All of these outcomes were of low-certainty evidence or very low-certainty evidence. None of the trials evaluated quality of life or adverse events.. There was no evidence for the potential efficacy of recommending CL beyond standard dietary advice on T2DM.. UMIN000039979.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Quality of Life

Because of the beneficial actions of the hormone glucagon-like peptide-1 on glucose metabolism and appetite, food intake and eventually body weight, and because of the observation that the similar metabolic effects of gastric bypass surgery are associated with excessive secretion of GLP-1, attempts are now being made to stimulate the endogenous secretion of this hormone. By targeting the natural cellular origin of GLP-1 it is anticipated that also the physiological pathways of hormone action (which may include neural mechanisms) would be engaged, which might generate fewer side effects. In addition, release of other products of the responsible intestinal endocrine cells, the L-cells, namely the appetite inhibitory hormone, PYY 3-36, and the dual glucagon-GLP-1 co-agonist, oxyntomodulin, would also be promoted. Here, the normal mechanisms for stimulation of L-cell secretion are reviewed, and the potential of identified secretagogues is discussed. Paracrine regulation of L-cell secretion is also discussed and the potential of somatostatin receptor antagonists is emphasized. A therapeutic approach based on stimulation of endogenous secretion of GLP-1/PYY still seems both attractive and potentially feasible.

Topics: Animals; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity

The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2-3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity

Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear.. To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach.. PubMed, Scopus, and Web-of-Science were searched. Studies measuring IE by the gold-standard protocol employing an oral glucose tolerance test (OGTT) and an intravenous glucose infusion at matched glucose levels were selected. We extracted IE, sex, age, body mass index (BMI), and hemoglobin A1c, fasting values, and area under curve (AUC) of glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). In subjects with T2D, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications.. The IE weighted mean difference between subjects with T2D and those with normal glucose tolerance (NGT) was -27.3% (CI -36.5% to -18.1%; P < .001; I2 = 86.6%) and was affected by age (P < .005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (P < .05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (P < .0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI 9.2-13.2%; P < .0001; I2 = 28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose.. The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in subjects with T2D only, the OGTT dose is a significant covariate.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucose; Humans; Incretins; Insulin

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic β-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Obesity; Weight Loss

The significant growth in type 2 diabetes mellitus (T2DM) prevalence strikes a common threat to the healthcare and economic systems globally. Despite the availability of several anti-hyperglycaemic agents in the market, none can offer T2DM remission. These agents include the prominent incretin-based therapy such as glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors that are designed primarily to promote GLP-1R activation. Recent interest in various therapeutically useful gastrointestinal hormones in T2DM and obesity has surged with the realisation that enteroendocrine L-cells modulate the different incretins secretion and glucose homeostasis, reflecting the original incretin definition. Targeting L-cells offers promising opportunities to mimic the benefits of bariatric surgery on glucose homeostasis, bodyweight management, and T2DM remission. Revising the fundamental incretin theory is an essential step for therapeutic development in this area. Therefore, the present review explores enteroendocrine L-cell hormone expression, the associated nutrient-sensing mechanisms, and other physiological characteristics. Subsequently, enteroendocrine L-cell line models and the latest L-cell targeted therapies are reviewed critically in this paper. Bariatric surgery, pharmacotherapy and new paradigm of L-cell targeted pharmaceutical formulation are discussed here, offering both clinician and scientist communities a new common interest to push the scientific boundary in T2DM therapy.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Hypoglycemic Agents; Incretins; L Cells; Mice

Nearly half of all adults with type 2 diabetes mellitus (T2DM) live in India and China. These populations have an underlying predisposition to deficient insulin secretion, which has a key role in the pathogenesis of T2DM. Indian and Chinese people might be more susceptible to hepatic or skeletal muscle insulin resistance, respectively, than other populations, resulting in specific forms of insulin deficiency. Cluster-based phenotypic analyses demonstrate a higher frequency of severe insulin-deficient diabetes mellitus and younger ages at diagnosis, lower β-cell function, lower insulin resistance and lower BMI among Indian and Chinese people compared with European people. Individuals diagnosed earliest in life have the most aggressive course of disease and the highest risk of complications. These characteristics might contribute to distinctive responses to glucose-lowering medications. Incretin-based agents are particularly effective for lowering glucose levels in these populations; they enhance incretin-augmented insulin secretion and suppress glucagon secretion. Sodium-glucose cotransporter 2 inhibitors might also lower blood levels of glucose especially effectively among Asian people, while α-glucosidase inhibitors are better tolerated in east Asian populations versus other populations. Further research is needed to better characterize and address the pathophysiology and phenotypes of T2DM in Indian and Chinese populations, and to further develop individualized treatment strategies.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Phenotype

Improving type 2 diabetes using incretin analogues is becoming increasingly plausible. Currently, tirzepatide is the most promising listed incretin analogue. Here, I briefly explain the evolution of drugs of this kind, analyze the residue discrepancies between tirzepatide and endogenous incretins, summarize some existing strategies for prolonging half-life, and present suggestions for future research, mainly involving biased functions. This review aims to present some useful information for designing a dual glucagon like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor agonist.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone

Diabetic kidney disease (DKD) is one of the most important diabetic complications. DKD is also the most common cause of chronic kidney disease (CKD) and end-stage renal disease. This review focused on potential therapeutic drugs for which there is established evidence of treatment for DKD. The earliest evidence for DKD treatment was established with renin-angiotensin system (RAS) inhibitors; however, their efficacy was partial. Recently, the sodium-glucose co-transporter 2 (SGLT2) inhibitors, including empagliflozin (EMPA-REG Outcome), canagliflozin (CREDENCE trial), and dapagliflozin (DAPA-CKD), demonstrated a significant and clinically relevant reduction in the risks of albuminuria and progression of nephropathy, doubling of serum creatinine levels, and initiation of renal replacement therapy. Additionally, incretin-based therapeutic agents, such as glucagon-like peptide 1, liraglutide (LEADER), and dipeptidyl peptidase 4 inhibitors, linagliptin (CARMERINA) have elicited vasotropic actions, suggesting a potential for reducing the risk of DKD. Until recently, mineralocorticoid receptor antagonists (MRAs) have not been suitable for DKD treatment because of their adverse effect of hyperkalemia. In contrast, finerenone, a non-steroidal MRA, significantly reduced renal composite endpoint without severe hyperkalemia that would force its discontinuation (FIDELIO-DKD). Thus, the mainstay treatments of DKD are RAS inhibitors, SGLT2 inhibitors, incretin-based therapeutic agents, and non-steroidal MRA, or in other words, the DKD "fantastic four".

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hyperkalemia; Incretins; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Intestinal epithelial cells constantly crosstalk with the gut microbiota and immune cells of the gut lamina propria. Enteroendocrine cells, secrete hormones, such as incretin hormones, which participate in host physiological events, such as stimulating insulin secretion, satiety, and glucose homeostasis. Interestingly, evidence suggests that the incretin pathway may influence immune cell activation. Consequently, drugs targeting the incretin hormone signaling pathway may ameliorate inflammatory diseases such as inflammatory bowel diseases, cancer, and autoimmune diseases. In this review, we discuss how these hormones may modulate two subsets of CD4 + T cells, the regulatory T cells (Treg)/Th17 axis important for gut homeostasis: thus, preventing the development and progression of inflammatory diseases. We also summarize the main experimental and clinical findings using drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) signaling pathways and their great impact on conditions in which the Treg/Th17 axis is disturbed such as inflammatory diseases and cancer. Understanding the role of incretin stimulation in immune cell activation and function, might contribute to new therapeutic designs for the treatment of inflammatory diseases, autoimmunity, and tumors.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; T-Lymphocytes, Regulatory

The incretin hormone system is the target of multiple type 2 diabetes mellitus (T2DM) treatments because defects in this system play major roles in the pathogenesis of diabetes. Currently, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for patients with atherosclerotic cardiovascular (CV) disease and those at high risk for atherosclerotic CV disease. In addition to the favorable CV effects, GLP-1 RAs also provide robust lowering of hemoglobin A1c and weight. Although these factors make GLP-1 RAs attractive options for T2DM, the currently available agents have no effect on glucose-dependent insulinotropic polypeptide (GIP). Patients with T2DM are known to have GIP defect which is significant due to its profound insulinotropic effects. Tirzepatide is a novel incretin agent currently recently approved by the Food and Drug Administration for the treatment of T2DM. This first-in-class agent serves as a coagonist for both the GLP-1 and GIP receptors. In this review, we report on the pharmacologic mechanism of GLP-1, GIP, and coagonist effects on the cardiometabolic system. In addition, we review the glycemic lowering, weight loss effects, and other cardiometabolic outcomes of tirzepatide based on phase 2 and 3 data. The safety profile of tirzepatide is consistent across all phase 3 trials. The most common adverse effects are gastrointestinal symptoms, but they generally have a low risk for discontinuation. Overall, preliminary data suggest that tirzepatide is an efficacious and safe agent for the treatment of T2DM.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been the most widely used for type 2 diabetes (T2D) available worldwide since 2006. DPP-4 inhibitors exert their effects by inhibiting dipeptidyl peptidase-4 to increase the concentration of endogenous incretin hormones (incretin hormone analogues and incretin potentiators) and promote insulin secretion, thereby acting as a glucose regulator. Evogliptin is a new member of the DPP-4 inhibitor family with high selectivity and low risk of hypoglycemia, and extensive clinical data has been accumulated in its treatment of T2D since its introduction in October 2015.. This review summarized the recently reported studies associated with the pharmacokinetics, pharmacodynamics, safety and tolerability, and clinical application of evogliptin for managing T2D. We searched the MEDLINE and PubMed databases with the titles 'evogliptin' to identify all the information. The abstracts and posters of the annual meetings of ADA and EASD and clinicalTrials.gov. have been searched up to now.. Evogliptin is a potent, orally effective, and highly selective DPP-4 inhibitor that is not only indicated for the treatment of T2D but may also be beneficial to arterial inflammation and atherosclerosis, with good safety and tolerance.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins

Dipeptidyl peptidase 4 (DPP4) inhibitors are a class of antidiabetic medications that cause glucose-dependent increase in incretins in diabetic patients. One of the two incretins, glucagon-like peptide-1 (GLP-1), beside its insulinotropic activity, has been studied for extra pancreatic effects. Most of DPP4 inhibitors (DPP4i) have been investigated in in vivo and in vitro models of diabetic and nondiabetic cardiovascular diseases including heart failure, hypertension, myocardial ischemia or infarction, atherosclerosis, and stroke. Results of preclinical studies proved prominent therapeutic potential of DPP4i in cardiovascular diseases, regardless the presence of diabetes. This review aims to present an updated summary of the cardiovascular protective and therapeutic effects of DPP4 inhibitors through the past 5 years focusing on the molecular mechanisms beneath these effects. Additionally, based on the results summary presented here, future studies may be conducted to elucidate or illustrate some of these findings which can add clinical benefits towards management of diabetic cardiovascular complications.

Topics: Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins

Incretin-based therapies like glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors help maintain the glycaemic control in patients with type 2 diabetes mellitus with additional systemic benefits and little risk of hypoglycaemia. These medications are associated with low-grade chronic pancreatitis in animal models inconsistently. The incidence of acute pancreatitis was also reported in some human studies. This inflammation provides fertile ground for developing pancreatic carcinoma (PC). Although the data from clinical trials and population-based studies have established safety regarding PC, the pathophysiological possibility that low-grade chronic pancreatitis leads to PC remains. We review the existing literature and describe the relationship between incretin-based therapies and PC.

Topics: Acute Disease; Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Pancreatic Neoplasms; Pancreatitis, Chronic

Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory roles in the incretin system. Though these drugs have been deemed effective in treating T2DM, the Food and Drug Administration (FDA) and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints. As a result, since 2008, the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety. The present review article strives to assess the safety and benefits of incretin-based therapy, a new class of antidiabetic drug, on the health of patient cardiovascular systems. In the process, this review will also provide a physiological overview of the incretin system and how key components function in T2DM.

Topics: Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; United States

Glucagon-like peptide-1 receptor (GLP-1R) is a well-studied incretin hormone receptor and target of several therapeutic drugs for type 2 diabetes (T2D), obesity and, more recently, cardiovascular disease. Some signalling pathways downstream of GLP-1R may be responsible for drug adverse effects such as nausea, while others mediate therapeutic outcomes of incretin-based T2D therapeutics. Understanding the interplay between different factors that alter signalling, trafficking, and receptor activity, including biased agonism, single nucleotide polymorphisms and structural modifications is key to develop the next-generation of personalised GLP-1R agonists. However, these interactions remain poorly described, especially for novel therapeutics such as dual and tri-agonists that target more than one incretin receptor. Comparison of GLP-1R structures in complex with G proteins and different peptide and non-peptide agonists has revealed novel insights into important agonist-residue interactions and networks crucial for receptor activation, recruitment of G proteins and engagement of specific signalling pathways. Here, we review the latest knowledge on GLP-1R structure and activation, providing structural evidence for biased agonism and delineating important networks associated with this phenomenon. We survey current biased agonists and multi-agonists at different stages of development, highlighting possible challenges in their translational potential. Lastly, we discuss findings related to non-synonymous genomic variants of GLP1R and the functional importance of specific residues involved in GLP-1R function. We propose that studies of GLP-1R polymorphisms, and specifically their effect on receptor dynamics and pharmacology in response to biased agonists, could have a significant impact in delineating precision medicine approaches and development of novel therapeutics.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Peptides

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent neurodegenerative disorders. Despite their pathophysiological and clinical differences, they share several mechanistic similarities at cellular and sub-cellular levels. The current treatments of AD and PD are only symptomatic, since many clinically-tested drugs failed to prevent or halt their progression. There is now evidence that type 2 diabetes mellitus is among the main risk factors for AD and PD and that the insulin resistance in the brain plays a crucial role in their neuropathological processes. Therefore, insulin nasal administration was suggested for the treatment of AD and PD, both in diabetic and non-diabetic patients. However, the adverse effects of chronic insulin prompted the research of alternative strategies, such as the novel antidiabetic drugs based on the incretin hormones glucagon-like protein-1 (GLP-1) and glucose-dependent insulinotropic Peptide (GIP). The rapid inactivation of these incretins by dipeptidyl-peptidase IV (DPP-IV) suggested the development of DPP-IV-resistant GLP-1 receptor agonists (GLP-1Ras), the recent dual GLP-1/GIP receptor agonists and the DPP-IV inhibitors (DPP-IVis). This review will first describe the experimental, pathophysiological and clinical approach for AD and PD treatment with insulin. Afterwards, the main pharmacologic properties of GLP-1Ras and of DPP-IVis will be discussed, detailing their ability to cross the BBB and get access to the brain for GLP-1Ras, and the novel strategies for BBB crossing as regards DPP-IVis. Emphasis will be placed on the main findings obtained from AD and PD experimental models about the neuroprotective effects of these drugs. For AD, the improvement of learning and memory exerted by incretin-based drugs correlated with reduction of chronic inflammation, brain Aβ plaque, tau hyperphosphorylation, protection of mitochondria, enhancement of energy utilisation. For PD, both GLP-1Ras and of DPP-IVis reversed the nigrostriatal dopaminergic cell loss progression, restored dopamine synthesis, exerted anti-inflammatory activity and improved motor functions. Finally, the encouraging results of the first clinical trials on AD and PD patients and the adverse effects of GLP-1Ras and DPP-IVis will be discussed, highlighting how the above-mentioned neuroprotective effects have a great potential to be translated into clinical settings and that the incretin-based approach represents novel promising strategy for the

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Neurodegenerative Diseases; Neuroprotective Agents

Non-alcoholic steatohepatitis (NASH) is a progressive form of Non-alcoholic fatty liver disease (NAFLD), which slowly progresses toward cirrhosis and finally leads to the development of hepatocellular carcinoma. Obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome are major risk factors contributing to NAFLD. Targeting these risk factors is a rational option for inhibiting NASH progression. In addition, NASH could be treated with therapies that target the metabolic abnormalities causing disease pathogenesis (such as de novo lipogenesis and insulin resistance) as well with medications targeting downstream processes such as cellular damage, apoptosis, inflammation, and fibrosis. Glucagon-like peptide (GLP-1), is an incretin hormone dysregulated in both experimental and clinical NASH, which triggers many signaling pathways including fibroblast growth factor (FGF) that augments NASH pathogenesis. Growing evidence indicates that GLP-1 in concert with FGF-21 plays crucial roles in the conservation of glucose and lipid homeostasis in metabolic disorders. In line, GLP-1 stimulation improves hepatic ballooning, steatosis, and fibrosis in NASH. A recent clinical trial on NASH patients showed that the upregulation of FGF-21 decreases liver fibrosis and hepatic steatosis, thus improving the pathogenesis of NASH. Hence, therapeutic targeting of the GLP-1/FGF axis could be therapeutically beneficial for the remission of NASH. This review outlines the significance of the GLP-1/FGF-21 axis in experimental and clinical NASH and highlights the activity of modulators targeting this axis as potential salutary agents for the treatment of NASH.

Topics: Diabetes Mellitus, Type 2; Fibroblast Growth Factors; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin Resistance; Lipids; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Gestational diabetes mellitus (GDM) is a metabolic disease affecting an increasing number of pregnant women around the world. It is not only associated with numerous perinatal complications but also has long-term consequences impacting maternal health and fetal development. To prevent them, it is important to keep glucose levels under control. As much as 15-30% of GDM patients will require treatment with insulin, metformin, or glyburide. With that in mind, it is crucial to keep searching for novel and improved pharmacotherapies. Nowadays, there are ongoing studies investigating the use of other groups of drugs that have proven successful in the treatment of T2DM. Glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor are among the drugs targeting the incretin system and are currently receiving significant attention. The aim of our review is to demonstrate the potential of these medications in treating GDM and preventing its later complications. It seems that both groups may be successful in the GDM management used alone or as an addition to better-known drugs, including metformin and glyburide. However, more clinical trials are needed to confirm their importance in GDM treatment and to demonstrate effective therapeutic strategies.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Glyburide; Humans; Hypoglycemic Agents; Incretins; Metformin; Pregnancy

Type 2 diabetes mellitus (T2DM) is a serious public health concern as it is one of the most common chronic diseases worldwide due to social and economic developments that have led to unhealthy lifestyles, with a considerable impact both in terms of morbidity and mortality. The management of T2DM, before starting specific therapies, includes cornerstones such as healthy eating, regular exercise and weight loss. Strict adherence to the Mediterranean diet (MedDiet) has been related to an inverse association with the risk of T2DM onset, as well as an improvement in glycaemic control; in particular, thanks to the consumption of extra virgin olive oil (EVOO). Agonists of gut-derived glucagon-like peptide-1 (GLP-1), gastrointestinal hormones able to increase insulin secretion in response to hyperglycaemia (incretins), have been recently introduced in T2DM therapy, quickly entering the international guidelines. Recent studies have linked the action of EVOO in reducing postprandial glycaemia to the increase in GLP-1 and the reduction of its inactivating protease, dipeptidyl peptidase-4 (DPP-4). In this review, we explore observations regarding the pathophysiological basis of the existence of an enhanced effect between the action of EVOO and incretins and, consequently, try to understand whether there is a rationale for their use in combination for T2DM therapy.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Secretion

Over the past century, since the discovery of insulin, the therapeutic offer for diabetes has grown exponentially, in particular for type 2 diabetes (T2D). However, the drugs in the diabetes pipeline are even more promising because of their impressive antihyperglycemic effects coupled with remarkable weight loss. An ideal medication for T2D should target not only hyperglycemia but also insulin resistance and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the new class of GLP1 and gastric inhibitory polypeptide dual RAs counteract 2 of these metabolic defects of T2D, hyperglycemia and obesity, with stunning results that are similar to the effects of metabolic surgery. An important role of antidiabetic medications is to reduce the risk and improve the outcome of cardiovascular diseases, including coronary artery disease and heart failure with reduced or preserved ejection fraction, as well as diabetic nephropathy, as shown by SGLT2 inhibitors. This review summarizes the main drugs currently under development for the treatment of type 1 diabetes and T2D, highlighting their strengths and side effects.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Obesity

The increasing prevalence of obesity and type 2 diabetes (T2DM) is provoking an important socioeconomic burden mainly in the form of cardiovascular disease (CVD). One successful strategy is the so-called metabolic surgery whose beneficial effects are beyond dietary restrictions and weight loss. One key underlying mechanism behind this surgery is the cooperative improved action of the preproglucagon-derived hormones, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) which exert their functions through G protein-coupled receptors (GPCR). Great success has been reached with therapies based on the GLP-1 receptor monoagonism; therefore, a logical and rational approach is the use of the dual and triagonism of GCPC to achieve complete metabolic homeostasis. The present review describes novel findings regarding the complex biology of the preproglucagon-derived hormones, their signaling, and the drug development of their analogues, especially those acting as dual and triagonists. Moreover, the main investigations into animal models and ongoing clinical trials using these unimolecular dual and triagonists are included which have demonstrated their safety, efficacy, and beneficial effects on the CV system. These therapeutic strategies could greatly impact the treatment of CVD with unprecedented benefits which will be revealed in the next years.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Incretins; Peptides; Proglucagon

Glucagon-like peptide-1 (GLP-1) is an incretin hormone, mainly produced by enteroendocrine L cells, which participates in the regulation of glucose homeostasis, and in reduction in body weight by promoting satiety. Actions of GLP-1 are mediated by activation of its receptor GLP-1R, which is widely expressed in several tissues including the retina. The effects of GLP-1R activation are useful in the management of type 2 diabetes mellitus (T2DM). In addition, the activation of GLP-1R has anti-inflammatory effects in several organs, suggesting that it may be also useful in the treatment of inflammatory diseases. Inflammation is a common element in the pathogenesis of several ocular diseases, and the protective effects of treatment with GLP-1 emerged also in retinal diseases. In this review we highlight the anti-inflammatory effects of GLP-1R activation in the retina. Firstly, we summarized the pathogenic role of inflammation in ocular diseases. Then, we described the pleiotropic effects of GLP-1R activation on the cellular components of the retina which are mainly involved in the pathogenesis of inflammatory retinal diseases: the retinal ganglion cells, retinal pigment epithelial cells and endothelial cells.

Topics: Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Endothelial Cells; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Inflammation; Retina; Retinal Diseases

Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Neurodegenerative Diseases; Neuroinflammatory Diseases; Parkinson Disease

Type 2 diabetes mellitus is a metabolic disorder resulting from impaired insulin secretion and resistance. Dipeptidyl peptidase (DPP)-IV is an enzyme known to trigger the catalysis of insulinotropic hormones, further abating the endogenous insulin levels and elevating the glucose levels in blood plasma. In the field of drug development, DPP-IV inhibitors have opened up numerous opportunities for leveraging this target to generate compounds as hypoglycemic agents by regulating incretin activity and subsequently decreasing blood glucose levels. However, the practice of synthetic drugs is an apparent choice but poses a great pharmacovigilance issue due to their incessant undesirable effects. The ideology was set to inventively look upon different ethnomedicinal plants for their anti-diabetic properties to address these issues. To date, myriads of phytochemicals are characterized, eliciting an anti-diabetic response by targeting various enzymes and augmenting glucose homeostasis. Antioxidants have played a crucial role in alleviating the symptoms of diabetes by scavenging free radicals or treating the underlying causes of metabolic disorders and reducing free radical formation. Plant-based DPP-IV inhibitors, including alkaloids, phenolic acid, flavonoids, quercetin, and coumarin, also possess antioxidant capabilities, providing anti-diabetic and antioxidative protection. This review article provides a new gateway for exploring the ability of plant-based DPP-IV inhibitors to withstand oxidative stress under pathological conditions related to diabetes and for reforming the strategic role of ethnomedicinal plants as potent DPP-IV inhibitors through the development of polyherbal formulations and nanophytomedicines to regulate incretin activity.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucose; Humans; Incretins; Phytochemicals

Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in response to nutrient intake and stimulate pancreatic beta cell activity secreting insulin. GIP and GLP1 also have other metabolic functions. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to reduce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety were assessed in a phase III SURPASS 1-5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes. Other clinical trials are currently underway to evaluate its use in other diseases. The scientific interest toward this novel, first-in-class medication is rapidly increasing. In this comprehensive and systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights into its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins

Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated with various health complications and increased mortality. Lifestyle modifications are central to weight management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an incretin metabolic hormone responsible for a range of physiological effects, including glucose and appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcutaneous) and liraglutide are currently US Food and Drug Administration (FDA)-approved for chronic weight management in patients with or without diabetes. The phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program was designed to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with overweight or obesity. Following the submission of the results of the STEP 1-4 trials, the FDA approved once-weekly subcutaneous semaglutide 2.4 mg for chronic weight management in people with overweight or obesity in April 2021. Data from the program demonstrated that semaglutide (2.4 mg once weekly) achieved significant and sustained weight loss, together with improvements in cardiometabolic risk factors compared with placebo, and was generally well tolerated, with a safety profile consistent with other GLP-1RAs. The most common adverse events reported in STEP 1-5 were gastrointestinal events, which were transient, mild-to-moderate in severity, and typically resolved without permanent treatment discontinuation. This article reviews the data from STEP 1-5 and highlights clinically relevant findings for primary care providers.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Overweight; Weight Loss

Proteins and peptides are fundamental components of the cereals, pseudocereals, and legumes, giving them numerous health-beneficial properties. Previous studies have demonstrated that these molecules exerted effects on current therapeutic targets related to type 2 diabetes mellitus, such as incretin hormones (responsible for appetite suppression), dipeptidyl peptidase IV (an enzyme involved in the inactivation and degradation of the incretin hormones), and glucose transporters (molecules that transport glucose in or out of cells). Therefore, this review presents the current biological activity of protein derivatives and peptides isolated from cereals, pseudocereals, and legumes on these therapeutic markers, highlighting their potential as a possible pharmacological treatment for type 2 diabetes mellitus.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Incretins; Peptides; Vegetables

Diabetes mellitus, particularly type 2 diabetes, is a major global health issue, the prevalence of which seems to be on the rise worldwide. Interventions such as healthy diet, physical activity, maintaining a healthy weight, and medication (for those with a diagnosis of diabetes) are among the most effective strategies to prevent and control diabetes. Three-quarters of patients diagnosed with diabetes are in countries with poor financial infrastructure, nutritional awareness and health care systems. Concomitantly, the cost involved in managing diabetes through the intake of antidiabetic drugs makes it prohibitive for majority of patients. Food protein-derived bioactive peptides have the potential of being formulated as nutraceuticals and drugs in combating the pathogenesis and pathophysiology of metabolic disorders with little or "no known" complications in humans. Coupled with lifestyle modifications, the potential of bioactive peptides to maintain normoglycemic range is actualized by influencing the activities of incretins, DPP-IV, α-amylase, and α-glucosidase enzymes. This article discusses the biofunctionality and clinical implications of anti-diabetic bioactive peptides in controlling the global burden of diabetes.

Topics: alpha-Glucosidases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Peptides

Newly developed anti-diabetic medications have had multiple activities, beyond a blood glucose-lowering effect. Current drugs for treating type 2 diabetes mellitus (T2DM) are based on the use of gastrointestinal hormones. Representative incretin preparations, such as those with glucagon-like peptide (GLP)-1 or gastric inhibitory polypeptide (GIP) activity, aim to provide new means of controlling blood glucose levels, body weight, and lipid metabolism.. In this manuscript, the pathophysiology of T2DM and the activities and characteristics of novel diabetic drugs are reviewed in the context of the Japanese population. This review also highlights the need for novel medicines to overcome the accompanying challenges. Finally, the author provides the reader with their expert perspectives.. The incidence of T2DM has been increasing in the aging of Japanese society. In older people, medical development should focus on safety, easier self-administration, and the relief of caregiver burden in terms of continuous administration. In the young, the focus should be on effectiveness, with a particular emphasis on the protection of organs, increasing the ease of adherence, and safety. Novel medicines will need to push the envelope in these areas.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Japan

Female breast cancer recently surpassed lung cancer and became the most commonly diagnosed cancer worldwide. As per the recent data from WHO, breast cancer accounts for one out of every 8 cancer cases diagnosed among an estimated 2.3 million new cancer cases. Breast cancer is the most prevailing cancer type among women causing the highest number of cancer-related mortality. It has been estimated that in 2020, 68,5000 women died due to this disease. Breast cancers have varying degrees of molecular heterogeneity; therefore, they are divided into various molecular clinical sub types. Recent reports suggest that type 2 diabetes (one of the common chronic diseases worldwide) is linked to the higher incidence, accelerated progression, and aggressiveness of different cancers; especially breast cancer. Breast cancer is hormone-dependent in nature and has a cross-talk with metabolism. A number of antidiabetic therapies are known to exert beneficial effects on various types of cancers, including breast cancer. However, only a few reports are available on the role of incretin-based antidiabetic therapies in cancer as a whole and in breast cancer in particular. The present review sheds light on the potential of incretin based therapies on breast cancer and explores the plausible underlying mechanisms. Additionally, we have also discussed the sub types of breast cancer as well as the intricate relationship between diabetes and breast cancer.

Topics: Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incretins

Glucagon-like peptide-1 (GLP-1) receptor agonists are recently discovered antidiabetic drugs with potent hypoglycemic effects. Among different mechanisms of activity, these compounds were shown to reduce blood glucose by suppression of glucagon secretion and stimulation of glucose-dependent insulin secretion. These antidiabetic agents have a minor risk of hypoglycemia and have been suggested as a second-line therapy to be added to metformin treatment to further optimize glycemic control in diabetes. More recently, scientific evidence suggests that GLP-1 receptor agonists may particularly afford protection from diabetic nephropathy through modulation of the molecular pathways involved in renal impairment and so improve renal function. This additional benefit adds further weight for these compounds to become promising drugs not only for glycemic control but also to prevent diabetic complications. In this review, we have updated evidence on the beneficial effects of GLP-1 receptor agonists on diabetic nephropathy and detailed the underlying pathophysiological mechanisms.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin Secretion

A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM).. We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease).. GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79-0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67-0.82, P < 0.001).. GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

Topics: Aged; Cardio-Renal Syndrome; Cardiovascular Diseases; Cause of Death; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Hospitalization; Humans; Hypoglycemic Agents; Incidence; Incretins; Kidney Diseases; Male; Middle Aged; Risk Assessment; Risk Factors; Treatment Outcome

The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Glucagon-Like Peptide-1 Receptor; Heart Disease Risk Factors; Heart Failure; Humans; Incretins; Risk Assessment; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs.. An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression.. The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I. The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Glycemic Control; Hospitalization; Humans; Incretins; Male; Middle Aged; Protective Factors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome

In my lecture given on the occasion of the 2021 Banting Medal for Scientific Achievement, I briefly described the history of the incretin effect and summarized some of the developments leading to current therapies of obesity and diabetes based on the incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In the text below, I discuss in further detail the role of these two hormones for postprandial insulin secretion in humans on the basis of recent studies with antagonists. Their direct and indirect actions on the β-cells are discussed next as well as their contrasting actions on glucagon secretion. After a brief discussion of their effect on insulin sensitivity, I describe their immediate actions in patients with type 2 diabetes and emphasize the actions of GLP-1 on β-cell glucose sensitivity, followed by a discussion of their extrapancreatic actions, including effects on appetite and food intake in humans. Finally, possible mechanisms of action of GIP-GLP-1 coagonists are discussed, and it is concluded that therapies based on incretin actions are likely to change the current hesitant therapy of both obesity and diabetes.

Topics: Awards and Prizes; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin-Secreting Cells; Obesity

Cardiovascular events related to atherosclerosis are responsible for high morbidity and mortality among patients with type 2 diabetes. Improvement in care, especially in early stages, is crucial. Oral semaglutide, a glucagon-like peptide 1 analogue, controls blood glucose and results in significant body weight loss in patients with type 2 diabetes. Beyond these well-known effects, an interesting aspect of this drug is its antiatherogenic activity, which should be further explored in clinical practice. This paper reviews the evidence related to oral semaglutide decreasing cardiovascular risk in patients with type 2 diabetes, focusing on the drug's antiatherosclerotic properties. The glucagon-like peptide 1 analogue restores endothelial dysfunction, induces vasodilatation, and reduces plasma lipids. Oral semaglutide showed cardiovascular safety profile, with significant reduced risk of death from cardiovascular events. Based on current data, clinicians should consider oral semaglutide for type 2 diabetes management.

Topics: Administration, Oral; Animals; Atherosclerosis; Biomarkers; Blood Glucose; Cause of Death; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycemic Control; Humans; Hypoglycemic Agents; Incretins; Risk Assessment; Risk Factors; Treatment Outcome

To assess the effects of incretin-based therapies on β-cell function in patients with type 1 diabetes mellitus (T1DM).. We searched the PubMed, Cochrane Library, Embase, and Web of Knowledge databases for eligible randomized clinical trials published up to July 2021. The inclusion criteria were patients with T1DM or latent autoimmune diabetes in adults, patients treated with dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists, and outcomes included one of the following: fasting plasma glucose, fasting C-peptide, postprandial C-peptide, C-peptide area under the curve (AUC), homeostasis model assessment for β cell function, and insulin resistance. The effects were analyzed using a random effect model with STATA 11.0.. Eight trials including 427 participants were included in the final analysis. A pooled analysis found no significant difference in fasting plasma glucose, fasting C-peptide, postprandial C-peptide, or C-peptide AUC between patients treated with incretin-based therapies and placebo. The two trials that reported changes in 2-hour postprandial C-peptide and two of the four trials that reported changes in C-peptide AUC reported increases after incretin-based therapies.. This meta-analysis showed that incretin-based therapies did not preserve β-cell function in patients with T1DM.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins

Although there are many different methods of treating type 2 diabetes (T2D), it is still difficult to draw coincident conclusions concerning the efficacy and safety of different classes of new drugs, and the recommendation level of them has still kept uncertain as second anti-diabetic agents. Therefore, the aim of this study was to summarize evidence on the efficacy and safety of DPP-4is, GLP-1RAs and SGLT-2is as monotherapy or add-on to metformin (Met) for treatment of T2D.. We searched PubMed, Embase, Cochrane library and ClinicalTrials.gov for relevant articles in keeping with established methods using terms associated with anti-diabetic agents up to February, 2020, with no start date restriction. Weighted mean difference and risk ratios with 95% confidence intervals were calculated within traditional and network meta-analysis. Primary outcomes were the mean change in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) change and the frequency of hypoglycemic events from baseline after 12 weeks of treatment.. In total, 64 eligible studies comprising 37,780 patients and 7 treatment strategies were included. The results of primary outcomes showed that GLP-1RAs were significantly more effective than DPP-4is or SGLT-2is in reducing HbA1c when add-on to Met. For FPG, both GLP-1RAs and SGLT-2is significantly reduced FPG compared with DPP-4is whether add-on to Met or not. For hypoglycemia, monotherapy has a lower risk than combination therapy except for SGLT-2is. Ranking probability analysis indicated that GLP-1RAs and SGLT-2is, respectively, reduced HbA1c and FPG most when add-on to Met. Meanwhile, GLP-1RAs took the lowest risk to induce the hypoglycemia, whereas GLP-1RAs plus Met the highest.. Both GLP-1RAs and SGLT-2is have their own advantages in efficacy and safety. Monotherapy is beneficial for reducing the risk of hypoglycemia. The recommendation should be a patient-centered approach when selecting treatment choices.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Metformin; Network Meta-Analysis; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Previous studies have demonstrated that individuals with type 2 diabetes mellitus (T2DM) have a two- to fourfold propensity to develop cardiovascular disease (CVD) than nondiabetic population, making CVD a major cause of death and disability among people with T2DM. The present treatment options for management of diabetes propose the earlier and more frequent use of new antidiabetic drugs that could control hyperglycaemia and reduce the risk of cardiovascular events. Findings from basic and clinical studies pointed out DPP-4 inhibitors as potentially novel pharmacological tools for cardioprotection. There is a growing body of evidence suggesting that these drugs have ability to protect the heart against acute ischaemia-reperfusion injury as well as reduce the size of infarction. Consequently, the prevention of degradation of the incretin hormones by the use of DPP-4 inhibitors represents a new strategy in the treatment of patients with T2DM and reduction of CV events in these patients. Here, we discuss the cardioprotective effects of DPP-4 inhibitors as well as proposed pathways that these hypoglycaemic agents target in the cardiovascular system.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Hypoglycemic Agents; Incretins

Diabetes mellitus is one of the most prevalent comorbidities identified in patients with coronavirus disease 2019 (COVID-19). This article aims to discuss the pharmacotherapeutic considerations for the management of diabetes in hospitalized patients with COVID-19.. We discussed various aspects of pharmacotherapeutic management in hospitalized patients with COVID-19: (i) susceptibility and severity of COVID-19 among individuals with diabetes, (ii) glycemic goals for hospitalized patients with COVID-19 and concurrent diabetes, (iii) pharmacological treatment considerations for hospitalized patients with COVID-19 and concurrent diabetes.. The glycemic goals in patients with COVID-19 and concurrent type 1 (T1DM) or type 2 diabetes (T2DM) are to avoid disruption of stable metabolic state, maintain optimal glycemic control, and prevent adverse glycemic events. Patients with T1DM require insulin therapy at all times to prevent ketosis. The management strategies for patients with T2DM include temporary discontinuation of certain oral antidiabetic agents and consideration for insulin therapy. Patients with T2DM who are relatively stable and able to eat regularly may continue with oral antidiabetic agents if glycemic control is satisfactory. Hyperglycemia may develop in patients with systemic corticosteroid treatment and should be managed upon accordingly.

Topics: Adrenal Cortex Hormones; Blood Glucose; Comorbidity; COVID-19; Deprescriptions; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Susceptibility; Glycemic Control; Hospitalization; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Metformin; Monitoring, Physiologic; Patient Care Planning; SARS-CoV-2; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

Few studies have evaluated the efficacy and safety of combining a glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus. Clinicians may frequently encounter this drug therapy combination in practice and should be aware of clinical evidence and risks associated with its use.. A literature search was conducted in Embase (1947-April 20, 2020), Medline - Ovid (1946-April 21, 2020), Medline - PubMed (1946-April 21, 2020), Cochrane Library CENTRAL Register of Controlled Trials (1991-April 20, 2020) and Web of Science (1900-April 17, 2020). Databases were searched using keywords and subject headings to identify studies assessing efficacy and safety of combination incretin therapy. The search identified 1255 studies. Of these, 383 were excluded for duplicate citations. Articles were then excluded based on title and abstract screen.. Six studies were included. A small reduction in haemoglobin A1c and weight loss was found by combining incretin therapy. Adverse effects such as hypoglycaemia, gastrointestinal upset and pancreatitis were infrequent.. On current evidence, the small benefit in glycaemic control that may be realized by using combination incretin therapy is unlikely to be offset by the potential increased risk of pancreatitis or additional cost. Additional long-term prospectively designed studies are needed to better understand the efficacy and safety of combination incretin therapy.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Practice Guidelines as Topic

Besides insulin-mediated transport of glucose into the cells, an important role is also played by the non-insulin-mediated transport. This latter process is called glucose effectiveness (acronym S

Topics: Administration, Intravenous; Adult; Aged; Animals; Biological Transport; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male; Mice; Middle Aged

The comparative efficacy of different glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular events (MACE) in type 2 diabetes with or without cardiorenal disease is undefined. PubMed and Embase were searched for relevant randomized trials. We conducted network meta-analysis within the Bayesian framework. Effect sizes were measured using hazard ratio (HR) and 95% confidence interval (CI). We calculated surface under the cumulative ranking curve (SUCRA) values to rank drug interventions for different type 2 diabetic subgroups. Albiglutide (HR 0.76, 95% CI 0.63-0.93) and subcutaneous semaglutide (HR 0.71, 95% CI 0.52-0.95), with the maximum SUCRA values, significantly reduced MACE versus lixisenatide in people with diabetes with cardiovascular disease; albiglutide (HRs: 0.69 and 0.72), with the maximum SUCRA value, significantly reduced MACE versus dapagliflozin and exenatide in people with diabetes with heart failure; and canagliflozin (HRs: 0.72 and 0.72) and liraglutide (HRs: 0.68 and 0.68), with the maximum SUCRA values, significantly reduced MACE versus exenatide and lixisenatide in people with diabetes with chronic kidney disease. In preventing MACE in type 2 diabetes, subcutaneous semaglutide and albiglutide are most effective for diabetes with cardiovascular disease, albiglutide is most effective for diabetes with heart failure, and canagliflozin and liraglutide are most effective for diabetes with chronic kidney disease.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Network Meta-Analysis; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Obesity is an important public health issue that has been on the rise over the last decades. It calls for effective prevention and treatment. Bariatric surgery is the most effective medical therapy for weight loss in morbid obesity, but we are in need for less aggressive treatments. Glucagon-like-peptide-1 receptor agonists are a group of incretin-based drugs that have proven to be productive for obesity treatment. Through activation of the GLP-1 receptor they not only have an important role stimulating insulin secretion after meals, but with their extrapancreatic actions, both peripheral and central, they also help reduce body weight by promoting satiety and delaying gastric emptying. Liraglutide in a dose of 3 mg is currently the only drug of this group that is approved by the FDA to treat obesity, with weight losses up to 8.5 kg in relatively short periods of time. Here we review the data so far collected of GLP-1 use for obesity with and without diabetes, including the recent data of oral semaglutide.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity

As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents - sodium-glucose cotransporter 2 inhibitors and incretin therapies - has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Kidney

Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the theory that GIP is obesogenic, limiting interest in developing GIPR agonists to treat type 2 diabetes. A resurgence of GIP research has occurred in the last five years, reinvigorating interest in this peptide. Two independent approaches have emerged for treating obesity, one promoting GIPR agonism and the other antagonism. In this report, evidence supporting both cases is discussed and hypotheses are presented to reconcile this apparent paradox.. This review presents evidence to support targeting GIPR to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR using both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R.. There is substantial evidence to support that GIPR agonism and antagonism can positively impact body weight. The long-standing theory that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight; however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required to understand how modulating this system impacts metabolic homeostasis.

Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Mice; Mice, Knockout; Obesity; Weight Gain

Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Gastric Inhibitory Polypeptide; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion

We aimed to conduct a systematic review and meta-analysis regarding the use of incretin-based therapies including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists as well as sodium-glucose co-transporter-2 (SGLT2) inhibitorsin persons with posttransplantation diabetes mellitus (PTDM) so as to assess both their efficacy and safety.. We searched for publications on Kidney/Renal Transplantation and DPP-4 inhibitors, GLP-1-receptor agonists and SGLT-2 inhibitors and included every study using these antidiabetics. A p-value < 0.05 was considered statistical significant.. DPP-4 inhibitors and SGLT2 inhibitors appear both efficacious and safe in renal transplant recipients. More high-quality studies are required to guide therapeutic choices for PTDM.

Topics: Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Incretins; Kidney Function Tests; Kidney Transplantation; Sodium-Glucose Transporter 2 Inhibitors

Topics: Adiposity; Adult; Anthropometry; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Loss

Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients.. We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized.. Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]).. In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Progression; Female; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Male; Network Meta-Analysis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Clinical Studies as Topic; Diabetes Mellitus, Type 2; Disease Management; Disease Susceptibility; Drug Design; Drug Development; Drug Evaluation, Preclinical; Dyslipidemias; Humans; Incretins; Lipid Metabolism; Molecular Targeted Therapy; PCSK9 Inhibitors; Risk Assessment; Risk Factors

To conduct a real-word-study-based cost-effectiveness analysis of a GLP-1 receptor agonist (GLP-1RA) versus insulin among type 2 diabetes patients requiring intensified injection therapy and a systematic review of cost-effectiveness studies of GLP-1RAs versus insulin.. Individual-level analyses incorporating real-world effectiveness and cost data were conducted for a cohort of 1022 propensity-score-matched pairs of GLP-1RA and insulin users from Taiwan's National Health Insurance Research Database, 2007-2016. Study outcomes included the number needed to treat (NNT) to prevent one case of clinical events, healthcare costs, and cost per case of event prevented. Costs were in 2019 US dollars. Analyses were performed from a third-party payer and healthcare sector perspectives. Structured systematic review procedures were conducted to synthesize updated evidence on the cost-effectiveness of GLP-1RAs versus insulin.. Over a mean follow-up of 2.3 years, the NNT using a GLP-1RA versus insulin to prevent one case of all-cause mortality and hospitalized hypoglycemia was 57 and 30, respectively. Using GLP-1RAs instead of insulin cost US$54,851 and US$29,115 per case of all-cause mortality and hospitalized hypoglycemia prevented, respectively, from the payer perspective, and saved US$19,391 and US$10,293, respectively, from the healthcare sector perspective. Sensitivity analyses showed that the probability of using GLP-1RAs versus insulin being cost-effective for preventing one case of all-cause mortality or hospitalized hypoglycemia ranged from 60 to 100%. The systematic review revealed a cost-effective profile of using GLP-1RAs versus insulin.. Using GLP-1RAs versus insulin for type 2 diabetes patients requiring intensified injection therapy in clinical practice is cost-effective.

Topics: Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Costs; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Models, Economic; Treatment Outcome

The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins-glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Incretins; Mice; Non-alcoholic Fatty Liver Disease; Obesity

Incretins are gut hormones that potentiate glucose-stimulated insulin secretion (GSIS) after meals. Glucagon-like peptide-1 (GLP-1) is the most investigated incretin hormone, synthesized mainly by L cells in the lower gut tract. GLP-1 promotes β-cell function and survival and exerts beneficial effects in different organs and tissues. Irisin, a myokine released in response to a high-fat diet and exercise, enhances GSIS. Similar to GLP-1, irisin augments insulin biosynthesis and promotes accrual of β-cell functional mass. In addition, irisin and GLP-1 share comparable pleiotropic effects and activate similar intracellular pathways. The insulinotropic and extra-pancreatic effects of GLP-1 are reduced in type 2 diabetes (T2D) patients but preserved at pharmacological doses. GLP-1 receptor agonists (GLP-1RAs) are therefore among the most widely used antidiabetes drugs, also considered for their cardiovascular benefits and ability to promote weight loss. Irisin levels are lower in T2D patients, and in diabetic and/or obese animal models irisin administration improves glycemic control and promotes weight loss. Interestingly, recent evidence suggests that both GLP-1 and irisin are also synthesized within the pancreatic islets, in α- and β-cells, respectively. This review aims to describe the similarities between GLP-1 and irisin and to propose a new potential axis-involving the gut, muscle, and endocrine pancreas that controls energy homeostasis.

Topics: Diabetes Mellitus, Type 2; Fibronectins; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Obesity

The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin; Insulin Secretion; Postprandial Period; Receptors, Gastrointestinal Hormone

The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium-glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Liver; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease; Pharmaceutical Preparations; Receptors, Cytoplasmic and Nuclear

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Development; Drug Synergism; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Patents as Topic; Receptors, G-Protein-Coupled

Non-alcoholic fatty liver disease is highly prevalent in patients with type 2 diabetes mellitus. Studies on glucagon-like peptide-1 receptor agonists for the treatment of non-alcoholic fatty liver disease have reported promising results. Despite this, there has been limited evidence of its efficacy in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. This meta-analysis examined existing evidence on the efficacy of glucagon-like peptide-1 receptor agonists on the management of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.. Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles discussing the efficacy of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Values of standardized mean differences (SMD) and risk ratio (RR) were determined for continuous outcomes and dichotomous outcomes respectively.. 8 studies involving 1,454 patients from 5 randomized controlled trials and 3 cohort studies were included in the analysis. Our analysis found significant improvements in hepatic fat content, liver biochemistry, body composition, glucose parameters, lipid parameters, insulin sensitivity and inflammatory markers following glucagon-like peptide-1 receptor agonist treatment. Glucagon-like peptide-1 receptor agonists significantly decreased hepatic fat content compared to metformin and insulin-based therapies. Glucagon-like peptide-1 receptor agonists also improved fibrosis markers, but this did not reach statistical significance.. With a high prevalence of obesity and non-alcoholic fatty liver disease among patients with type 2 diabetes mellitus, glucagon-like peptide-1 receptor agonist treatment shows promise in improving both diabetes and non-alcoholic fatty liver disease phenotype.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease

Postprandial glycemic control is an important target for optimal type 2 diabetes management, but is often difficult to achieve. The gastrointestinal tract plays a major role in modulating postprandial glycaemia in both health and diabetes. The various strategies that have been proposed to modulate gastrointestinal function, particularly by slowing gastric emptying and/or stimulating incretin hormone GLP-1, are summarized in this review.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Incretins; Postprandial Period

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits.

Topics: Biomarkers; Blood Glucose; Clinical Decision-Making; Decision Support Techniques; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Incretins; Patient Selection; Primary Health Care; Sodium-Glucose Transporter 2 Inhibitors; Terminology as Topic; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time and its prevalence is projected to increase by >50% globally by 2045. Currently, 10 classes of drugs are approved by the US Food and Drug Administration for the treatment of T2DM. Drugs in development for T2DM must show meaningful reductions in glycaemic parameters as well as cardiovascular safety. Results from an increasing number of cardiovascular outcome trials using modern T2DM therapeutics have shown a reduced risk of atherosclerotic cardiovascular disease, congestive heart failure and chronic kidney disease. Hence, guidelines have become increasingly evidence based and more patient centred, focusing on reaching individualized glycaemic goals while optimizing safety, non-glycaemic benefits and the prevention of complications. The bar has been raised for novel therapies under development for T2DM as they are now expected to achieve these aims and possibly even treat concurrent comorbidities. Indeed, the pharmaceutical pipeline for T2DM is fertile. Drugs that augment insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production are active in more than 7,000 global trials using new mechanisms of action. Our collective goal of being able to truly personalize medicine for T2DM has never been closer at hand.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucose Transporter Type 4; Humans; Hypoglycemic Agents; Incretins; Insulin Secretion; Precision Medicine; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide 1 receptor agonists and dipeptidyl-peptidase 4 inhibitors are medications used for managing diabetes, mimicking the metabolic effects of incretin hormones. Recent evidence suggests that these medications have antioxidative potentials in the diabetic milieu. The pathophysiology of most diabetic complications involves oxidative stress. Therefore, if incretin-based antidiabetic medications can alleviate the free radicals involved in oxidative stress, they can potentially provide further therapeutic effects against diabetic complications. However, the molecular mechanisms by which these medications protect against oxidative stress are not fully understood. In the current review, we discuss the potential molecular mechanisms behind these pharmacologic agents' antioxidative properties.

Topics: Antioxidants; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

The effect of incretins including dipeptidyl peptidase 4 inhibitors (DPP4-Is) and glucagon-like peptide1 receptor agonists (GLP1-ras) in the treatment of type 2 diabetes increasing the risk of fracture remains controversial. No meta-analysis has been written to discuss this from the prospective interventional studies. The objective was to evaluate the association between the use of incretins and fracture risk.. Multiple databases were searched for original articles that investigated the relationship between the use of incretin agents and fracture risk, up to December 2019. Trials using the Mantel-Haenszel method to calculate OR and 95% CI were pooled. The multiple sensitivity, heterogeneity, publication bias, and quality were analysed among the studies to evaluate the robustness of results.. The fixed-effects model was used on account of the I² test for heterogeneity (I² = 0.0%). Incretins were not associated with fracture risk [0.97 (95% CI: 0.88-1.08)]. But in the subgroup analysis, when sitagliptin 100 mg per day (OR 0.495, 95% CI: 0.304-0.806) or liraglutide 1.8 mg per day was administered (OR 0.621, 95% CI: 0.413-0.933), it reduced fracture risk. The sensitivity analysis and publication bias prompted the robustness of results.. This meta-analysis suggested that the current use of incretins not only is safe for fracture in type 2 diabetes patients from RCT studies, but also, when sitagliptin 100 mg or liraglutide 1.8 mg per day was administered, it may exhibit protective effects on bone metabolism.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Prospective Studies; Sitagliptin Phosphate

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Receptors, Gastrointestinal Hormone

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

Topics: Arteriosclerosis; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hyperglycemia; Incretins; Insulin-Secreting Cells

A number of anti-diabetic treatments have been favored during the continuing spread of the current SARS-CoV-2 pandemic. Glucagon like peptide-1 receptor agonists (GLP1-RAs) are a group of antidiabetic drugs, the glucose reducing effect of which is founded on augmenting glucose-dependent insulin secretion with concomitant reduction of glucagon secretion and delayed gastric emptying. Apart from their glucose lowering effects, GLP1-RAs also exert a plethora of pleiotropic activities in the form of anti-inflammatory, anti-thrombotic and anti-obesogenic properties, with beneficial cardiovascular and renal impact. All these make this class of drugs a preferred option for managing patients with type 2 diabetes (T2D), and potentially helpful in those with SARS-CoV2 infection.. In the present article we propose a hypothetical molecular mechanism by which GLP1-RAs may interact with SARS-CoV-2 activity.. The beneficial properties of GLP1-RAs may be of specific importance during COVID-19 infection for the most fragile patients with chronic comorbid conditions such as T2D, and those at higher cardiovascular and renal disease risk. Yet, further studies are needed to confirm our hypothesis and preliminary findings available in the literature.

Topics: Animals; COVID-19; COVID-19 Drug Treatment; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Signal Transduction; Treatment Outcome

Incretins are hormones secreted from enteroendocrine cells after nutrient intake that stimulate insulin secretion from β cells in a glucose-dependent manner. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the only two known incretins. Dysregulation of incretin secretion and actions are noted in diseases such as obesity and diabetes. In this review, we first summarize our traditional understanding of the physiology of GIP and GLP-1, and our current knowledge of the relationships between GIP and GLP-1 and obesity and diabetes. Next, we present the results from major randomized controlled trials on the use of GLP-1 receptor agonists for managing type 2 diabetes, and emerging data on treating obesity and prediabetes. We conclude with a glimpse of the future with possible complex interactions between nutrients, gut microbiota, the endocannabinoid system, and enteroendocrine cells.

Topics: Animals; Diabetes Mellitus, Type 2; Endocannabinoids; Gastrointestinal Microbiome; Guidelines as Topic; Humans; Incretins; Obesity

Harnessing the translational potential of the GLP-1/GLP-1R system in pancreatic beta cells has led to the development of established GLP-1R-based therapies for the long-term preservation of beta cell function. In this review, we discuss recent advances in the current research on the GLP-1/GLP-1R system in beta cells, including the regulation of signaling by endocytic trafficking as well as the application of concepts such as signal bias, allosteric modulation, dual agonism, polymorphic receptor variants, spatial compartmentalization of cAMP signaling and new downstream signaling targets involved in the control of beta cell function.

Topics: Animals; Cyclic AMP; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Polymorphism, Single Nucleotide; Signal Transduction

In recent large-scale cardiovascular outcome trials, two new classes of glucose-lowering medications-sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs)-demonstrated cardiovascular benefits in adults with type 2 diabetes mellitus (T2DM). These findings have prompted growing optimism among clinicians regarding the potential for these agents to reduce the burden of cardiovascular disease in people with T2DM. GLP-1RAs and SGLT2i are now advocated as second-line agents in European and US guidelines for management of both hyperglycaemia and for primary prevention of cardiovascular disease in people with T2DM. Given the high prevalence of T2DM in patients with cardiovascular disease, cardiologists will increasingly encounter these agents in routine clinical practice. In this review, we summarise evidence from cardiovascular outcome trials of GLP-1RAs and SGLT2i, give practical advice on prescribing and detail safety considerations associated with their use. We also highlight areas where further work is needed, giving details on active clinical trials. The review aims to familiarise cardiologists with these emerging treatments, which will be increasingly encountered in clinical practice, given the expanding representation of T2DM in patients with cardiovascular disease. Whether these drugs will be initiated by cardiologists remains to be determined.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Down-Regulation; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Patient Safety; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

We aimed to determine whether sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and incretin-based agents combination therapy produces more benefits than SGLT2is alone in patients with type 2 diabetes mellitus (T2DM). PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing SGLT2is plus Dipeptidyl-Peptidase 4 inhibitors (SGLT2is/DPP4is) or glucagon like peptide-1 receptor agonists (SGLT2is/GLP-1RAs) against SGLT2is as monotherapy or add-on to metformin in T2DMs. A total of 13 studies with 7350 participants were included. Combination with GLP-1RAs exhibited more HbA1c reduction (WMD: -0.8; 95% CI, -1.14 to -0.45%), weight loss (-1.46; 95% CI, -2.38 to -0.54 kg), and systolic blood pressure (SBP) reduction (-2.88; 95% CI, -4.52 to -1.25 mmHg) versus SGLT2is alone but increased the gastrointestinal disorder risk (RR: 1.68; 95% CI, 1.14-2.47). Combination with DPP4is exhibited an extra effect on HbA1c reduction (-0.47; 95% CI, -0.58 to -0.37%), a neutral effect on weight (0.19; 95% CI, -0.11 to 0.48 kg) and SBP (-0.01; 95% CI, -0.85 to 0.63 mmHg), and ameliorated the genital infections risk (0.73; 95% CI, 0.54-0.97) versus SGLT2is. Meta-regression indicated the hypoglycemic efficacy of SGLT2is/DPP4is is higher in Asians than in other ethnics, and the differences in BMI across ethnic groups may mediate this effect. SGLT2is and incretin-based agents combination therapy is efficacious and safe versus SGLT2is alone in T2DMs. Particularly, combination with GLP-1RAs shows additional benefits to glycemic, weight, and SBP control to a larger extent than DPP4is, while combination with DPP4is ameliorates the risk for genital infection seen with SGLT2is. We highlight the need for individualized treatment related to the selection of this novel combination therapy.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Metformin; Prognosis; Sodium-Glucose Transporter 2 Inhibitors

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) potentiate glucose-induced insulin secretion and are therefore thought to be responsible for the incretin effect. The magnitude of the incretin effect, defined as the fraction of postprandial insulin secretion stimulated by intestinal factors, has been reported to be up to ∼60% in healthy individuals. In several pathological conditions but especially in patients with type 2 diabetes, the incretin effect is severely reduced or even absent. In line with this, the insulinotropic effects of GIP and GLP-1 are impaired in patients with type 2 diabetes, even when administered in supraphysiological doses. In healthy individuals, GIP has been proposed to be the most important incretin hormone of the two, but the individual contribution of the two is difficult to determine. However, using incretin hormone receptor antagonists: the novel GIP receptor antagonist GIP(3-30)NH

Topics: Diabetes Mellitus, Type 2; Evaluation Studies as Topic; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin Secretion; Peptide Fragments; Receptors, Gastrointestinal Hormone

Incretin-based therapies mimic or augment the gut-hormone glucagon-like peptide (GLP)-1 and, due to their glucose-lowering potential and beneficial safety profile, as well as their cardiovascular safety and/or protection, are prescribed on a large scale to treat individuals with type 2 diabetes (T2D). However, whether the two drug-classes that belong to this category, respectively GLP-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, also reduce the risk of diabetic kidney disease (DKD) is at present heavily debated. This review aims to discuss the current evidence.. Evidence from land-mark cardiovascular safety trials, conducted in people with T2D at high-cardiovascular risk but with normal kidney function, suggest that both drug-classes have excellent renal safety profiles. In contrast to DPP-4 inhibitors, it seems that GLP-1 receptor agonists reduce albuminuria and possibly induce a reduction of estimated glomerular filtration rate decline. However, the trials were not properly designed to test renal outcomes.. A dedicated renal trial involving a GLP-1 receptor agonist has recently commenced and will answer the question whether these drugs will be effective to reduce DKD. Moreover, ongoing mechanism-of-action studies are focusing on the renal physiological effects of GLP-1, as the effects on particularly albuminuria reduction remain currently unexplained.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glomerular Filtration Rate; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Kidney

Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta-analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP-1 receptor agonists and DPP-4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient-years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP-1 receptor agonists and DPP-4 inhibitors. Neither data on individual CVOTs of GLP-1 receptor agonists nor their meta-analysis [rate ratio: 1.05 (0.78-1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP-4 inhibitors displayed a non-significant trend towards an increased risk of acute pancreatitis, which was significant in the meta-analysis [1.75 (1.14-2.70); P = 0.01]. Neither GLP-1 receptor agonists nor DPP-4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo-controlled, prospective cardiovascular outcomes studies with GLP-1 receptor agonists and DPP-4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta-analysis of DPP-4 inhibitor CVOTs.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Neoplasms; Pancreatitis; Prospective Studies

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide (GLP-1) are the two incretin hormones secreted by the enteroendocrine system in response to nutrient ingestion. Compared with GLP-1, GIP is less well studied as a hormone or as a potential pharmacological treatment. Beyond its insulinotropic effects in the pancreas, GIP has important biological actions in many other tissues but its role in dietary fat metabolism and lipid storage in adipose tissue has been most studied. It is still unclear if such effects of GIP on adipose tissue/fat metabolism are protective or deleterious in the long term. Antagonising GIP actions through genetic and chemical disruption in mice models prevented diet induced obesity and improved insulin sensitivity. Whilst such effects of GIP antagonism are yet to be evaluated in humans, recent studies using combined GIP and GLP-1 agonists have shown weight reduction and improved glycaemic control in people with type 2 diabetes (T2D). Therapeutic manipulation of GIP physiology is intriguing in that both agonists and antagonists of GIP are being investigated to explore their potential weight-reducing and other metabolic benefits in people with obesity, T2D and non-alcoholic fatty liver disease (NAFLD). This review will discuss the physiological effects of GIP on fat metabolism in human adipose and other non-adipose tissues such as liver, pancreas, skeletal muscle and heart, describe where the actions of GIP may contribute to the pathophysiology of obesity, T2D and NAFLD and finally describe the therapeutic implications of GIP antagonism and agonism in these conditions.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Humans; Incretins; Lipid Metabolism; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Receptors, Gastrointestinal Hormone

Among the gastrointestinal hormones, the incretins: glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 have attracted interest because of their importance for the development and therapy of type 2 diabetes and obesity. New agonists and formulations of particularly the GLP-1 receptor have been developed recently showing great therapeutic efficacy for both diseases.. The status of the currently available GLP-1 receptor agonists (GLP-1RAs) is described, and their strengths and weaknesses analyzed. Their ability to also reduce cardiovascular and renal risk is described and analysed. The most recent development of orally available agonists and of very potent monomolecular co-agonists for both the GLP-1 and GIP receptor is also discussed.. The GLP-1RAs are currently the most efficacious agents for weight loss, and show potential for further efficacy in combination with other food-intake-regulating peptides. Because of their glycemic efficacy and cardiorenal protection, the GLP-1 RAs will be prominent elements in future diabetes therapy.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Kidney; Obesity; Treatment Outcome; Weight Loss

Type 2 diabetes mellitus (T2DM) is currently one of the most prevalent diseases, with as many as 415 million patients worldwide. T2DM is characterized by elevated blood glucose levels and is often accompanied by several comorbidities, such as cardiovascular disease. Treatment of T2DM is focused on reducing glucose levels by either lifestyle changes or medical treatment. One treatment option for T2DM is based on the gut-derived hormone glucagon-like peptide 1 (GLP-1). GLP-1 reduces blood glucose levels by stimulating insulin secretion, however, it is rapidly degraded, and thereby losing its glycaemic effect. GLP-1 receptor agonists (GLP-1RAs) are immune to degradation, prolonging the glycaemic effect. Lately, GLP-1RAs have spiked the interest of researchers and clinicians due to their beneficial effects on cardiovascular disease. Preclinical and clinical data have demonstrated that GLP-1 receptors are abundantly present in the heart and that stimulation of these receptors by GLP-1 has several effects. In this review, we will discuss the effects of GLP-1RA on heart rate, blood pressure, microvascular function, lipids, and inflammation, as measured in human mechanistic studies, and suggest how these effects may translate into the improved cardiovascular outcomes as demonstrated in several trials.

Topics: Animals; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Risk Factors; Signal Transduction; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelin A Receptor Antagonists; Humans; Incretins; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase 4 inhibitors (DPP-4i) are two classes of antidiabetic agents used in the management of diabetes based on incretin hormones. There is emerging evidence that they have anti-inflammatory effects. Since most long-term complications of diabetes have a background of chronic inflammation, these agents may be beneficial against diabetic complications not only due to their hypoglycemic potential but also via their anti-inflammatory effects. However, the exact molecular mechanisms by which GLP-1RAs and DPP-4i exert their anti-inflammatory effects are not clearly understood. In this review, we discuss the potential molecular pathways by which these incretin-based therapies exert their anti-inflammatory effects.

Topics: Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Inflammation

Although a variety of antidiabetic drugs have significant protective action on the cardiovascular system, it is still unclear which antidiabetic drugs can improve ventricular remodeling and fundamentally delay the process of heart failure. The purpose of this network meta-analysis is to compare the efficacy of sodium glucose cotransporter type 2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, metformin (MET), sulfonylurea (SU) and thiazolidinediones (TZDs) in improving left ventricular (LV) remodeling in patients with type 2 diabetes (T2DM) and/or cardiovascular disease (CVD).. We searched articles published before October 18, 2019, regardless of language or data, in 4 electronic databases: PubMed, EMBASE, Cochrane Library and Web of Science. We included randomized controlled trials in this network meta-analysis, as well as a small number of cohort studies. The differences in the mean changes in left ventricular echocardiographic parameters between the treatment group and control group were evaluated.. The difference in the mean change in LV ejection fraction (LVEF) between GLP-1 agonists and placebo in treatment effect was greater than zero (MD = 2.04% [0.64%, 3.43%]); similar results were observed for the difference in the mean change in LV end-diastolic diameter (LVEDD) between SGLT-2 inhibitors and placebo (MD = - 3.3 mm [5.31, - 5.29]), the difference in the mean change in LV end-systolic volume (LVESV) between GLP-1 agonists and placebo (MD = - 4.39 ml [- 8.09, - 0.7]); the difference in the mean change in E/e' between GLP-1 agonists and placebo (MD = - 1.05[- 1.78, - 0.32]); and the difference in the mean change in E/e' between SGLT-2 inhibitors and placebo (MD = - 1.91[- 3.39, - 0.43]).. GLP-1 agonists are more significantly associated with improved LVEF, LVESV and E/e', SGLT-2 inhibitors are more significantly associated with improved LVEDD and E/e', and DPP-4 inhibitors are more strongly associated with a negative impact on LV end-diastolic volume (LVEDV) than are placebos. SGLT-2 inhibitors are superior to other drugs in pairwise comparisons.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Incretins; Male; Middle Aged; Recovery of Function; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

MicroRNAs (miRNA) are one class of the small regulatory RNAs that can impact the expression of numerous genes including incretin hormones and their G protein-coupled receptors. Incretin peptides, including GLP-1, GLP-2, and GIP, are released from the gastrointestinal tract and have an crucial role in the glucose hemostasis and pancreatic beta-cell function. These hormones and their analogs with a longer half-life, glucagon like peptide-1 receptor agonists (GLP1RA), modify the expression of miRNAs. Dipeptidyl peptidase IV (DPP-4) is an enzyme that degrades the incretin hormones and is inactivated by DPP-4 inhibitors, which are a class of compounds used in the management of type 2 diabetes. DPP-4 inhibitors may also increase or reduce the expression of miRNAs. In this review, we describe the possible interactions between miRNAs and incretin hormones and the relevance of such interactions to physiological processes and diseases.

Topics: Animals; Cell Line; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; MicroRNAs

There is substantial interest in how GLP-1RA (glucagon-like peptide-1 receptor agonists) and SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce cardiovascular and renal events; yet, robust mechanistic data in humans remain sparse. We conducted a narrative review of published and ongoing mechanistic clinical trials investigating the actions of SGLT2 inhibitors and GLP-1RAs to help the community appreciate the extent of ongoing work and the variety and design of such trials. Approach and Results: To date, trials investigating the mechanisms of action of SGLT2 inhibitors have focused on pathways linked to glucose metabolism and toxicity, hemodynamic/volume, vascular and renal actions, and cardiac effects, including those on myocardial energetics. The participants studied have included those with established cardiovascular disease (including coronary artery disease and heart failure), liver disease, renal impairment, obesity, and hypertension; some of these trials have enrolled patients both with and without type 2 diabetes mellitus. GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure-lowering effects, as well as possible direct vascular, cardiac, and renal effects of these agents. Very few mechanisms of action of SGLT2 inhibitors or GLP-1RAs have so far been convincingly demonstrated. One small trial (n=97) of SGLT2 inhibitors has investigated the cardiac effects of these drugs, where a small reduction in left ventricular mass was found. Data on vascular effects are limited to one trial in type 1 diabetes mellitus, which suggests some beneficial actions. SGLT2 inhibitors have been shown to reduce liver fat. We highlight the near absence of mechanistic data to explain the beneficial effects of SGLT2 inhibitors in patients without diabetes mellitus. GLP-1RAs have not been found to have major cardiovascular mechanisms of action in the limited, completed trials. Conflicting data around the impact on infarct size have been reported. No effect on left ventricular ejection fraction has been demonstrated.. We have tabulated the extensive ongoing mechanistic trials that will report over the coming years. We report 2 exemplar ongoing mechanistic trials in detail to give examples of the designs and techniques employed. The results of these many ongoing trials should help us understand how SGLT2 inhibitors and GLP-1RAs improve cardiovascular and renal outcomes and may also identify unexpected mechanisms suggesting novel therapeutic applications.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Type 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose-lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end-stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co-morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Renal Insufficiency, Chronic

The link of acute pancreatitis (AP) with Incretin based therapies (IBTs) in type 2 diabetes has existed since United States Food and Drug Administration alert in 2010. This issue still remains unresolved due to conflicting results among studies.. We performed a systematic search of the PubMed, Embase, and Cochrane Library databases until 31 July 2019, and retrieved all cardiovascular outcome trials (CVOTs) of IBTs conducted for ≥12 months that reported the pre-specified and or pre-adjudicated pancreatitis outcomes. Subsequently, we conducted a meta-analysis to study the risk of AP observed with IBT in CVOTs.. A meta-analysis of seven CVOTs of GLP-1 receptor agonists (GLP-1RAs) compared with placebo (N = 55,932) found no significant increase in AP (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.77-1.42; p = 0.77). In contrast, meta-analysis of five CVOTs comparing DPP-4 inhibitors with placebo (N = 47,714) and six CVOTs comparing DPP-4 inhibitors with placebo or active comparator (N = 53,747), found a significant increase (OR, 1.81; 95% CI, 1.21-2.70; p = 0.04 and OR, 1.54; 95% CI, 1.08-2.18; p = 0.02, respectively) in AP without any significant heterogeneity.. This meta-analysis revealed a significant association between pancreatitis and DPP-4 inhibitors; however, no such association was observed for GLP-1RAs.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Pancreatitis

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown their beneficial effects on cardiovascular outcomes and multiple cardiovascular risk factors, including hypertension. However, the mechanism of blood pressure (BP)-lowering effects of these agents has not been elucidated. This study aims to evaluate the effect of hemoglobin A1c reduction or body weight reduction with GLP-1RA treatment and SGLT2i treatment on BP changes in patients with type 2 diabetes mellitus. Methods and Results Studies were identified by a search of MEDLINE, EMBASE, and the Cochrane Central Register until June 2019. Meta-regression analysis was performed to evaluate the association between hemoglobin A1c reduction or body weight reduction and changes of BP. A total of 184 trials were included. Both GLP-1RA and SGLT2i led to significant reductions in systolic BP (weighted mean difference, -2.856 and -4.331 mm Hg, respectively;

Topics: Aged; Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Incretins; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Weight Loss

The discovery that glucagon-like peptide 1 (GLP-1) mediates a significant proportion of the incretin effect during the postprandial period and the subsequent observation that GLP-1 bioactivity is retained in type 2 diabetes (T2D) led to new therapeutic strategies being developed for T2D treatment based on GLP-1 action. Although owing to its short half-life exogenous GLP-1 has no use therapeutically, GLP-1 mimetics, which have a much longer half-life than native GLP-1, have proven to be effective for T2D treatment since they prolong the incretin effect in patients. These GLP-1 mimetics are a desirable therapeutic option for T2D since they do not provoke hypoglycaemia or weight gain and have simple modes of administration and monitoring. Additionally, over more recent years, GLP-1 action has been found to mediate systemic physiological beneficial effects and this has high clinical relevance due to the post-diagnosis complications of T2D. Indeed, recent studies have found that certain GLP-1 analogue therapies improve the cardiovascular outcomes for people with diabetes. Furthermore, GLP-1-based therapies may enable new therapeutic strategies for diseases that can also arise independently of the clinical manifestation of T2D, such as dementia and Parkinson's disease. GLP-1 functions by binding to its receptor (GLP-1R), which expresses mainly in pancreatic islet beta cells. A better understanding of the mechanisms and signalling pathways by which acute and chronic GLP-1R activation alleviates disease phenotypes and induces desirable physiological responses during healthy conditions will likely lead to the development of new therapeutic GLP-1 mimetic-based therapies, which improve prognosis to a greater extent than current therapies for an array of diseases.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells

The effects of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors/DPP-4I) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) on cognition in patients with type 2 diabetes mellitus (T2DM) remain controversial. We aimed to explore this clinical issue through a systematic review and meta-analysis.. PubMed, EMBASE and the Cochrane Library were searched, and data were expressed as mean difference (MD) or hazard ratio (HR)/odds ratio (OR) with a 95% confidence interval (CI). Heterogeneity was assessed using the Chi-squared test and the I. Eleven studies (n = 304,258 T2DM patients) were included in our review. In the DPP-4I group, six studies were enrolled to estimate ΔMini-Mental State Examination (MMSE) scores from baseline to the final evaluations after DPP-4I treatment, which showed no statistical difference (MD 0.20; 95% CI - 0.75 to 1.15, p = 0.68). ΔMMSE scores in the DPP-4I group and the other antidiabetic groups were compared, revealing no statistical difference (MD 0.57; 95% CI - 0.05 to 1.19, p = 0.07). Two cohort studies were pooled to determine the HRs for dementia, showing a lower risk of dementia after DPP-4I treatment (HR 0.52; 95% CI 0.29-0.93, p = 0.03). In the GLP-1 analogs group, two studies were included, one of which revealed a downward trend in the risk of dementia after GLP-1 analog treatment, while the other revealed no significant difference after incretins treatment.. Currently there is not enough irrefutable evidence to support the hypothesis of positive effects of incretins on cognition. Further clinical studies need to be performed.

Topics: Adult; Cognition; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

In recent years guidelines for the treatment of type 2 diabetes (T2DM) have evolved substantially. Initially limited to a few glucose lowering agents, early guidelines predicated strict glycemic control as a main goal in the attempt to reduce the risk of long-term diabetic complications. Nowadays, guidelines are not limited to such a goal but include cardiovascular (and renal) protection. This rapid evolution was made possible by the introduction of new glucose lowering agents, which have been extensively tested in randomized clinical studies including large cardiovascular outcome trials (CVOTs). In this review we will specifically consider the use of incretin-based medications in T2DM as recommended in the recent ADA/EASD consensus, and other international guidelines, with special consideration of their glucose-lowering efficacy, their cardiovascular (and renal) benefit, their effect on body weight and risk of hypoglycemia, as well as the economic implications for their use.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Guidelines as Topic; Humans; Hypoglycemic Agents; Incretins

Incretin pathway plays an important role in the development of diabetes medications. Interventions in DPP-4 and GLP-1 receptor have shown remarkable efficacy in experimental and clinical studies and imperatively become one of the most promising therapeutic approaches in the T2DM drug discovery pipeline. Herein, we analyzed the actionmechanismsof DPP-4 and GLP-1 receptor targeting the incretin pathway in T2DM treatment. We gave an insight into the structural requirements for the potent DPP-4 inhibitors and revealed a classification of DPP-4 inhibitors by stressing on the binding modes of these ligands to the enzyme. We then reviewed the drug discovery strategies for the development of peptide and non-peptide GLP-1 receptor agonists (GLP-1 RAs). Furthermore, the drug design strategies for DPP-4 inhibitors and GLP-1R agonists were detailed accurately. This review might provide an efficient evidence for the highly potent and selective DPP-4 inhibitors and the GLP-1 RAs, as novel medicines for patients suffering from T2DM.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Models, Molecular; Peptides

Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90-95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Design; Drug Discovery; Drug Evaluation, Preclinical; Glucose; Humans; Hypoglycemic Agents; Incretins; Ligands; Molecular Targeted Therapy; Structure-Activity Relationship

Glucagon-like Peptide 1 Receptor Agonists (GLP1-RA) has been associated with a reduction of major cardiovascular events (MACE) and mortality on the basis of the results of cardiovascular outcome trials (CVOT). Several meta-analyses on this issue have been recently published; however, they were all restricted to CVOT, with the exclusion of all studies designed for other endpoints; moreover, other cardiovascular endpoints, such as atrial fibrillation and heart failure have not been fully explored.. A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. We included 43 trials, enrolling 63,134 patients. A significant reduction of MACE (MH-OR 0.87 [0.83, 0.92]), all-cause mortality (MH-OR 0.89 [0.83, 0.96]), and a nonstatistical trend toward reduction of heart failure (MH-OR 0.93 [0.85, 1.01]) was observed - GLP1-RA did not increase the risk of atrial fibrillation (MH-OR 0.94 [0.84, 1.04]).. The present meta-analysis confirms the favorable effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events, cardiovascular and all-cause mortality, stroke, and possibly myocardial infarction. Conversely, the effects on heart failure remain uncertain. Available data on atrial fibrillation seems to exclude any major safety issues in this respect.. CRD42018115577.

Topics: Aged; Atrial Fibrillation; Cause of Death; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Incidence; Incretins; Male; Middle Aged; Myocardial Infarction; Protective Factors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome

The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and antagonist of the GIP receptor should be useful, at least for weight-losing therapy. How is this possible? We here review recent experimental evidence that agonist-induced internalization of the two receptors differs markedly and that modifications of the ligand structures, as in co-agonists, profoundly influence these cellular processes and may explain that an antagonist may activate while an agonist may block receptor signaling.

Topics: Anti-Obesity Agents; Appetite; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Obesity; Receptors, Gastrointestinal Hormone; Signal Transduction; Weight Loss

The advent of Sodium Glucose Transporter 2-inhibitors (SGLT2-i) in recent years gave endocrinologists the opportunity to actively treat and prevent heart failure (HF) in patients with type 2 diabetes (T2DM). While the relationship between T2DM and HF has been extensively reviewed, previous works focused mostly on epidemiology, pathophysiology and treatment of HF in T2DM. The aim of our work was to aid health care professionals in identifying individuals at high risk for this dreadful complication. Recent guidelines recommend to use drugs with proven cardiovascular benefits (Glucagon-like peptide-1 receptor agonists (GLP1-RA) and SGLT2-i) in patients with previous cardiovascular disease (CVD) and to prefer SGLT2-i in patients with known HF. In everyday clinical practice, the choice between these two drug classes in patients without known HF or atherosclerotic CVD is mostly arbitrary and based on the side effect profile. Recently, risk stratification tools to estimate HF incidence have been developed in order to guide treatment with a view to bring precision medicine into diabetes care. With this purpose, we provide a review of the tools able to predict HF incidence for patients in primary CVD prevention as well as risk of future hospitalizations for patients with known HF.

Topics: Clinical Decision Rules; Clinical Decision-Making; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Heart Failure; Hospitalization; Humans; Incidence; Incretins; Primary Prevention; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Derangements in triglyceride and cholesterol metabolism (dyslipidemia) are major risk factors for the development of cardiovascular diseases in obese and type-2 diabetic (T2D) patients. An emerging class of glucagon-like peptide-1 (GLP-1) analogues and next generation peptide dual-agonists such as GLP-1/glucagon or GLP-1/GIP could provide effective therapeutic options for T2D patients. In addition to their role in glucose and energy homeostasis, GLP-1, GIP and glucagon serve as regulators of lipid metabolism. This review summarizes the current knowledge in GLP-1, glucagon and GIP effects on lipid and lipoprotein metabolism and frames the emerging therapeutic benefits of GLP-1 analogs and GLP-1-based multiagonists as add-on treatment options for diabetes associated dyslipidemia.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Intestinal Mucosa; Lipid Metabolism; Lipoproteins

To provide an update on the acute effects of glucose, insulin, and incretins on markers of bone turnover in those with and without diabetes.. Bone resorption is suppressed acutely in response to glucose and insulin challenges in both healthy subjects and patients with diabetes. The suppression is stronger with oral glucose compared with intravenous delivery. Stronger responses with oral glucose may be related to incretin effects on insulin secretion or from a direct effect on bone turnover. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) infusion acutely suppresses bone resorption without much effect on bone formation. The bone turnover response to a metabolic challenge may be attenuated in type 2 diabetes, but this is an understudied area. A knowledge gap exists regarding bone turnover responses to a metabolic challenge in type 1 diabetes. The gut-pancreas-bone link is potentially an endocrine axis. This linkage is disrupted in diabetes, but the mechanism and progression of this disruption are not understood.

Topics: Bone Remodeling; Bone Resorption; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 2; Glucose; Humans; Incretins; Insulin; Insulin Secretion; Osteogenesis

DPP-4 inhibitors are a well-established treatment for type 2 diabetes. They act by improving glycemic control through the incretin system. This class of molecules are well-tolerated and are associated with a low risk of hypoglycemia. Yet, their efficacy in glycemic control is rather moderate and they don't offer a benefit in terms of cardiovascular or renal protection. Even if they have a good safety profile, it is important to pay attention to the risk of cardiac failure and pancreatitis. This article provides an overview of the use of DPP-4 inhibitors in 2020.. Les inhibiteurs de la dipeptidyl peptidase-4 (iDPP-4) représentent un traitement d’usage courant pour le diabète de type 2. Leur action permet une amélioration du contrôle glycémique

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins

Recent advances in anti-diabetic medications and glucose monitoring have led to a paradigm shift in diabetes care. Newer anti-diabetic medications such as DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1RAs), and SGLT2 inhibitors have enabled optimal glycemic control to be achieved without increasing the risk of hypoglycemia and weight gain. Treatment with GLP-1RAs and SGLT2 inhibitors has been demonstrated to improve cardiorenal outcomes, positioning these agents as the mainstay of treatment for patients with type 2 diabetes (T2DM). The development of these newer agents has also prompted a paradigm shift in the concept of T2DM, highlighting the importance of beta cell dysfunction in the pathophysiology of T2DM.. Recent advances in pharmacotherapy for diabetes are summarized with a focus on the role of incretin-based drugs and SGLT2 inhibitors. The importance of a paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM is also discussed, given from an Asian perspective.. Management of T2DM including lifestyle modification as well as pharmacotherapy should be focused on reducing beta cell workload, to preserve functional beta cell mass. A paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM enhances the implementation of person-centered diabetes care.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Precision Medicine; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds

Incretin-based therapies include pharmacologic agents such as glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors which exert potent anti-hyperglycemic effects in the diabetic milieu. They are also shown to have extra-pancreatic effects. Renin-angiotensin system is part of the endocrine system which is widely distributed in the body and is closely involved in water and electrolyte homeostasis as well as renal and cardiovascular functions. Hence the renin-angiotensin system is the main target for treating patients with various renal and cardiovascular disorders. There is growing evidence that incretins have modulatory effects on renin-angiotensin system activity; thereby, can be promising therapeutic agents for the management of renal and cardiovascular disorders. But the exact molecular interactions between incretins and renin-angiotensin system are not clearly understood. In this current study, we have reviewed the possible molecular mechanisms by which incretins modulate renin-angiotensin system activity.

Topics: Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Renal Insufficiency; Renin-Angiotensin System; Treatment Outcome

It is well known that type 2 diabetes mellitus (T2D) is a globally increasing health burden. Despite recent therapeutic advances and the availability of many different classes of antihyperglycemic therapy, a large proportion of people do not achieve glycemic control. A decline in pancreatic beta-cell function has been defined as a key contributing factor to progression of T2D. In fact, a significant proportion of beta-cell secretory capacity is thought to be lost well before the diagnosis of T2D is made. Several models have been proposed to explain the reduction in beta-cell function, including reduced beta-cell number, beta-cell exhaustion, and dedifferentiation or transdifferentiation into other cell types. However, there have been reports that suggest remission of T2D is possible, and it is believed that beta-cell dysfunction may be, in part, reversible. As such, the question of whether beta cells are committed to failure in people with T2D is complex. It is now widely accepted that early restoration of normoglycemia may protect beta-cell function. Key to the successful implementation of this approach in clinical practice is the appropriate assessment of individuals at risk of beta-cell failure, and the early implementation of appropriate treatment options. In this review, we discuss the progression of T2D in the context of beta-cell failure and describe how C-peptide testing can be used to assess beta-cell function in primary care practice. In conclusion, significant beta-cell dysfunction is likely in individuals with certain clinical characteristics of T2D, such as long duration of disease, high glycated hemoglobin (≥9%), and/or long-term use of therapies that continuously stimulate the beta cell. In these people, measurement of beta-cell status could assist with choice of appropriate therapy to delay or potentially reverse beta-cell dysfunction and the progression of T2D.

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Disease Progression; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Oxidative Stress

The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents.. This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review.. DPP4is are moderately efficient in decreasing the HbA1c by an average of 0.5% as monotherapy, and 1.0% in combination therapy with other drugs. They have a good tolerability and safety profile compared to other glucose-lowering drugs. However, there are possible risks pertaining to acute pancreatitis and pancreatic cancer.. Cardiovascular outcome trials thus far have proven the cardiovascular safety for ischemic events in patients treated with sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of hospitalisation in the case of saxagliptin did not seem to be a class effect.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Pancreatic Neoplasms; Pancreatitis; Treatment Outcome

The cardiovascular outcome trials (CVOTs) have shown that glucagon like peptide-1 receptor agonists (GLP1RAs) have varying degrees of cardiovascular (CV) safety in patients with type 2 diabetes mellitus (T2DM.) The lack of any head-to-head comparative trials among GLP1RAs urged the need for an indirect comparison of these agents. Therefore, this study was conducted to indirectly compare the CV safety and mortality effects among different GLP1RAs in patients with T2DM using network meta-analysis (NMA).. Medline was searched to identify GLP1RA CVOTs to date. The outcomes of interest were CV death, myocardial infarction (IM), stroke, and death from any cause. An NMA with binomial likelihood logit link model was used for the binary outcomes. We conducted both fixed effects and random effects models for each outcome, and selected the best model based on the deviance information and the average posterior residual deviance. This NMA was reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA-NMA).. A total of seven GLP1RA CVOTs were included having 56,004 patients. The NMA results showed that oral semaglutide was statistically better than exenatide (OR 0.47, 95% CI 0.21-0.99), dulaglutide (OR 0.46, 95% CI 0.20-0.97), albiglutide (OR 0.45, 95% CI 0.19-0.97), lixisenatide (OR 0.43, 95% CI 0.19-0.92) in reducing CV death events. No significant differences were detected between most of the treatments regarding reducing death from any cause, MI and stroke events. The ranking results showed that oral semaglutide had the highest probability to be ranked first (> 90%) in reducing CV death and death from any cause. Moreover, once weekly semaglutide had the highest probability to be ranked first in reducing MI and stroke events.. The GLP1RAs have shown significant benefits in terms of CV safety. The indirect comparison and ranking probability results have shown that one weekly semaglutide and oral semaglutide seems to be the preferred option in patients with T2DM and established or at high risk of CVD. This result can aid health care providers, pharmacy and therapeutics committees in hospitals, and insurance companies when deciding which GLP1RA to start or add to their formulary.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Network Meta-Analysis; Protective Factors; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is a global disease that poses a significant threat to public health. The incidence of both diabetes and dementia has increased simultaneously. Researchers have found that a large proportion of dementia patients have T2DM. In recent years, increasing evidence has demonstrated a link between cognitive decline and T2DM. Although the exact pathogenesis of cognitive impairment in T2DM is still unknown, current studies suggest that hyperglycemia, cerebrovascular disease, brain insulin resistance, and changes in γ-aminobutyric acid (GABAergic) neurons may mediate the association between T2DM and cognitive impairment. These potential mechanisms may become targets for the treatment of cognitive disorders in patients with T2DM. Glucagon-like peptide-1 (GLP-1), a widely used anti-diabetic drug, has been shown to not only effectively lower blood glucose but also improve neurological function. Previous research has confirmed that GLP-1 and its analogues are effective in the treatment of cognitive impairment in patients with T2DM. This review describes current evidence on the mechanisms underlying the association between T2DM and cognitive impairment. In particular, this review focuses on recent advances in GLP-1 and its analogues for the treatment of T2DM-related cognitive impairment.

Topics: Cognitive Dysfunction; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins

The current coronavirus disease 2019 (COVID-19) pandemic has led the scientific community to breach new frontiers in the understanding of human physiology and disease pathogenesis. It has been hypothesized that the human dipeptidyl peptidase 4 (DPP4) enzyme receptor may be a functional target for the spike proteins of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Since DPP4-inhibitors are currently used for the treatment of patients with type-2 diabetes (T2DM), there is currently high interest in the possibility that these agents, or incretin-based therapies (IBTs) in general, may be of benefit against the new coronavirus infection. Diabetes is associated with increased COVID-19 severity and mortality, and accumulating evidence suggests that IBTs may favorably alter the clinical course of SARS-CoV-2 infection due to their inherent mechanisms of action. Further research into prognostic variables associated with various antidiabetic treatment regimens, and in particular the IBT, in patients with T2DM affected by the COVID-19 pandemic is therefore warranted.

Topics: Betacoronavirus; Coronavirus Infections; COVID-19; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Inflammation Mediators; Pandemics; Pneumonia, Viral; SARS-CoV-2; Severity of Illness Index

New antihyperglycemic medications have been proven to have cardiovascular (CV) and renal benefits in type 2 diabetes mellitus (T2DM); however, an evidence-based decision tree in specific clinical scenarios is lacking.. Systematic review and meta-analysis of randomized controlled trials (RCTs), with trial sequential analysis (TSA). Randomized controlled trial inclusion criteria were patients with T2DM from 1 of these subgroups: elderly, obese, previous atherosclerotic CV disease (ASCVD), previous coronary heart disease (CHD), previous heart failure (HF), or previous chronic kidney disease (CKD). Randomized controlled trials describing those subgroups with at least 48 weeks of follow-up were included. Outcomes: 3-point major adverse cardiovascular events (MACE), CV death, hospitalization due to HF, and renal outcomes. We performed direct meta-analysis with the number of events in the intervention and control groups in each subset, and the relative risk of the events was calculated.. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) were the only antihyperglycemic agents related to a reduction in CV events in different populations. For obese and elderly populations, GLP-1 RA were associated with benefits in 3-point MACE; for patients with ASCVD, both SGLT2i and GLP-1 RA had benefits in 3-point MACE, while for patients with CHD, only SGLT2i were beneficial.. SGLT2i and GLP-1 RA reduced CV events in selected populations: SGLT2i led to a reduction in events in patients with previous CHD, ASCVD, and HF. GLP-1 RA led to a reduction in CV events in patients with ASCVD, elderly patients, and patients with obesity. Trial sequential analysis shows that these findings are conclusive. This review opens a pathway towards evidence-based, personalized treatment of T2DM.. PROSPERO CRD42019132807.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Management; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Patient-Centered Care; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium-glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Decision-Making; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Global Health; Glucagon-Like Peptide-1 Receptor; Glycemic Control; Humans; Incretins; Kidney Diseases; Practice Guidelines as Topic; Practice Patterns, Physicians'; Protective Factors; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Non-alcoholic fatty liver disease (NAFLD), affecting over 25% of the general population worldwide, is characterized by a spectrum of clinical and histological manifestations ranging from simple steatosis (>5% hepatic fat accumulation without inflammation) to non-alcoholic steatohepatitis (NASH) which is characterized by inflammation, and finally fibrosis, often leading to liver cirrhosis, and hepatocellular carcinoma. Up to 70% of patients with type 2 diabetes mellitus (T2DM) have NAFLD, and diabetics have much higher rates of NASH compared with the general non-diabetic population.. The aim of this study is to report recent approaches to NAFLD/NASH treatment in T2DM patients. To-date, there are no approved treatments for NAFLD (apart from lifestyle measures).. Current guidelines (2016) from 3 major scientific organizations suggest that pioglitazone and vitamin E may be useful in a subset of patients for adult NAFLD/NASH patients with T2DM. Newer selective PPAR-γ modulators (SPPARMs, CHRS 131) have shown to provide even better results with fewer side effects in both animal and human studies in T2DM. Newer antidiabetic drugs might also be useful, but detailed studies with histological outcomes are largely lacking. Nevertheless, prior animal and human studies on incretin mimetics, glucagon-like peptide-1 receptor agonists (GLP-1 RA) approved for T2DM treatment, have provided indirect evidence that they may also ameliorate NAFLD/NASH, whereas dipeptidyl dipeptidase-4 inhibitors (DDP-4i) were not better than placebo in reducing liver fat in T2DM patients with NAFLD. Sodium-glucoseco-transporter-2 inhibitors (SGLT2i) have been reported to improve NAFLD/NASH. Statins, being necessary for most patients with T2DM, may also ameliorate NAFLD/NASH, and could potentially reinforce the beneficial effects of the newer antidiabetic drugs, if used in combination, but this remains to be identified.. Newer antidiabetic drugs (SPPARMs, GLP-1 RA and SGLT2i) alone or in combination and acting alone or with potent statin therapy which is recommended in T2DM, might contribute substantially to NAFLD/NASH amelioration, possibly reducing not only liver-specific but also cardiovascular morbidity. These observations warrant long term placebo-controlled randomized trials with appropriate power and outcomes, focusing on the general population and more specifically on T2DM with NAFLD/NASH. Certain statins may be useful for treating NAFLD/NASH, while they substantially reduce cardiovascular disease risk.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Incretins; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

To report the cardiovascular and renal effects of incretin-based therapies.. The studies of clinical trials on incretin-based therapy published in medical journals from the years 2010 to 2017 were comprehensively searched using MEDLINE and EMBASE with no language restriction. The studies were reviewed and the cardiovascular and renal risks reported were recorded.. Incretin-based therapeutics represent novel and promising anti-diabetes drugs, the direct cardiovascular actions which may translate into demonstrable clinical benefits on cardiovascular outcomes. Furthermore, incretin-based therapies do not adversely affect renal function.

Topics: Cardiovascular System; Diabetes Mellitus, Type 2; Humans; Incretins

The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.

Topics: Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Renal Insufficiency

Recent trials suggested that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduced cardiovascular events. Comparative effectiveness of these new antidiabetic drug classes remains unclear. We therefore performed a network meta-analysis to compare the effect on cardiovascular outcomes among GLP-1 RAs, SGLT-2 and dipeptidyl peptidase-4 (DPP-4) inhibitors.. MEDLINE, EMBASE, Cochrane database, ClinicalTrials.gov, and congress proceedings from recent cardiology conferences were searched up to April 20, 2019. Cardiovascular outcome trials and renal outcome trials reporting cardiovascular outcomes on GLP-1 RAs, SGLT-2 and DPP-4 inhibitors in patients with type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality, all-cause mortality, hospitalisation for heart failure (HF), and renal composite outcome. ORs and 95% CI were calculated using random-effects models.. Fourteen trials enrolling 121,047 patients were included. SGLT-2 inhibitors reduced cardiovascular deaths and all-cause deaths compared to placebo (OR 0.82, 95% CI 0.73-0.93 and OR 0.84, 95% CI 0.77-0.92) and DPP-4 inhibitors (OR 0.83, 95% CI 0.70-0.99 and OR 0.83, 95% CI 0.73-0.94), respectively. SGLT-2 inhibitors and GLP-1 RAs significantly reduced MACE (OR 0.88, 95% CI 0.82-0.95 and OR 0.87, 95% CI 0.82-0.93), hospitalisation for HF (OR 0.68, 95% CI 0.61-0.77 and OR 0.87, 95% CI 0.82-0.93), and renal composite outcome (OR 0.59, 95% CI 0.52-0.67 and OR 0.86, 95% CI 0.78-0.94) compared to placebo, but SGLT-2 inhibitors reduced hospitalisation for HF (OR 0.79, 95% CI 0.69-0.90) and renal composite outcome (OR 0.69, 95% CI 0.59-0.80) more than GLP-1 RAs. Only GLP-1 RAs reduced nonfatal stroke (OR 0.88, 95% CI 0.77-0.99). DPP-4 inhibitors did not lower the risk of these outcomes when compared to placebo and were associated with higher risks of MACE, hospitalisation for HF, and renal composite outcome when compared to the other two drug classes.. SGLT-2 inhibitors show clear superiority in reducing cardiovascular and all-cause deaths, hospitalisation for HF, and renal events among new antidiabetic drug classes. GLP-1 RAs also have cardiovascular and renal protective effects. DPP-4 inhibitors have no beneficial cardiovascular effects and are therefore inferior to the other two drug classes. SGLT-2 inhibitors should now be the preferred treatment for type 2 diabetes mellitus.

Topics: Cardiovascular Diseases; Cause of Death; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Hospitalization; Humans; Incretins; Network Meta-Analysis; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome

Heart failure is one of the major cardiovascular complications in patients with type 2 diabetes mellitus (T2DM) and increases the risk of morbidity and mortality. Although active management for heart failure is needed in patients with T2DM, traditional treatment and some new class of antihyperglycemic drugs, such as glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors, could not reduce the risk of heart failure. Recent major trials demonstrated sodium-glucose co-transporter-2 (SGLT2) inhibitors improve prognosis of T2DM patients through prevention of heart failure. Both heart failure with reduced ejection fraction and that with preserved ejection fraction (HFpEF) is observed in T2DM patients, and HFpEF is often overlooked and misdiagnosed in these population. Left ventricular hypertrophy, left atrial dilatation, diastolic dysfunction, and subclinical systolic dysfunction indicated as reduced global longitudinal strain are major abnormalities on echocardiography in patients with diabetic cardiomyopathy. These structural and functional changes are also prevalent in the general patients with T2DM, and those with these abnormalities have higher incidence of heart failure than those without them. Glycemic control might improve some of these abnormalities on echocardiography, but it is still unclear whether their improvement could be associated with risk reduction for heart failure. At now, there are only limited data on the effects of DPP-4 inhibitors or SGLT2 inhibitors on echocardiography in T2DM patients. Large-scale trials are needed to clarify how antihyperglycemic drugs affect echocardiographic parameters.

Topics: Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Echocardiography; Heart Failure; Humans; Hypertrophy, Left Ventricular; Hypoglycemic Agents; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume

To evaluate the risk of cancers of digestive system with incretin-based therapies among patients with type 2 diabetes mellitus.. Medline, Embase, Cochrane Library and ClinicalTrials.gov databases were searched for randomized controlled clinical trials that compared incretin-based drugs with placebo or other antidiabetic drugs. Paired reviewers independently screened citations, extracted data and assessed risk of bias of included studies. Network meta-analysis was performed, followed by subgroup analysis. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess the quality of evidence.. A total of 84 studies (n=101 595) involving cancers of digestive system were identified (a median follow-up of 30 weeks). The risk of cancers of digestive system with incretin-based therapies was comparable with insulin (OR: 0.86, 95% CI 0.27 to 2.69), metformin (OR: 0.32, 95% CI 0.07 to 1.38), sodium-glucose co-transporter 2 (OR: 5.26, 95% CI 0.58 to 47.41), sulfonylureas (OR: 1.27, 95% CI 0.68 to 2.39), thiazolidinediones (OR: 0.42, 95% CI 0.13 to 1.42), alpha-glucosidase inhibitors (OR: 2.98, 95% CI 0.12 to 73.80), and placebo (OR: 0.87, 95% CI 0.71 to 1.05). The results of subgroup analysis based on the type of digestive system cancers indicated that incretin-based therapies did not increase the risk of gastrointestinal cancers, respectively. The results of subgroup analysis based on age, duration, mean HbA1c, trial duration, and sample size did not indicate the risk of digestive system cancers.. Moderate to high Grading of Recommendations Assessment, Development and Evaluation evidence suggests that incretin-based therapies were not associated with an increased risk of cancer of digestive system in patients with type 2 diabetes mellitus.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Digestive System Neoplasms; Humans; Hypoglycemic Agents; Incretins; Network Meta-Analysis; Prognosis

Patients with diabetes mellitus are at an increased risk of bone fractures. Several groups of effective antidiabetic drugs are available, which are very often given in combination. The effects of these medications on bone metabolism and fracture risk must not be neglected. Commonly used antidiabetic drugs might have a positive, neutral or negative impact on skeletal health. Increased risk of fracture has been identified with use of thiazolidinediones, most definitively in women. Also treatment with sulfonylureas can have adverse effects on bone. One consequence of these findings has been greater attention to fracture outcomes in trails of new diabetes medication (incretins and SGLT-2 inhibitors). The effect of insulin on bone is discussed and the risk of fractures in patients using insulin seems to be unrelated to insulin as itself. The aim of the review is to summarize effects of antidiabetic treatment on bone - bone mineral density, fractures and bone turnover markers. The authors also try to recommend a strategy how to treat patients with diabetes mellitus regarding the risk of osteoporotic fractures. In this review the problem of how to treat osteoporosis in patient with diabetes is also discussed.

Topics: Animals; Bone and Bones; Bone Density Conservation Agents; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Osteoporosis; Sulfonylurea Compounds; Thiazolidinediones

The most significant manifestation of heart failure is exercise intolerance. This systematic review and meta-analysis was performed to investigate whether dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1 RAs), widely used anti-diabetic drugs, could improve exercise tolerance in heart failure patients with or without type 2 diabetes mellitus.. An electronic search of PubMed, EMBASE and the Cochrane Library was carried out through March 8th, 2019, for eligible trials. Only randomized controlled studies were included. The primary outcome was exercise tolerance [6-min walk test (6MWT) and peak O. After the literature was screened by two reviewers independently, four trials (659 patients) conducted with heart failure patients with or without type 2 diabetes met the eligibility criteria. The results suggested that targeting the DPP-4-GLP-1 pathway can improve exercise tolerance in heart failure patients [MD 24.88 (95% CI 5.45, 44.31), P = 0.01] without decreasing QoL [SMD -0.51 (95% CI -1.13, 0.10), P = 0.10]; additionally, targeting the DPP-4-GLP-1 pathway did not show signs of increasing the incidence of serious AEs or mortality.. Our results suggest that DPP-4 inhibitors or GLP-1 RAs improve exercise tolerance in heart failure patients. Although the use of these drugs for heart failure has not been approved by any organization, they may be a better choice for type 2 diabetes mellitus patients with heart failure. Furthermore, as this pathway contributes to the improvement of exercise tolerance, it may be worth further investigation in exercise-intolerant patients with other diseases.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Exercise Tolerance; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Incretins; Male; Middle Aged; Quality of Life; Randomized Controlled Trials as Topic; Recovery of Function; Signal Transduction; Treatment Outcome

Liraglutide is a glucagon-like 1 (GLP-1) agonist approved for treatment of type 2 diabetes and obesity.. To review the cardiovascular effects of liraglutide including macrovascular and microvascular events, its use in heart failure, and its effects on heart rate and blood pressure.. The impact of liraglutide on cardiovascular outcomes was examined in a large welldesigned study published in 2016, the LEADER trial. This study included 9,340 patients with advanced type 2 diabetes and high baseline cardiovascular risk. The primary outcome was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 3.8 years, patients randomized to liraglutide had significant reduction in the composite primary outcome compared to patients randomized to placebo, hazard ratio (HR) 0.87; 95% CI 0.78-0.97. Death from cardiovascular causes was significantly reduced with liraglutide therapy (HR, 0.78; 95% CI 0.66-0.93), as well as death from any cause (HR, 0.85; 95% CI 0.74-0.97). In 2017, the LEADER investigators reported that nephropathy events were significantly lower after liraglutide therapy than placebo (HR 0.78; 95% CI 0.67-0.92), but there was no significant difference in retinopathy events. Meanwhile, other studies suggested that the use of liraglutide may be harmful in patients with severe heart failure, in part due to increase in heart rate.. Liraglutide is a useful therapy in patients with advanced type 2 diabetes complicated by cardiovascular disease, except patients with severe heart failure. Further studies are needed to evaluate the long-term effects of liraglutide, and to see whether its beneficial effects extend to patients with type 2 diabetes and low cardiac risk.

Topics: Cardiovascular Diseases; Cardiovascular System; Clinical Decision-Making; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Patient Selection; Risk Assessment; Risk Factors; Signal Transduction; Treatment Outcome

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. In some patients with NAFLD, isolated steatosis can progress to advanced stages with non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is believed to be involved in the pathogenesis of common disorders such as type 2 diabetes and cardiovascular disease. In this Review, we highlight novel concepts related to diagnosis, risk prediction, and treatment of NAFLD. First, because NAFLD is a heterogeneous disease, the advanced stages of which seem to be strongly affected by comorbidities such as insulin resistance and type 2 diabetes, early use of reliable, non-invasive diagnostic tools is needed, particularly in patients with insulin resistance or diabetes, to allow the identification of patients at different disease stages. Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3 and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease. If consistent across diverse populations, this discordance in NAFLD-related risk prediction between hepatic and extrahepatic disease might need to be accounted for in the management of NAFLD. Third, drug treatments assessed in NAFLD seem to differ with respect to cardiometabolic and antifibrotic efficacy, suggesting the need to better identify and tailor the most appropriate treatment approach, or to use a combination of approaches. These emerging concepts could contribute to the development of a multidisciplinary approach for endocrinologists and hepatologists working together in the management of NAFLD.

Topics: Antioxidants; Bariatric Surgery; Carcinoma, Hepatocellular; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Progression; Dysbiosis; Gastrointestinal Microbiome; Genetic Predisposition to Disease; Humans; Incretins; Insulin Resistance; Lipase; Liver Cirrhosis; Liver Neoplasms; Membrane Proteins; Non-alcoholic Fatty Liver Disease; Obesity, Abdominal; Risk Assessment; Risk Reduction Behavior; Sodium-Glucose Transporter 2 Inhibitors

Our aim was to compare once-weekly semaglutide to incretin-based therapies - defined as either dipeptidyl peptidase-4 inhibitors (DPP-4i) or other glucagon-like peptide-1 receptor agonist (GLP-1RA) - in patients with type 2 diabetes.. We searched for randomized trials comparing once-weekly semaglutide to other incretin-based therapies in patients with type 2 diabetes. We pooled trials that compared semaglutide to other GLP-1RA together, and those comparing semaglutide to DPP-4i together. The primary outcome was the change in haemoglobin A. Five trials met our inclusion criteria. There was a significantly greater reduction in haemoglobin A. While both once-weekly semaglutide and other incretin-based therapies can reduce haemoglobin A

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome

To evaluate the comparative effects of incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is), on β-cell function and insulin resistance in patients with type 2 diabetes mellitus (T2DM).. Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with a duration of at least 4 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Outcomes of interest include homeostasis model assessment for β cell function (HOMA-β) and insulin resistance (HOMA-IR), fasting C-peptide and fasting plasma glucose (FPG). Weighted mean difference (WMD) with 95% confidence interval (CI) was calculated as the measure of effect size.. A total of 360 RCTs (74% at least double-blinded) with 157 696 patients were included. Incretin-based therapies were compared with six other classes of glucose-lowering drugs or with placebo. Compared with placebo, a significant increase in HOMA-β and fasting C-peptide was detected for GLP-1RAs (WMD = 20.31 [95% CI, 16.34-24.39] with low quality; WMD = 0.16 ng/mL [95% CI, 0.03-0.29] with low quality) and for DPP-4Is (WMD = 9.90 [95% CI, 8.27-11.61] with moderate quality; WMD = 0.09 ng/mL [95% CI, 0.04-0.14] with moderate quality) separately, while a significant reduction in HOMA-IR and FPG were found in favour of GLP-1RAs (WMD = -0.67 [95% CI, -1.08 to -0.27] with low quality; WMD = -1.04 mmol/L [95% CI, -1.26 to -0.83] with moderate quality) and DPP-4Is (WMD = -0.23 [95% CI, -0.38 to -0.08] with low quality; WMD = -0.77 mmol/L [95% CI, -0.98 to -0.57] with moderate quality), respectively.. Incretin-based therapies not only show an increase in HOMA-β and fasting C-peptide level, but also achieve a reduction in HOMA-IR and FPG in comparison with placebo. Although GRADE scores indicate low to moderate for most comparisons, incretin-based therapies seem to be an advisable option for long-term treatment to preserve β-cell function.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Network Meta-Analysis

Type 2 diabetes is the leading cause of impaired kidney function, albuminuria, and renal replacement therapy globally, thus placing a large burden on health-care systems. Current treatment strategies rely on intensive glucose lowering as well as strict blood pressure control through blockade of the renin-angiotensin-aldosterone system. Such approaches might slow decline in kidney function, but many patients progress to end-stage kidney failure despite optimal therapy. In recent clinical trials, new-generation glucose-lowering drug classes, the sodium-glucose co-transporter-2 inhibitors and agents that target the incretin pathway, have been shown to improve kidney outcomes in patients with type 2 diabetes. Other new approaches, which have been developed on the basis of an improved understanding of the mechanisms that contribute to kidney damage in the context of diabetes, include use of drugs that block endothelin receptors (eg, atrasentan) and non-steroidal mineralocorticoid receptors (eg, finerenone). In this Review, we provide an overview of recent clinical data relevant to these new therapeutic approaches for management of kidney disease in the context of type 2 diabetes.

Topics: Antihypertensive Agents; Atrasentan; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin Receptor Antagonists; Humans; Hypoglycemic Agents; Incretins; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Treatment Outcome

The aim of this network meta-analysis (NMA) was to indirectly compare the cardiovascular (CV) safety of new antidiabetic medications in patients with type 2 diabetes mellitus (T2DM). DATA SYNTHESIS: A search of the Embase and MEDLINE databases was conducted systematically to identify cardiovascular outcome trials (CVOTs) of new antidiabetic medications (DPP-4 inhibitors, GLP-1 agonists and SGLT-2 inhibitors) in patients with T2DM. The primary outcomes were the composite endpoint of CV death, nonfatal MI, and nonfatal stroke (MACE), death from CV causes, nonfatal MI, nonfatal stroke and death from any cause. Hospitalization for HF and unstable angina were evaluated as secondary endpoints. A total of 9 trials, including 87,162 patients, met the eligibility criteria and were retained for the analysis. The NMA results showed no significant differences among the DPP-4 inhibitors (sitagliptin, alogliptin, and saxagliptin) in any of the CV endpoints. Similarly, no significant changes were seen in the NMA among the GLP-1 receptor agonists nor the SGLT-2 inhibitors. The pairwise meta-analysis showed that DPP-4 inhibitors have a CV safety profiled comparable to placebo. GLP-1 agonists on the other hand, showed significant reduction in MACE (RR 0.92; 95% CI 0.87-0.97), death from CV causes (RR=0.88; 95% CI 0.80-0.97), and death from any cause (RR=0.89; 95% CI 0.82-0.96). SGLT-2 inhibitors showed significant reduction in hospitalization for heart failure events (RR 0.72; 95% CI 0.6-0.86) compared to placebo. CONCLUSION: This meta-analysis has shown that new antidiabetic medications do not impose any additional CV risk. The indirect comparison among the medications of each class resulted in no significant changes regarding CV endpoints and death from any cause.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Female; Glucagon-Like Peptide-1 Receptor; Hospitalization; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Network Meta-Analysis; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

In health, postprandial glycemic excursions are attenuated via stimulation of insulin secretion, suppression of glucagon secretion, and slowing of gastric emptying. The incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are primary modulators of this response. Drugs have recently been developed that exploit the incretin-axis for the management of type 2 diabetes. There is burgeoning interest in the potential of incretin therapies for the management of acute hyperglycemia in the critically ill. This article outlines basic incretin physiology, highlights relevant pharmacology, and briefly summarizes the literature on incretins for glycemic control in the critically ill.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Critical Care; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycemic Index; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Receptors, Gastrointestinal Hormone

Numerous micro-organisms naturally reside in the human body assuming a symbiotic, or, at times, even a dysbiotic relationship with the host. These microbial populations are referred to as the human microbiota. Host microbial populations are an important mediator of gastro-intestinal mucosal permeability, bile acid metabolism, short-chain fatty acids synthesis, fermentation of dietary polysaccharides and FXR/TGR5 signaling. Variations in the composition and function of gut microbiota have been observed in type 2 diabetes mellitus, insulin resistance and obesity, as well as in inflammatory bowel diseases. The microbial imbalance induced by such pathological processes is described as dysbiosis. In this review, we describe the pathophysiological links between type 2 diabetes mellitus and gut microbiota, explore the effect of anti-diabetic drugs on gut microbiota and suggest possible therapeutic targets.

Topics: alpha-Glucosidases; Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dysbiosis; Fermentation; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Metformin; Mice; Obesity; Permeability; Polysaccharides; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors

Diabetic kidney disease (DKD) still remains a progressive condition that is associated with higher risk of end-stage kidney disease and significant cardiovascular morbidity and mortality. Twelve cardiovascular outcome trials in type 2 diabetes (T2D) have been published to date. Most trials with dipeptidyl-peptidase inhibitors (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin, and CARMELINA with linagliptin) and with glucagon-like peptide-1 receptor agonists (GLP-1RAs) (ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, and HARMONY with albiglutide) pointed towards reduced albuminuria, which is a surrogate endpoint possibly heralding renal function preservation. The three trials with sodium-glucose co-transporter-2 inhibitors (SGLT-2is) (empagliflozin, canagliflozin and dapagliflozin) also showed a salutary effect on long-term estimated glomerular filtration rate, suggesting that SGLT-2is are more effective at mitigating loss of kidney function than incretin-based therapies; moreover, SGLT-2is also have the advantage of plausible haemodynamic mechanisms for improved renal outcomes. Despite some residual limitations linked to differences in study populations and patient characteristics, the cardiorenal protective actions of SGLT-2is, and to a lesser extent some GLP-1RAs, make them favourable medications for patients with T2D at increased cardiorenal risk. There is room for optimism that their use may change the paradigm of the ineluctable progression of DKD.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glomerular Filtration Rate; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Insulin resistance has a broad pathogenic impact affecting metabolic, cardio-renal and other disease areas. Extensive studies to dissect the mechanisms of insulin resistance have provided valuable insights to shape current clinical awareness and advance therapeutic practice. However, the development of direct interventions against insulin resistance has been hindered by its complex and highly variable presentations, especially in type 2 diabetes. Among glucose-lowering agents, metformin and thiazolidinediones provide cellular actions that counter some effects of insulin resistance: reduced glucotoxicity and weight-lowering with antidiabetic therapies also improve insulin action, except that endogenously- or exogenously-created hyperinsulinaemia may partially compromise these benefits. Increasing awareness of the pervasiveness and damaging ramifications of insulin resistance heightens the need for more specifically targeted and more effective therapies.

Topics: Animals; Anti-Obesity Agents; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

There is a growing body of evidence that diabetes represents a significant and largely modifiable risk factor for cardiovascular disease (CVD). It is known to markedly increase the risk of CVD-with CVD accounting for 2 of every 3 deaths in patients with diabetes. It is suggested that once patients with diabetes develop clinical coronary disease, they have a grim prognosis. In 2008, the Food and Drug Association mandated the evidence of CV safety in any new diabetic therapy, leading to a multitude of large CV outcome trials to assess CV risk from these medications. However, several of these outcome trials with novel antidiabetic therapies have demonstrated not only safety but a clear and definite CV advantage in patients with type 2 diabetes. In this review, we discuss 2 relatively newer classes of diabetic drugs, sodium glucose cotransport 2 inhibitors and glucagon-like peptide 1 agonists, evaluate their efficacy in improving CV outcomes, and discuss the future of CV prevention with these agents.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

The authors of 2 large randomized trials have recently published their findings related to the effects of a glucagon-like peptide 1 receptor agonist (GLP-1RA) (the HARMONY trial) and a dipeptidyl peptidase 4 (DPP-4) inhibitor (the CARMELINA trial) on cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus. In light of these new data, we conducted a systematic review and meta-analysis of GLP-1RAs and DPP-4 inhibitors in CV outcome trials to assess their CV safety in patients with type 2 diabetes.. We conducted a comprehensive literature search in the Embase and MEDLINE databases to identify trials involving GLP-1RAs and DPP-4 inhibitors with major CV-related outcomes reported, including major adverse CV events, CV death, myocardial infarction, stroke, death from any cause and hospitalization because of heart failure. A total of 9 CV outcome trials were included. Odds ratios and 95% confidence intervals were calculated based on the Mantel-Haenszel method.. Relative to placebo, GLP-1RAs were associated with a statistically significant reduction in the odds of major adverse CV events (13%), CV death (12%), death from any cause (11%) and stroke (13%). DPP-4 inhibitors were comparable to placebo for all outcomes. Moreover, DPP-4 inhibitors were associated with a nonsignificant 5% increase in the odds of hospitalization from heart failure compared to placebo.. This meta-analysis demonstrated that GLP-1RAs were associated with a significant reduction in major adverse CV events, CV death, stroke and death from any cause, while DPP-4 inhibitors were comparable to placebo for all CV outcomes, including hospitalizations for heart failure.

Topics: Adult; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Incretins; Patient Safety; Prognosis

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) have become firmly established in the treatment of type 2 diabetes and obesity, disorders frequently associated with diminished reproductive health. Understanding of the role of GLP-1 and GLP-1 RAs in reproduction is currently limited and largely unaddressed in clinical studies.. The purpose of this narrative review is to provide a comprehensive overview of the role of GLP-1 in reproduction and to address a therapeutic perspective that can be derived from these findings.. We performed a series of PubMed database systemic searches, last updated on 1 February 2019, supplemented by the authors' knowledge and research experience in the field. A search algorithm was developed incorporating the terms glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor, GLP-1R, or incretins, and this was combined with terms related to reproductive health. The PICO (Population, Intervention, Comparison, Outcome) framework was used to identify interventional studies including GLP-1 RAs and dipeptidyl peptidase-4 (DPP-4) inhibitors, which prevent the degradation of endogenously released GLP-1. We identified 983 potentially relevant references. At the end of the screening process, we included 6 observational (3 preclinical and 3 human) studies, 24 interventional (9 preclinical and 15 human) studies, 4 case reports, and 1 systematic and 2 narrative reviews.. The anatomical distribution of GLP-1 receptor throughout the reproductive system and observed effects of GLP-1 in preclinical models and in a few clinical studies indicate that GLP-1 might be one of the important modulating signals connecting the reproductive and metabolic system. The outcomes show that there is mostly stimulating role of GLP-1 and its mimetics in mammalian reproduction that goes beyond mere weight reduction. In addition, GLP-1 seems to have anti-inflammatory and anti-fibrotic effects in the gonads and the endometrium affected by obesity, diabetes, and polycystic ovary syndrome (PCOS). It also seems that GLP-1 RAs and DPP-4 inhibitors can reverse polycystic ovary morphology in preclinical models and decrease serum concentrations of androgens and their bioavailability in women with PCOS. Preliminary data from interventional clinical studies suggest improved menstrual regularity as well as increased fertility rates in overweight and/or obese women with PCOS treated with GLP-1 RAs in the preconception period.. GLP-1 RAs and DPP-4 inhibitors show promise in the treatment of diabetes and obesity-related subfertility. Larger interventional studies are needed to establish the role of preconception intervention with GLP-1 based therapies, assessing fertility outcomes in obesity, PCOS, and diabetes-related fertility problems. The potential impact of the dose- and exposure time-response of different GLP-1 RAs need further exploration. Future research should also investigate sex-specific variability of GLP-1 on reproductive outcomes, in particular on the gonads where the observations in males are most conflicting.

Topics: Animals; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Gonadal Disorders; Humans; Hypoglycemic Agents; Incretins; Infertility; Male; Obesity; Polycystic Ovary Syndrome; Reproduction; Weight Loss

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Patient Selection; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD), and when it causes CKD it is collectively referred to as diabetic kidney disease. One of the newer therapies for managing hyperglycemia is the glucagon-like peptide-1 receptor agonist (GLP-1RA) drug class. This review summarizes the effects of GLP-1RAs in patients with T2DM with CKD and evidence for renoprotection with GLP-1RAs using data from observational studies, prospective clinical trials, post hoc analyses, and meta-analyses. Evidence from some preclinical studies was also reviewed. Taken together, subgroup analyses of patients with varying degrees of renal function demonstrated that glycemic control with GLP-1RAs was not markedly less effective in patients with mild or moderate renal impairment vs that in patients with normal function. GLP-1RAs were associated with improvements in some cardiorenal risk factors, including systolic blood pressure and body weight. Furthermore, several large cardiovascular outcome studies showed reduced risks of composite renal outcomes, mostly driven by a reduction in macroalbuminuria, suggesting potential renoprotective effects of GLP-1RAs. In conclusion, GLP-1RAs effectively reduced hyperglycemia in patients with mild or moderately impaired kidney function in the limited number of studies to date. GLP-1RAs may be considered in combination with other glucose-lowering medications because of their ability to lower glucose in a glucose-dependent manner, lowering their risk for hypoglycemia, while improving some cardiorenal risk factors. Potential renoprotective effects of GLP-1RAs, and their renal mechanisms of action, warrant further investigation.. 2型糖尿病(type 2 diabetes mellitus, T2DM)是慢性肾脏病(chronic kidney disease, CKD)最常见的病因, 当引起CKD时统称为糖尿病肾病。胰高血糖素样肽-1受体激动剂(glucagon-like peptide-1 receptor agonist, GLP-1RA)是一类较新的降糖药物。本综述利用来自观察性研究、前瞻性临床试验、事后分析以及meta分析的数据, 总结了GLP-1RAs在T2DM合并CKD患者中的疗效及GLP-1RAs肾脏保护的证据。同时还回顾了一些来自临床前研究的证据。分析显示, 不同程度肾功能患者的亚组分析表明, 与肾功能正常的患者相比较, 轻度或中度肾功能受损患者使用GLP-1Ras治疗的降糖疗效并未明显降低。GLP-1RAs可改善一些心肾危险因素, 包括收缩压与体重。此外, 几项大型心血管结局研究结果显示, 复合肾脏结局的风险降低, 这主要是由于大量白蛋白尿减少所致, 表明GLP-1RAs具有潜在的肾脏保护作用。总之, 迄今为止有限的几项研究显示GLP-1RAs可有效降低轻度或中度肾功能受损患者的血糖水平。目前认为GLP-1RAs可与其他降糖药物联合使用, 因其降糖作用呈葡萄糖依赖性, 可降低发生低血糖的风险, 同时还可改善一些心肾危险因素。GLP-1RAs的潜在肾脏保护作用及其作用机制值得进一步研究。.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Kidney; Renal Insufficiency, Chronic; Signal Transduction; Treatment Outcome

The worldwide rise in overweight and obesity is paralleled by an increasing prevalence of type-2 diabetes. Apart from bariatric surgery, treatment options to decrease body weight are often underwhelming. Innovative pharmacological options are required to cope with the global "diabesity" pandemic.. Particular novel pharmacological approaches are discussed, with a special focus on polyagonist-based pharmacotherapies.. Articles on co- and tri-agonists for the treatment of obesity and diabetes are presented and discussed.. Unimolecular peptides have been developed for the treatment of obesity and type-2 diabetes. These peptides activate the receptors of multiple hormones and bundle their positive effects in one single molecule. In preclinical studies, polyagonists targeting the receptors for glucagon-like peptide-1 (GLP-1), glucagon, or glucose-dependent insulinotropic peptide (GIP) were promising to reduce body weight and blood glucose. GLP-1-mediated delivery of the nuclear hormones estrogen or dexamethasone also yielded beneficial effects in preclinical studies of obesity.. Polyagonists represent an innovative strategy for the development of novel pharmacotherapies to treat obesity and diabetes.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Obesity; Polypharmacology

The provocative idea that type 2 diabetes (T2D) may be a surgically treated disorder is based on accumulating evidence suggesting impressive remission rates of obesity and diabetes following bariatric surgery interventions. According to the "anti-incretin" theory, ingestion of food in the gastrointestinal (GI) tract, apart from activating the well-described incretin effect, also results in the parallel stimulation of a series of negative feedback mechanisms (anti-incretin effect). The primary goal of these regulations is to counteract the effects of incretins and other postprandial glucose-lowering adaptive mechanisms. Disruption of the equilibrium between incretins and anti-incretins could be an additional pathway leading to the development of insulin resistance and hyperglycemia. This theory provides an alternative theoretical framework to explain the mechanisms behind the optimal effects of metabolic surgery on T2D and underlines the importance of the GI tract in the homeostatic regulation of energy balance in humans. The anti-incretin concept is currently based on a limited amount of evidence and certainly requires further validation by additional studies. The aim of the present review is to discuss and critically evaluate recent evidence on the anti-incretin theory, providing an insight into current state and future perspectives.

Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Homeostasis; Humans; Incretins; Insulin Resistance; Obesity; Weight Loss

Recent findings indicate that incretin hormones and incretin-based therapies may affect the metabolism of lipoproteins, although the corresponding mechanisms are not clearly defined.. To summarize the available data on the mechanisms linking incretins with the characteristics of serum lipoproteins and discuss the clinical implications of these relationships.. PubMed was searched using the terms "incretins", "GLP-1", "GIP" and "lipids", "dyslipidemia", "triglycerides", "apolipoprotein B48". All articles published in the English language until June 2016 were assessed and the relevant information is presented here.. GLP-1, and therapies that increase its activity, exert a beneficial effect on lipoprotein metabolism that is translated in a reduction in the fasting and postprandial concentration of triglycerides and a small improvement in the concentration and function of HDLs. In addition, a shift towards larger, less atherogenic particles usually follows the administration of GLP-1 receptor agonists. The mechanisms that underlie these changes involve a direct effect of GLP- 1 on the hepatic and intestinal production of triglyceride-rich lipoproteins, the GLP-1 induced increase in the production and function of insulin, the activation of specific areas of central nervous system as well as the increase in the peripheral utilization of triglycerides for energy production. On the other hand, GLP-2 increases the absorption of dietary fat and the production of triglyceride-rich lipoproteins while the role of GIP on lipid metabolism remains indeterminate.. GLP-1 and incretin-based therapies favorably affect lipid metabolism. These effects may contribute to the beneficial effects of incretin-based therapies on atherosclerosis and fatty liver disease.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Lipoproteins, HDL; Lipoproteins, LDL; Liver Diseases; Triglycerides

The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti-diabetic treatment aims to control glucose homeostasis as tightly as possible in order to reduce these complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a recent addition to the anti-diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side-effect profile and their low hypoglycaemia risk. The actions of DPP-4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are known substrates, but other incretin-independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP-4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Gastrointestinal Motility; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Models, Biological; Pancreas; Proteolysis; Signal Transduction; Synaptic Transmission

The relationship between gut and skeleton is increasingly recognized as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism. We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP-1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre-clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify whether similar effects are present and clinically relevant in humans.

Topics: Animals; Bone and Bones; Bone Density; Bone Resorption; Diabetes Mellitus, Type 2; Disease Models, Animal; Fractures, Bone; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Obesity; Osteoblasts; Osteocalcin; Osteoclasts

With cardiovascular disease accounting for approximately 50% of deaths in patients diagnosed with type 2 diabetes, it is pertinent to initiate anti-diabetic medications with cardiovascular benefits. This systematic clinical review critically examines the clinical therapeutic effect of lixisenatide.. Data were gathered from articles indexed in PubMed, Google Scholar and Medline from 2010 - 2017, with the following search terms, "lixisenatide" and "GLP-1 receptor agonist". Studies written in the English language were included.. Thirteen clinical studies which evaluated the efficacy of lixisenatide were analyzed. Results from these studies showed that lixisenatide is an effective monotherapy in the reduction of glycated hemoglobin (A1C), Postprandial Glucose (PPG) and Fasting Blood Glucose (FPG). As an add-on therapy to metformin or sulfonylureas and insulin, it was found to be clinically effective compared to placebo. In all reviewed trials, there were higher proportions of patients who achieved A1C < 7% or < 6.5% compared to placebo without a corresponding increase in weight. Finally, the use of lixisenatide was not associated with an increased risk of cardiovascular events. The most common adverse events in all lixisenatide groups were nausea, vomiting, and diarrhea.. Lixisenatide appears to be safe and effective therapy for the management of type 2 diabetes mellitus. It is not associated with either the risk of cardiovascular events or symptomatic hypoglycemia. Finally, lixisenatide may be best used as an adjunct therapy for patients who are inadequately controlled with other diabetic medications, or select group of patients at risk of insulin induced obesity, hypertension or heart failure.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Peptides; Protective Factors; Risk Factors; Signal Transduction; Treatment Outcome

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have attracted considerable scientific and clinical interest due largely to their insulin-releasing and glucose-lowering properties. Indeed, GLP-1-based therapies are now key treatment options for many people with diabetes worldwide. In contrast, GIP-based agents have yet to reach the clinic based primarily on the impaired insulinotropic action of GIP observed in people with diabetes. Nevertheless, GIP is a key physiological regulator of insulin secretion and stable forms of GIP show much promise in rodent models to alleviate diabetes-obesity. Recent studies suggest that GIP may have an important role to play in a combination therapeutic approach or bioengineered with other gut peptides. Moreover, recent experimental studies indicate that incretins also exert pleiotropic effects in regions of the brain associated with learning and memory, thereby supporting preclinical data demonstrating that incretin-based drugs improve cognitive function. This review article, based on the RD Lawrence Lecture presented at Diabetes UK Annual Professional Conference (2017), provides a brief overview of incretins with a major focus on GIP, the development of designer GIP analogues, and how these molecules can improve cognition. Thus, incretins can be considered as 'the intelligent hormones' and may hold the key to successfully treating the alarming rise in neurodegenerative disorders.

Topics: Alzheimer Disease; Animals; Cognition; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Learning; Memory; Nootropic Agents

Incretin based therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) are increasingly used for the treatment of Type 2 diabetes mellitus. In clinical practice and in previously performed clinical trials, these agents are often used in combination with other oral anti-diabetic agents (OADs) and Insulin. Prior meta-analytic reviews however do not adequately address the impact of background therapy and active comparator arms. Accordingly, we aimed to further investigate the efficacy of incretin based therapies by updating existing reviews by including clinical trial evidence after 2008; estimating the pooled effect of incretin therapies on glycemic efficacy and weight-loss, stratified by comparator therapy (placebo, mono-therapy, etc.), estimating the impact of background OADs and within class (GLP-1Ra or DPP-4i) comparative efficacy, on glycemia control. 82 randomized controlled trials after 2008 with glycemic control and weight loss as primary end-points were included. Both DPP-4i and GLP-1Ra reduced HbA1c, but only GLP-1Ra caused weight loss when compared to either active comparator drugs or placebo. GLP-1Ra were more effective than DPP-4i in glycemia lowering. Long acting GLP-1Ra were more effective in HbA1c lowering than short-acting agents but with similar weight loss effect. The effect of DPP-4i incretin glycemic efficacy was not modified by background therapy used in the study.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins

To perform a meta-analysis of randomized controlled trials (RCTs), including 6 recently published large-scale cardiovascular outcome trials (CVOTs), to evaluate the risk of pancreatic cancer with incretin-based therapies in patients with type 2 diabetes (T2DM).. For the period January 1, 2007 to May 1, 2017, the PubMed, Embase, Cochrane Central Register and ClininalTrials.gov databases were searched for RCTs in people with T2DM that compared incretin drugs with placebo or other antidiabetic drugs, with treatment and follow-up durations of ≥52 weeks. Two reviewers screened the studies, extracted the data and assessed the risk of bias independently and in duplicate.. A total of 33 studies (n = 79 971), including the 6 CVOTs, with 87 pancreatic cancer events were identified. Overall, the pancreatic cancer risk was not increased in patients administered incretin drugs compared with controls (Peto odds ratio [OR] 0.67, 95% confidence interval [CI] 0.44-1.02). In the 6 CVOTs, 79 pancreatic cancer events were identified in 55 248 participants. Pooled estimates of the 6 CVOTs showed an identical tendency (Peto OR 0.65, 95% CI 0.42-1.01). Notably, in the subgroup of participants who received treatment and follow-up for ≥104 weeks, 84 pancreatic cancer events were identified in 59 919 participants, and a lower risk of pancreatic cancer was associated with incretin-based therapies (Peto OR 0.62, 95% CI 0.41-0.95).. Treatment with incretin drugs was not associated with an increased risk of pancreatic cancer in people with T2DM. Instead, it might protect against pancreatic malignancy in patients treated for ≥104 weeks.

Topics: Adult; Aged; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Risk Factors

Therapies to prevent diabetes in particular the progressive loss of β-cell mass and function and/or to improve the dysregulated metabolism associated with diabetes are highly sought. The incretin-based therapy comprising GLP-1R agonists and DPP-4 inhibitors have represented a major focus of pharmaceutical R&D over the last decade. The incretin hormone GLP-1 has powerful antihyperglycemic effect through direct stimulation of insulin biosynthesis and secretion within the β-cells; it normalizes β-cell sensitivity to glucose, has an antiapoptotic role, stimulates β-cell proliferation and differentiation, and inhibits glucagon secretion. However, native GLP-1 therapy is inappropriate due to the rapid post-secretory inactivation by DPP-4. Therefore, incretin mimetics developed on the backbone of the GLP-1 or exendin-4 molecule have been developed to behave as GLP-1R agonists but to display improved stability and clinical efficacy. New formulations of incretins and their analogs based on micro- and nanomaterials (i.e., PEG, PLGA, chitosan, liposomes and silica) and innovative encapsulation strategies have emerged to achieve a better stability of the incretin, to improve its pharmacokinetic profile, to lower the administration frequency or to allow another administration route and to display fewer adverse effects. An important advantage of these formulations is that they can also be used at the targeted non-invasive imaging of the beta-cell mass. This review therefore focuses on the current state of these efforts as the next step in the therapeutic evolution of this class of antidiabetic drugs.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Microtechnology; Nanotechnology; Pancreas

To evaluate the comparative cardiovascular safety of incretin-based therapies in patients with type 2 diabetes mellitus (T2DM).. Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with duration≥12 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess the quality of evidence. The outcome of interest was a composite of cardiovascular death, myocardial infarction, stroke and heart failure. Odds ratio (OR) with 95% confidence interval (CI) was calculated as the measure of effect size.. 281 RCTs (76.9% double-blinded) with 180,000 patients were included, comparing incretin-based therapies with other six classes of anti-diabetic drugs or placebo. A statistically significant reduction in the risk of cardiovascular events was found in favour of GLP-1RAs when compared with placebo (OR 0.89, 95%CI: 0.80-0.99) and sulfonylurea (OR 0.76, 95%CI: 0.59-0.99), whereas DPP-4 inhibitors showed a neutral effect compared with placebo (OR 0.92, 95%CI: 0.83-1.01).. Incretin-based therapies show similar cardiovascular risk in comparison with metformin, insulin, thiazolidinediones, alpha-glucosidase inhibitor and sodium-glucose co-transporter 2. GLP-1RA could decrease the risk compared with sulfonylurea or placebo, while DPP-4I appears to have neutral effect on cardiovascular risk.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Risk

Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose-dependent insulinotropic polypeptide) und GLP-1 (glucagon-like peptide-1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP-1, L cells) gut. Together, they are responsible for the incretin effect: a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP-1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP-1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP-1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin-based glucose-lowering medications (GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 or DPP-4). GLP-1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP-1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP-1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux-en-Y gastric bypass). GIP and GLP-1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP-1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high-risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well-characterized physiological effects.

Topics: Diabetes Mellitus, Type 2; Eating; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Health; Humans; Incretins; Insulin Secretion; Obesity; Weight Loss

Enzyme-resistant receptor agonists of the incretin hormone glucagon-like peptide-1 (GLP-1) have shown positive therapeutic effects in people with type 2 diabetes mellitus (T2DM). T2DM has detrimental effects on brain function and impairment of cognition and memory formation has been described. One of the underlying mechanisms is most likely insulin de-sensitization in the brain, as insulin improves cognitive impairments and enhances learning. Treatment with GLP-1 receptor agonists improves memory formation and impairment of synaptic plasticity observed in animal models of diabetes-obesity. Furthermore, it has been shown that diabetes impairs growth factor signalling in the brain and reduces energy utilization in the cortex. Inflammation and apoptotic signalling was also increased. Treatment with GLP-1 receptor agonists improved neuronal growth and repair and reduced inflammation and apoptosis as well as oxidative stress. In comparison with the diabetes drug metformin, GLP-1 receptor agonists were able to improve glycemic control and reverse brain impairments, whereas metformin only normalized blood glucose levels. Clinical studies in non-diabetic patients with neurodegenerative disorders showed neuroprotective effects following administration with GLP-1 receptor agonists, demonstrating that neuroprotective effects are independent of blood glucose levels.

Topics: Animals; Blood Glucose; Brain; Cognition; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Metformin; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress

Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide-based incretin therapy and bone physiology.

Topics: Animals; Bone Remodeling; Comorbidity; Diabetes Mellitus, Type 2; Disease Models, Animal; Fractures, Bone; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Mice; Mice, Knockout

Bariatric surgery is very effective in achieving and maintaining weight loss but it is also associated with improvement of obesity metabolic complications, primarily type 2 diabetes (T2D). Remission of T2D or at least a net improvement of glycemic control persists for at least 5 years. The bypass of duodenum and of the first portion of the jejunum up to the Treitz ligament as in Roux-en-Y Gastric Bypass (RYGB), or the bypass of the duodenum, the entire jejunum and the first tract of the ileum, such as in Bilio-Pancreatic Diversion (BPD), achieve different results on insulin sensitivity. Insulin resistance is the major driver of T2D manifesting long before insulin secretion failure. In fact, T2D development can be prevented by treatment with insulin sensitizing agents. Interestingly, RYGB improves hepatic insulin sensitivity while BPD ameliorates whole-body insulin sensitivity. Two major theories have been advocated to explain the early remission of T2D following RYGB or BPD before a meaningful weight loss takes place, the foregut and the hindgut hypotheses. The former holds that the bypass of the proximal intestine, i.e. duodenum and jejunum, prevents the secretion of signals - including nervous transmitters and hormones - promoting insulin resistance, the latter instead states that the delivery of nutrients directly into the ileum stimulates the secretion of hormones improving glucose disposal. The most studied candidate is Glucagon Like Peptide 1 (GLP1). However, while there is unambiguous evidence that GLP-1 stimulates insulin secretion, its direct action in lowering insulin resistance, independently of the effect on weight loss secondary to its satiety action, is utterly controversial. In this review we examine the effects on T2D and gastrointestinal peptide secretion produced by different types of metabolic surgery and by minimally invasive endoscopic surgery, whose utilization for the treatment of obesity and T2D is gaining wider interest and acceptance.

Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Obesity; Remission Induction

Dipeptidyl peptidase 4 (DPP4) is a widely expressed, serine protease which regulates the bioactivity of many peptides through cleavage and inactivation including the incretin hormones, glucagon like peptide -1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP). Inhibitors of DPP4 are used therapeutically to treat patients with Type 2 Diabetes Mellitus (T2DM) as they potentiate incretin action to regulate islet hormone secretion and improve glycemia and post-prandial lipid excursions. The widespread clinical use of DPP4 inhibitors has increased interest in the molecular mechanisms by which these drugs mediate their beneficial effects. Traditionally, focus has remained on inhibiting the catalytic activity of DPP4 within the plasma compartment, however evidence is emerging on the importance of inactivation of membrane-bound DPP4 in selective tissue beds to potentiate local hormone gradients. Here we review the recent advances in identifying the cellular sources of both circulating and membrane-bound DPP4 important for cleavage of the incretin hormones and regulation of glucose and lipoprotein metabolism.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose; Humans; Incretins; Lipid Metabolism; Postprandial Period

Chemical derivatives of the gut-derived peptide hormone glucagon-like peptide 1 (GLP-1) are among the best-in-class pharmacotherapies to treat obesity and type 2 diabetes. However, GLP-1 analogs have modest weight lowering capacity, in the range of 5-10%, and the therapeutic window is hampered by dose-dependent side effects. Over the last few years, a new concept has emerged: combining the beneficial effects of several key metabolic hormones into a single molecular entity. Several unimolecular GLP-1-based polyagonists have shown superior metabolic action compared to GLP-1 monotherapies. In this review article, we highlight the history of polyagonists targeting the receptors for GLP-1, GIP and glucagon, and discuss recent progress in expanding of this concept to now allow targeted delivery of nuclear hormones via GLP-1 and other gut hormones, as a novel approach towards more personalized pharmacotherapies.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Obesity; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

Globally, 13% of the world's adult population is obese, and more than 400 million people suffer from diabetes. These conditions are both associated with significant morbidity, mortality and financial cost. Therefore, finding new pharmacological treatments is an imperative. Relative hyperglucagonaemia is seen in all types of diabetes, and has been implicated in its pathogenesis. Consequently, clinical trials are underway using drugs which block glucagon activity to treat type 2 diabetes. Conversely, exogenous glucagon can increase energy expenditure. Therefore, researchers are designing peptides that combine activation of the glucagon receptor with further incretin properties, which will treat obesity while mitigating the hyperglycaemic effects of glucagon. This review will discuss these conflicting physiological properties of glucagon, and the attempts to harness these effects pharmacologically.

Topics: Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon; Humans; Hyperglycemia; Incretins; Insulin; Obesity; Receptors, Glucagon

Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut-derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage. Greater understanding of the interactions between the GLP-1 receptor (GLP-1R) and both the endogenous and artificial ligands therefore holds promise to provide more efficacious compounds. Here, we discuss recent findings concerning the signalling and trafficking of the GLP-1R in pancreatic beta cells. Leveraging "bias" at the receptor towards cAMP generation versus the recruitment of β-arrestins and extracellular signal-regulated kinases (ERK1/2) activation may allow the development of new analogues with significantly improved clinical efficacy. We describe how, unexpectedly, relatively low-affinity agonists, which prompt less receptor internalisation than the parent compound, provoke greater insulin secretion and consequent improvements in glycaemia.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Ligands; MAP Kinase Signaling System; Obesity; Peptides

A new strategy under development for the treatment of type 2 diabetes and obesity is to mimic some of the effects of bariatric surgery by delivering food-related stimuli to the distal gastrointestinal tract where they should enhance the release of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Methods include inhibition of food digestion and absorption in the upper GI tract, or oral delivery of stimuli in capsules or pelleted form to protect them against gastric degradation. A variety of agents have been tested in humans using capsules, microcapsules or pellets, delivering nutrients, bile acids, fatty acids and bitter compounds. This review examines the outcomes of these different approaches and supporting evidence from intestinal perfusion studies.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Food-Drug Interactions; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Obesity; Peptide YY; Secretagogues

The aim of this study is to examine the cardioprotective properties of Glucagon-like peptide-1 receptor agonist, a class of antihyperglycemic therapy, via meta-analysis of four recently published cardiovascular outcomes trials.. Meta-analysis was performed pooling data from the ELIXA, LEADER, SUSTAIN-6 and EXSCEL trials. A random effects model was used to generate risk ratio with 95% confidence interval for cardiovascular and safety outcomes.. A total of 33,457 patients were included in the meta-analysis. Based on the study, GLP-1R agonists significantly reduced all-cause mortality (RR 0.89; 95% CI 0.82 to 0.96) and cardiovascular mortality (RR 0.88; 95% CI 0.80 to 0.97) when compared to placebo. When long-acting agents were analyzed alone, reduction in major adverse cardiac events (RR 0.88; 95% CI 0.81 to 0.97) and non-fatal strokes (RR 0.87; 95% CI 0.76 to 0.99) also showed significance.. Overall, GLP-1R agonists appear to have cardioprotective properties likely via modification of metabolic parameters such as glycemic control, weight loss, and improvement in blood pressure. Additional studies are warranted to compare cardiovascular outcomes among the different agents.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Risk Factors; Signal Transduction; Treatment Outcome

As Type 2 diabetes progresses, treatment is intensified with additional therapies in an effort to manage hyperglycaemia effectively and therefore avoid complications. When greater efficacy is required, options for injectable treatments include glucagon-like peptide-1 receptor agonists and insulin, which may be added on to oral glucose-lowering treatments. Among individuals receiving long-acting basal insulin as their first injectable treatment, ~40-60% are unable to achieve or maintain their target HbA

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Peptides; Postprandial Period; Treatment Outcome

Non-alcoholic fatty liver disease (NAFLD) is currently one of the leading forms of chronic liver disease, and its rising frequency worldwide has reached epidemic proportions. NAFLD, particularly its progressive variant NASH (non-alcoholic steatohepatitis), can lead to advanced fibrosis, cirrhosis, and HCC. The pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex, and as such myriad therapies are under investigation targeting different pathophysiological mechanisms. Incretin-based therapies, including GLP-1RAs and DPP-4 inhibitors and the inhibition of ASK1 pathway have provided two such novel mechanisms in the management of this disease, and will remain focus of this review.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; MAP Kinase Kinase Kinase 5; MAP Kinase Signaling System; Non-alcoholic Fatty Liver Disease; Reactive Oxygen Species; Treatment Outcome

Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors produce some beneficial and deleterious effects in diabetic patients not mediated by their glycemic lowering effects, and there is a need for better understanding of the molecular basis of these effects. They possess antioxidant and anti-inflammatory effects with some direct vasodilatory action (animal and human trial data) that may indirectly influence heart failure (HF). Unlike GLP-1R agonists, signaling for HF adverse effects was observed with two DPP-4 inhibitors, saxagliptin and alogliptin. Accordingly, these drugs should be used with caution in heart failure patients.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Global Health; Heart Failure; Humans; Incretins; Morbidity

In healthy individuals, the incretin hormone glucagon-like peptide 1 (GLP1) potentiates insulin release and suppresses glucagon secretion in response to the ingestion of nutrients. GLP1 also delays gastric emptying and increases satiety. In patients with type 2 diabetes mellitus (T2DM), supraphysiological doses of GLP1 normalize the endogenous insulin response during a hyperglycaemic clamp. Owing to the short plasma half-life of native GLP1, several GLP1 receptor agonists (GLP1RAs) with longer half-lives have been developed for the treatment of T2DM. These compounds vary in chemical structure, pharmacokinetics and size, which results in different clinical effects on hyperglycaemia and body weight loss; these variations might also explain the difference in cardiovascular effect observed in large-scale cardiovascular outcome trials, in which certain GLP1RAs were shown to have a positive effect on cardiovascular outcomes. Owing to their metabolic effects, GLP1RAs are also considered for the treatment of several other lifestyle-induced conditions, such as obesity, prediabetes and liver disease. This Review provides insights into the physiology of GLP1 and its involvement in the pathophysiology of T2DM and an overview of the currently available and emerging GLP1RAs. Furthermore, we review the results from the currently available large-scale cardiovascular outcome trials and the use of GLP1RAs for other indications.

Topics: Biomarkers; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Reference Values; Treatment Outcome

Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional infor

Topics: Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Hospitalization; Humans; Hypoglycemic Agents; Incretins; Meta-Analysis as Topic; Multicenter Studies as Topic; Observational Studies as Topic; Risk; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Plaque, Atherosclerotic

Diabetes mellitus is a chronic disease prevalence of which is high and continually growing. Cardiovascular disease continues to be the leading cause of death in patients with T2DM. The prevention of cardiovascular complications and the cardiovascular safety of treatments should be a primary objective when selecting treatment. Among all the drugs available, the compounds known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) appear to be not just innocuous in terms of CVD but indeed to be beneficial. GLP-1 RA actions not only translate on an improvement of well-known cardiovascular risk factors such as glycaemic control, dyslipidaemia, weight, or arterial hypertension but also might show benefits on endothelial function, coronary ischaemia, and heart failure. On the other hand, recent clinical trials aimed at studying cardiovascular episodes have been conducted with GLP-1 RAs. Only liraglutide and semaglutide have shown superiority in cardiovascular benefit compared with placebo. Although many of the mechanisms by which liraglutide and semaglutide produce a cardiovascular benefit are still unknown it would be desirable for these benefits to be incorporated into the therapeutic algorithms routinely used in clinical practice. The purpose of this review is to explore GLP-1 RA actions not only in cardiovascular risk factors (glucose, weight, and hypertension) but also the possible effects on established cardiovascular disease.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Glucagonlike peptide 1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of glucagonlike peptide 1 receptor-directed strategies is submaximal, and the only potent, sustainable treatment of metabolic dysfunction is bariatric surgery, necessitating the development of unique therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development of intermixed, unimolecular peptides with activity at each of their respective receptors. In this review, we discuss the range of tissue targets and added benefits afforded by the inclusion of each of GIP and glucagon. We discuss considerations for the development of sequence-intermixed dual agonists and triagonists, highlighting the importance of evaluating balanced signaling at the targeted receptors. Several multireceptor agonist peptides have been developed and evaluated, and the key preclinical and clinical findings are reviewed in detail. The biological activity of these multireceptor agonists are founded in the success of GLP-1-directed strategies; by including GIP and glucagon components, these multireceptor agonists are thought to enhance GLP-1's activities by broadening the tissue targets and synergizing at tissues that express multiple receptors, such at the brain and pancreatic islet β cells. The development and utility of balanced, unimolecular multireceptor agonists provide both a useful tool for querying the actions of incretins and glucagon during metabolic disease and a unique drug class to treat type 2 diabetes with unprecedented efficacy.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

While sodium-glucose cotransporter-2 (SGLT2) inhibitors have been used for the routine management of type 2 diabetes for several years, it is perhaps their natriuretic effects that are most important clinically. This natriuresis activates tubuloglomerular feedback, resulting in reduced glomerular hypertension and proteinuria, leading to renal protective effects in the EMPA-REG OUTCOME and CANVAS Program trials. In the cardiovascular system, it is likely that plasma volume contraction due to natriuresis in response to SGLT2 inhibition is at least in part responsible for the reduction in the risk of heart failure observed in these trials. We compare this mechanism of action with other antidiabetics. Importantly, other diuretic classes, including thiazide and loop diuretics, have not resulted in such robust clinical benefits in patients with type 2 diabetes, possibly because these older agents do not influence intraglomerular pressure directly. In contrast, SGLT2 inhibitors do have important physiological similarities with carbonic anhydrase inhibitors, which also act proximally, and have been shown to activate tubuloglomerular feedback.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Kidney; Natriuresis; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Atherosclerosis is a major underlying cause of ischemic heart diseases, ischemic stroke, and peripheral artery disease. Atherosclerotic plaque progression is characterized by chronic progressive inflammation of the arterial wall, endothelial cell dysfunction, and subendothelial lipoprotein retention. Incretin drugs, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase-IV (DPP-IV) inhibitors, are promising anti-hyperglycemic agents used for the treatment of type 2 diabetes mellitus (T2DM). In addition to glucose-lowering effects, emerging data suggest that incretin drugs have anti-atherogenic effects with the potential to stabilize atherosclerotic plaques and treat arterial inflammation. Clinical and preclinical studies have reported a plethora of therapeutic benefits of incretin drugs, including modulation of inflammatory response, reduction of intima-media thickening, improvement in lipid profiles, endothelial and smooth muscle cell modulation. Despite extensive research and widespread clinical use of incretin-based therapies, the research on the incretin hormones continues to expand. This review outlines clinical studies, molecular aspects, and potential therapeutic implications of incretin drugs in attenuation of atherosclerosis.

Topics: Anti-Inflammatory Agents; Atherosclerosis; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Carotid Intima-Media Thickness; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Incretins; Inflammation; Lipids; Peptides

Bariatric and metabolic surgery is creating new concepts about how the intestine assimilates food. Recent studies highlight the role of the gastrointestinal tract in the genesis and evolution of type 2 diabetes. This article has been written to answer frequent questions about metabolic surgery results and the mechanisms of action. For this purpose, a non-systematic search of different databases was carried out, identifying articles published in the last decade referring to the mechanisms of action of metabolic techniques. Understanding these mechanisms will help grasp why some surgeries are more effective than others and why the results can be so disparate among patients undergoing the same surgical approach.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Gastrointestinal Tract; Humans; Incretins

Diabetic foot ulcers are a serious complication of diabetes and are associated with pain, disability, and poor quality of life. Incretin-based therapy is available for type-2 diabetes. Aside from glucose control, such treatment can impart numerous beneficial effects.. This review summarizes the preclinical and clinical evidence supporting incretin-based treatment approaches for diabetic ulcers.. Incretin-based therapy may have a role in the treatment of diabetic foot ulcers; the benefits of such treatment arise from attenuation of inflammatory response, improvement of keratinocyte migration, induction of angiogenesis, and the enhancement of tissue remodeling. Large-scale clinical trials are required to determine the advantages of GLP-1 receptor agonists and DPP4 inhibitors. Future research on the topical application of incretin-based therapy is necessary. Such therapeutic approaches may provide new hope in improving the treatment of impaired diabetic foot ulcers.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Foot; Drug Design; Humans; Hypoglycemic Agents; Incretins; Quality of Life

Patients with type 2 diabetes (T2DM) have a substantial risk of developing cardiovascular disease. The strong connection between the severity of hyperglycaemia, metabolic changes secondary to T2DM and vascular damage increases the risk of macrovascular complications. There is a challenging demand for the development of drugs that control hyperglycaemia and influence other metabolic risk factors to improve cardiovascular outcomes such as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina and heart failure (major adverse cardiovascular events). In recent years, introduction of the new drug class of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has changed the treatment landscape as GLP-1RAs have become well-established therapies in T2DM. The benefits of GLP-1RAs are derived from their pleiotropic effects, which include appetite control, glucose-dependent secretion of insulin and inhibition of glucagon secretion. Importantly, their beneficial effects extend to the cardiovascular system. Large clinical trials have evaluated the cardiovascular effects of GLP-1RAs in patients with T2DM and elevated risk of cardiovascular disease and the results are very promising. However, important aspects still require elucidation, such as the specific mechanisms involved in the cardioprotective effects of these drugs. Careful interpretation is necessary because of the heterogeneity across the trials concerning the definition of cardiovascular risk or cardiovascular disease, baseline characteristics, routine care and event rates. The aim of this review is to describe the main clinical aspects of the GLP-1RAs, compare them using data from both the mechanistic and randomized controlled trials and discuss potential reasons for improved cardiovascular outcomes observed in these trials. This review may help clinicians to decide which treatment is most appropriate in reducing cardiovascular risk in patients with T2DM.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Signal Transduction; Treatment Outcome

The review addresses the questions of the literature devoted to the problem of the influence of bariatric surgery on the course of diabetic nephropathy in patients with diabetes mellitus type 2 after achieving a surgically induced remission. This approach was shown to have positive aspects, such as decrease in creatinine, decrease in albuminuria, an increase in GFR, normalization of glycemia and blood pressure, "incretin effect"'s influence on the kidneys. Descriptions of the currently expected pathogenetic mechanisms involved in achieving the observed improvement in microvascular complications of diabetes, namely diabetic kidney disease, are also described in details.

Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Incretins

Nowadays, obesity is seriously increasing in most of the populations all over the world, and is associated with the development and progression of high-mortality diseases such as type-2 diabetes mellitus (T2DM) and its subsequent cardiovascular pathologies. Recent data suggest that both body fat distribution and adipocyte phenotype, can be more determinant for fatal outcomes in obese patients than increased general adiposity. In particular, visceral adiposity is significantly linked to long term alterations on different cardiac structures, and in developed forms of myocardial diseases such as hypertensive and ischaemic heart diseases, and diabetic cardiomyopathy. Interestingly, this depot may be also related to epicardial fat accumulation through secretion of lipids, adipokines, and pro-inflammatory and oxidative factors from adipocytes. Thus, visceral adiposity and its white single-lipid-like adipocytes, are risk factors for different forms of heart disease and heart failure, mainly in higher degree obese subjects. However, under specific stimuli, some of these adipocytes can transdifferentiate to brown multi-mitochondrial-like adipocytes with anti-inflammatory and anti-apoptotic proprieties. Accordingly, in order to improve potential cardiovascular abnormalities in obese and T2DM patients, several therapeutic strategies have been addressed to modulate the visceral and epicardial fat volume and phenotypes. In addition to lifestyle modifications, specific genetic manipulations in adipose tissue and administration of PPARγ agonists or statins, have improved fat volume and phenotype, and cardiovascular failures. Furthermore, incretin stimulation reduced visceral and epicardial fat thickness whereas increased formation of brown adipocytes, alleviating insulin resistance and associated cardiovascular pathologies.

Topics: Adipose Tissue; Adipose Tissue, Brown; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Incretins; Intra-Abdominal Fat; Obesity; Pericardium

Dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent two distinct classes of incretin-based therapies used for the treatment of type 2 diabetes. Non-inferiority versus placebo was shown in large prospective cardiovascular outcome trials in patients with high cardiovascular risk: SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), and TECOS (sitagliptin); ELIXA (lixisenatide), LEADER (liraglutide) and SUSTAIN 6 (semaglutide). The promises raised by meta-analyses of phase 2-3 trials with DPP-4is were non confirmed as no cardiovascular protection could be evidenced. However, LEADER showed a significant reduction in major cardiovascular events, myocardial infarction, cardiovascular and all-cause mortality in patients treated by liraglutide compared to placebo. These positive results contrasted with the non-inferiority results with lixisenatide in ELIXA. They were partially confirmed with semaglutide in SUSTAIN 6 despite the absence of reduction in cardiovascular mortality. Hospitalisation for heart failure was not increased except with saxagliptin in SAVOR-TIMI 53. The reasons for different outcomes between trials remain largely unknown as well as the precise underlying mechanisms explaining the cardiovascular protection by liraglutide. The clinical relevance of results with DPP-4is and GLP-1RAs is discussed. Ongoing trials with linagliptin and several once-weekly GLP-1RAs should provide new insights into remaining fundamental questions.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Outcome Assessment, Health Care; Prospective Studies; Risk Factors

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins

Topics: Acute Disease; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Odds Ratio; Pancreatic Neoplasms; Pancreatitis; Risk; Risk Factors; Treatment Outcome

Older adults with diabetes are at higher risk of fracture and of complications resulting from a fracture. Hence, fracture risk reduction is an important goal in diabetes management. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Beata Lecka-Czernik (DOI 10.1007/s00125-017-4269-4 ). Specifically, this review discusses the challenges of accurate fracture risk assessment in diabetes. Standard tools for risk assessment can be used to predict fracture but clinicians need to be aware of the tendency for the bone mineral density T-score and the fracture risk assessment tool (FRAX) to underestimate risk in those with diabetes. Diabetes duration, complications and poor glycaemic control are useful clinical markers of increased fracture risk. Glucose-lowering agents may also affect fracture risk, independent of their effects on glycaemic control, as seen with the negative skeletal effects of the thiazolidinediones; in this review, the potential effects of glucose-lowering medications on fracture risk are discussed. Finally, the current understanding of effective fracture prevention in older adults with diabetes is reviewed.

Topics: Adult; Aged; Blood Glucose; Bone and Bones; Bone Density; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Fracture Healing; Fractures, Bone; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Odds Ratio; Risk Assessment; Sodium-Glucose Transporter 2; Thiazolidinediones; Treatment Outcome

The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown.. To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these.. We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017.. We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these.. Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence using the GRADE instrument.. We included seven completed RCTs; about 98 participants were randomised to a DPP-4 inhibitor as monotherapy and 1620 participants were randomised to a GLP-1 analogue as monotherapy. Two trials investigated a DPP-4 inhibitor and five trials investigated a GLP-1 analogue. A total of 924 participants with data on allocation to control groups were randomised to a comparator group; 889 participants were randomised to placebo and 33 participants to metformin monotherapy. One RCT of liraglutide contributed 85% of all participants. The duration of the intervention varied from 12 weeks to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported.All-cause and cardiovascular mortality following treatment with GLP-1 analogues were rarely reported; one trial of exenatide reported that no participant died. Another trial of liraglutide 3.0 mg showed that 2/1501 in the liraglutide group versus 2/747 in the placebo group died after 160 weeks of treatment (very low-quality evidence).The incidence of T2DM following treatment with liraglutide 3.0 mg compared to placebo after 160 weeks was 26/1472 (1.8%) participants randomised to liraglutide versus 46/738 (6.2%) participants randomised to placebo (very low-quality evidence). The trial established the risk for (diagnosis of) T2DM as HbA1c 5.7% to 6.4% (6.5% or greater), fasting plasma glucose 5.6 mmol/L or greater to 6.9 mmol/L or less (7.0 mmol/L or greater) or two-hour post-load plasma glucose 7.8 mmol/L or greater to 11.0 mmol/L (11.1 mmol/L). Altogether, 70/1472 (66%) participants regressed from intermediate hyperglycaemia to normoglycaemia compared with 268/738 (36%) participants in the plac. There is no firm evidence that DPP-4 inhibitors or GLP-1 analogues compared mainly with placebo substantially influence the risk of T2DM and especially its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fasting; Glucagon-Like Peptide 1; Glucose Intolerance; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Metformin; Nitriles; Peptides; Pyrrolidines; Randomized Controlled Trials as Topic; Risk Factors; Venoms; Vildagliptin

Non-alcoholic fatty liver disease (NAFLD) is defined as hepatic steatosis exceeding 5% of hepatocytes with no other reason for hepatic fat accumulation. The association between NAFLD and type 2 diabetes is strong. Accordingly, up to 70% of obese patients with type 2 diabetes have NAFLD. The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis with variable degrees of fibrosis and cirrhosis. Cirrhosis is the end-stage of chronic liver disease and is characterised by diffuse fibrosis and nodular regeneration of hepatocytes. Alcoholic liver disease and NAFLD are the most common aetiologies of cirrhosis. The WHO estimates that 70% of patients with cirrhosis have impaired glucose tolerance and 30% have manifest diabetes. The latter is termed hepatic diabetes and is associated with increased complications to cirrhosis and hepatocellular carcinoma. The objective of this thesis was to study the impact of liver dysfunction on incretin and glucagon (patho)physiology in relation to glucose metabolism. We hypothesised that NAFLD patients with normal glucose tolerance would develop reduced incretin effect and that NAFLD would worsen the incretin effect in patients with existing type 2 diabetes. Thus, in study I, we investigated the incretin effect and glucagon secretion in patients with NAFLD with and without type 2 diabetes compared to controls. We also hypothesised that the incretin effect would be disturbed in non-diabetic patients with more severe liver disease. Hence, the objective of study II was to investigate the incretin effect in patients with cirrhosis. Finally, the hypothesis in study III was that an impaired glucagonostatic effect of GLP-1 contributes to the hyperglucagonaemia of patients with liver disease. We therefore explored the glucagonostatic properties of GLP-1 in non-diabetic patients with NAFLD. The results of study I show that patients with NAFLD have normal secretion of GLP-1 and GIP and a reduced incretin effect. The groups with type 2 diabetes have the lowest incretion effect. We also find that NAFLD patients have high fasting glucagon concentrations regardless of their glucose (in)tolerance. We further demonstrated that patients with normal glucose tolerance and NAFLD have preserved glucagon suppression to both oral and intravenous glucose.  In study II, we find that non-diabetic patients with cirrhosis have elevated concentrations of GLP-1 and GIP and a reduced incretin effect. Patients with cirrhosis also have f

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Humans; Incretins; Insulin; Liver; Mice; Non-alcoholic Fatty Liver Disease

In this communication we discuss the role of the gut for the development of type 2 diabetes mellitus (T2DM). Gastric emptying rates importantly determine postprandial glucose excursions and regulate postprandial secretion of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). It thereby also determines their powerful, amplifying effect on glucose-induced insulin secretion and thus the ability of the body to regulate glucose disposal. Although disturbances in gastric emptying are not consistent findings in type 2 diabetes, the incretin system is seriously impaired, probably associated with insulin resistance and obesity. Both of the incretin hormones lose (part of) their insulinotropic activity resulting, together with (genetically) defective beta cell function, in the impaired postprandial insulin secretion of T2DM. In addition, glucagon responses are inappropriately increased and importantly contribute to both fasting and postprandial hyperglycemia. This may involve stimulation by GIP, but evidence also points to a role of circulating amino acids, which are elevated due to steatosis-induced impaired glucagon-mediated hepatic clearance, in line with recent work suggesting that the alpha cells and the liver are linked in a close, amino acid-mediated feedback circuit. Thus, the gut plays an important role in the development of T2DM spurred by overeating and defective beta cells.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Emptying; Gastrointestinal Tract; Glucagon; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Intestines; Postprandial Period

A clinical appraisal of existing scientific literature sought to assess the need for long-term prospective epidemiological studies to investigate an increased cancer risk of anti-hyperglycemic medication in type 2 diabetes.. A focus statement was formulated as: "With a higher risk of cancers in patients with type 2 diabetes, all anti-hyperglycemic drugs should undergo long-term, prospective epidemiological studies for cancer risks." Field surveys were sent to practicing physicians and endocrinologists to identify the currently prevalent level of acceptance of this statement. Subsequently, a meeting with a six-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This publication reviews the publications and discussion points brought forth in this meeting and their effect on statement acceptance by the panel.. Whereas the majority of field survey responders primarily agreed with the statement, panel members were divided in their statement support. This division remained intact after review of the literature.. While there was evidence that type 2 diabetes is associated with an increased risk of cancer, existing studies seemed insufficient to definitively demonstrate a link between cancer risk and use of specific anti-hyperglycemic therapies.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Neoplasms; Risk Factors; Thiazolidinediones

Metabolic disorders are common in patients with chronic hepatitis C virus (HCV) infection. Epidemiologic and clinical data indicate an overprevalence of lipids abnormalite, steatosis, insuline resistance (IR) and diabetes mellitus in HCV patients, suggesting that HCV itself may interact with glucido-lipidic metabolism. HCV interacts with the host lipid metabolism by several mechanisms leading to hepatic steatosis and hypolipidemia which are reversible after viral eradication. Liver and peripheral IR are HCV genotype/viral load dependent and improved after viral eradication. This article examines examine the relationship between HCV, lipid abnormalities, steatosis, IR, and diabetes and the pathogenic mechanisms accounting for these events in HCV-infected patients.

Topics: Animals; Cytokines; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Liver; Hepacivirus; Hepatitis C, Chronic; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Mice; Prevalence; Risk Factors; Signal Transduction

The gastrointestinal tract - the largest endocrine network in human physiology - orchestrates signals from the external environment to maintain neural and hormonal control of homeostasis. Advances in understanding entero-endocrine cell biology in health and disease have important translational relevance. The gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) is secreted upon meal ingestion and controls glucose metabolism by modulating pancreatic islet cell function, food intake and gastrointestinal motility, amongst other effects. The observation that the insulinotropic actions of GLP-1 are reduced in type 2 diabetes mellitus (T2DM) led to the development of incretin-based therapies - GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors - for the treatment of hyperglycaemia in these patients. Considerable interest exists in identifying effects of these drugs beyond glucose-lowering, possibly resulting in improved macrovascular and microvascular outcomes, including in diabetic kidney disease. As GLP-1 has been implicated as a mediator in the putative gut-renal axis (a rapid-acting feed-forward loop that regulates postprandial fluid and electrolyte homeostasis), direct actions on the kidney have been proposed. Here, we review the role of GLP-1 and the actions of associated therapies on glucose metabolism, the gut-renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Risk Factors

Insulin secretagogues including sulfonylureas, glinides and incretin-related drugs such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists are widely used for treatment of type 2 diabetes. In addition, glucokinase activators and G-protein-coupled receptor 40 (GPR40) agonists also have been developed, although the drugs are not clinically usable. These different drugs exert their effects on insulin secretion by different mechanisms. Recent advances in β-cell signalling studies have not only deepened our understanding of insulin secretion but also revealed novel mechanisms of insulin secretagogues. Clarification of the signalling mechanisms of the insulin secretagogues will contribute to improved drug therapy for diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Drugs, Investigational; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Models, Biological; Signal Transduction

Personalized management of diabetes has become an imperative since majority of monotherapy fails within 3 years of its use. Identifying responders from nonresponders for a certain type of therapy would reduce a period of unsuccessful treatment and minimize health care costs. Incretin therapies, mainly glucagon-like peptide (GLP)-1 receptor agonists (GLP- 1RA) are relatively new glucose-lowering agents which increase insulin and lower glucagon response as well as slow down glucose absorption by acting on gastric emptying. However, problem with incretin- based therapy is distinguishing responders from non-responders and currently lack of specific predictors of treatment response.. Experimental data demonstrated that activation of GLP-1 and gastrin signaling induces beta cell neogenesis, leading to glucose-dependent insulin secretion. Several studies demonstrated better glycemic control in patients with type 2 diabetes (DMT2) co-treated with proton pump inhibitors (PPI) and incretin based therapy agents.. Higher gastrin levels in patients with diabetes prior to initiation of treatment with incretin mimetics could suggest a better potential for reversible human β-cell reprogramming with concomitant incretin therapy. Therefore, baseline levels of endogenous gastrin could be used as a predictor of response to GLP-1 therapy. In addition, treatment with PPI could also raise gastrin levels and in patients treated with GLP-1RA, lead to better glycemic control by initiating β-cell neogenesis and proliferation of pancreatic β-cells.

Topics: B-Lymphocytes; Biomarkers; Diabetes Mellitus, Type 2; Gastrins; Humans; Incretins; Predictive Value of Tests; Treatment Outcome

Two of the most popular bariatric procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), are commonly considered metabolic surgeries because they are thought to affect metabolism in a weight loss-independent manner. In support of this classification, improvements in glucose homeostasis, insulin sensitivity, and even discontinuation of type 2 diabetes mellitus (T2DM) medication can occur before substantial postoperative weight loss. The mechanisms that underlie this effect are unknown. However, one of the common findings after VSG and RYGB in both animal models and humans is the sharp postprandial rise in several gut peptides, including the incretin and satiety peptide glucagonlike peptide-1 (GLP-1). The increase in endogenous GLP-1 signaling has been considered a primary pathway leading to postsurgical weight loss and improvements in glucose metabolism. However, the degree to which GLP-1 and other gut peptides are responsible for the metabolic successes after bariatric surgery is continually debated. In this review we discuss the mechanisms underlying the increase in GLP-1 and its potential role in the metabolic improvements after bariatric surgery, including remission of T2DM. Understanding the role of changes in gut peptides, or lack thereof, will be crucial in understanding the critical factors necessary for the metabolic success of bariatric surgery.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus, Type 2; Gastrectomy; Glucagon-Like Peptide 1; Humans; Incretins; Metabolism; Obesity; Postprandial Period

The secretion of insulin and glucagon from the pancreas and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract is essential for glucose homeostasis. Several novel treatment strategies for type 2 diabetes (T2D) mimic GLP-1 actions or inhibit incretin degradation (DPP4 inhibitors), but none is thus far aimed at increasing the secretion of endogenous incretins. In order to identify new potential therapeutic targets for treatment of T2D, we performed a meta-analysis of a GWAS and an exome-wide association study of circulating insulin, glucagon, GIP, and GLP-1 concentrations measured during an oral glucose tolerance test in up to 7,828 individuals. We identified 6 genome-wide significant functional loci associated with plasma incretin concentrations in or near the SLC5A1 (encoding SGLT1), GIPR, ABO, GLP2R, F13A1, and HOXD1 genes and studied the effect of these variants on mRNA expression in pancreatic islet and on metabolic phenotypes. Immunohistochemistry showed expression of GIPR, ABO, and HOXD1 in human enteroendocrine cells and expression of ABO in pancreatic islets, supporting a role in hormone secretion. This study thus provides candidate genes and insight into mechanisms by which secretion and breakdown of GIP and GLP-1 are regulated.

Topics: ABO Blood-Group System; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Enteroendocrine Cells; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Genetic Variation; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-2 Receptor; Glucose; Glucose Tolerance Test; Homeodomain Proteins; Humans; Incretins; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Middle Aged; Prospective Studies; Receptors, Gastrointestinal Hormone; RNA, Messenger; Sodium-Glucose Transporter 1

Glucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events.. MEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804-0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757-0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830-1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759-1.023; p = 0.097), HF (RR: 0.967; CI: 0.803-1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807-1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625-1.199; p = 0.385).. Treatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality.

Topics: Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Risk Assessment; Risk Factors; Signal Transduction; Treatment Outcome

Patients with type 2 diabetes mellitus (T2DM) experience many cardiovascular complications. Several studies have demonstrated the cardioprotective effects of incretin-based therapies; however, there are few studies on the effects of long-term incretin-based therapies on cardiovascular events. Therefore, the present study conducted a systematic review and network meta-analysis to evaluate the effects of long-term incretin-based therapies on ischaemic diseases. We searched PubMed, CENTRAL, and Clinicaltrial.gov to retrieve randomised control trials reported until December 2016 and enrolled only RCTs with more than a 1-year follow-up. The network meta-analysis was performed using R Software with a GeMTC package. A total of 40 trials were included. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 agonists were associated with a lower risk of myocardial infarction (MI) than were sulfonylureas (odds ratio [95% credible interval] 0.41 [0.24-0.71] and 0.48 [0.27-0.91], respectively). These results suggested that patients with T2DM receiving long-term incretin-based therapies have a lower risk of MI than do those receiving sulfonylurea-based therapy. These findings highlight the risks of cardiovascular events in patients who receive long-term incretin-based therapies, and may provide evidence for the selection of antidiabetic therapy in the future.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Myocardial Ischemia; Publication Bias; Risk Factors; Time Factors

Topics: Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Protective Agents

Bone is a tissue with multiple functions that is built from the molecular to anatomical levels to resist and adapt to mechanical strains. Among all the factors that might control the bone organization, a role for several gut hormones called "incretins" has been suspected. The present review summarizes the current evidences on the effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in bone physiology.

Topics: Animals; Bone and Bones; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Osteoblasts; Osteoclasts; Receptors, Gastrointestinal Hormone; Stress, Mechanical

Diabetes is a major risk factor for heart failure (HF). Patients with diabetes have a high incidence of both clinical HF and subclinical LV dysfunction. Although intensive glucose lowering does not appear to impact on HF outcomes, the choice of glucose-lowering agents plays an important role in the development of HF and related cardiovascular outcomes. Whilst metformin and insulin appear to have little impact on HF progression, the role of sulphonylurea agents in this patient population remains uncertain. Thiazolidinediones (TZDs) are associated with a significant risk of HF progression and are best avoided in patients at risk. The incretin-based therapies (GLP agonists and DPP-4 inhibitors) are generally not associated with any HF interaction. However, a small increase in HF admissions was observed with the DPP-4 inhibitor saxagliptin. The GLP-1 agonist liraglutide was recently shown to reduce cardiovascular and all-cause mortality, yet hospitalization for HF was not significantly reduced. The SGLT2 inhibitor empagliflozin was shown to reduce HF admissions and cardiovascular mortality in patients with prior cardiovascular disease including HF. These recent data showing improved outcomes with a glucose-lowering category provide a novel strategy to improve survival and reduce morbidity in diabetic patients at high cardiovascular disease risk.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Incretins; Insulin; Mortality; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones

Since 2005, several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been approved to treat people with type 2 diabetes. These agents are considered for use at the same point in the treatment paradigm as basal insulins. A comprehensive comparison of these drug classes, therefore, can help inform treatment decisions. This systematic review and meta-analysis assessed the clinical efficacy and safety of GLP-1 RAs compared with basal insulins.. MEDLINE, EMBASE, CENTRAL and PubMed databases were searched. Randomized clinical trials (RCTs) of ≥16 weeks' duration comparing GLP-1 RAs vs basal insulins in adults with type 2 diabetes inadequately controlled with oral antihyperglycemic drugs were included. Data on the change from baseline to 26 weeks (±10 weeks) of treatment in hemoglobin A1c (HbA1c) and weight, as well as the proportion of patients experiencing hypoglycaemia, were extracted. Fixed-effect pairwise meta-analyses were conducted where data were available from ≥2 studies.. Fifteen RCTs were identified and 11 were meta-analysed. The once-weekly GLP-1 RAs, exenatide long acting release (LAR) and dulaglutide, led to greater, statistically significant mean HbA1c reductions vs basal insulins (exenatide: -0.31% [95% confidence interval -0.42, -0.19], dulaglutide: -0.39% [-0.49, -0.29]) whilst once-daily liraglutide and twice-daily exenatide did not (liraglutide: 0.06% [-0.06, 0.18], exenatide: 0.01% [-0.11, 0.13]). Mean weight reduction was seen with all GLP-1 RAs while mean weight gain was seen with basal insulins. Interpretation of the analysis of hypoglycaemia was limited by inconsistent definitions and reporting. Because of the limited number of available studies sensitivity analyses to explore heterogeneity could not be conducted.. Although weight reduction is seen with all GLP-1 RA's, only the once-weekly agents, exenatide LAR and dulaglutide, demonstrate significant HbA1c reductions when compared to basal insulins.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Peptides; Recombinant Fusion Proteins; Venoms

To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM).. Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared.. Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P < .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ -1.8 mmol/L, P < .0001). GLP-1 RAs reduced bodyweight more effectively (Δ -3.71 kg; P < .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP-1 RAs ( P < .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight.. Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs.

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Fasting; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Peptides; Treatment Outcome; Venoms

Diabetes is a well-established pro-inflammatory state with an increased risk for cardiovascular (CV) diseases. In recent years, the number of different classes of agents for the treatment of type 2 diabetes has increased substantially, and while glycemic control is the major focus of these medications, CV safety has become of interest. Two incretin-based therapies are currently available: glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors.. The literature was reviewed for information regarding the incretin-based therapies and their effects on the CV system.. Independent of their glucose-lowering action, incretin-based therapies may have incretin-dependent mechanisms that positively affect blood pressure, weight, and other markers of CV disease risk, and, in the case of DPP-4 inhibition, nonincretin-dependent actions such as improving endothelial function. Several CV outcomes trials (CVOTs) with incretin-based therapies have recently completed with no excess CV risk observed, and positive effects have been reported in at least 1 trial of GLP-1 RAs, with more studies ongoing. Results for the risk for heart failure with DPP-4 inhibitor use are mixed, but no increase has been demonstrated with GLP-1 RAs.. Future CVOTs will need to be redesigned to help address these questions in the context of the emerging scope of the underlying mechanisms of cardio-metabolic disease in populations with diabetes.. A1C = hemoglobin A1C ACS = acute coronary syndrome CHD = coronary heart disease CI = confidence interval CV = cardiovascular CVOT = Cardiovascular Outcome Trial DPP-4 = dipeptidyl peptidase 4 FDA = U.S. Food and Drug Administration GIP = glucose-dependent insulinotropic polypeptide GLP-1 = glucagon-like protein 1 GLP-1 RA = glucagon-like protein 1 receptor agonist HF = heart failure HR = hazard ratio LVEF = left ventricular ejection fraction MACE = major adverse cardiovascular events MI = myocardial infarction T2D = type 2 diabetes.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Treatment Outcome

Regulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are evaluated to show that they do not increase cardiovascular (CV) risk.. A systematic review was undertaken to evaluate the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). The National Institutes of Health Medline database was searched for pooled analyses, meta-analyses, and randomized controlled trials (RCTs) of DPP-4 inhibitors and GLP-1 receptor agonists that included CV endpoints.. Thirty-six articles met the inclusion criteria encompassing 11 pooled analyses, 17 meta-analyses, and eight RCTs (including secondary analyses). Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT CV outcome studies. In four RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.. Overall, incretin therapy does not appear to increase risk for MACE in the short term.

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Meta-Analysis as Topic; Peptides; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Uracil

The purpose of this study was to review the results of clinical trials assessing the cardiovascular effects of drugs for type 2 diabetes and the cardiovascular effects of newer available drugs.. We performed a detailed search of PubMed-listed publications, reports from international meetings, and ongoing studies from clinical trials.gov.. Currently available drugs have neutral or, in some cases, negative effects on cardiovascular outcomes. Modern sulfonylureas appear to be safe, although the biguanide metformin has a slightly better cardiovascular safety profile than the sulfonylureas and is the first choice for monotherapy. The cardiovascular tolerability of thiazolidinediones (glitazones) remains controversial, with particularly adverse effects in patients with cardiac failure. The cardiovascular effects of insulin in type 2 diabetes appear neutral. Newer incretin-based therapies have been closely examined in a large number of clinical trials, some of which are still ongoing. The dipeptidyl peptidase-4 inhibitor (gliptins) trials to date have all found a neutral effect. Of the glucagon-like peptide-1 (GLP-1) agonists, lixisenatide had a neutral effect, whereas liraglutide and semaglutide had a benefit on outcomes. The results of the sodium-glucose transporter-2 (SGLT-2) inhibitor empaglifozin attracted interest when it was the first to report a strong benefit on cardiovascular mortality. Liraglutide and semaglutide had a neutral effect on cardiac failure admissions, whereas empaglifozin had a benefit. In each of the trials, there was not a clear effect on myocardial infarction and stroke. The mechanism of the cardiovascular benefit is debated, and further studies with other GLP-1 agonists and SGLT-2 inhibitors are awaited.. After 2 decades of disappointment in attempting to control cardiovascular progression in type 2 diabetes with careful glycemic control, there is distinct hope that newer drugs, particularly the GLP-1 agonists and the SGLT-2 inhibitors, will have cardiovascular benefits independent of glycemic control.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones

Topics: Cardiovascular Diseases; Comorbidity; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incretins; Male; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Survival Rate; Treatment Outcome

There is a relative lack of long-term data for individual glucose-lowering therapies for the treatment of type 2 diabetes mellitus. A systematic search of published literature reporting data of approximately ≥3 years of follow-up from randomized controlled trials and their extensions was conducted. Trials to evaluate the efficacy and/or safety of glucose-lowering drugs currently approved for the treatment of adults with type 2 diabetes were included. Search results included long-term published data for traditional oral glucose-lowering drugs, insulin, α-glucosidase inhibitors, and incretin-based therapies. In general, results indicated that the short-term risk/benefit profile of these therapies is in line with longer-term evaluations. Individual results from these trials are reviewed in this report. These findings support the use of approved drug classes for longer-term treatment of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Follow-Up Studies; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Randomized Controlled Trials as Topic; Risk Assessment; Sulfonylurea Compounds; Thiazolidinediones

To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes.. We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis.. A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from -0.55% and -0.73 mmol/L, respectively, for lixisenatide to -1.21% and -1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting.. The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Liraglutide; Male; Middle Aged; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome; Venoms

Infusion of oxyntomodulin and the separate and combined infusion of GLP-1 and glucagon inhibited food intake similarly in healthy individuals, with no superior effect of combining GLP-1 and glucagon. We confirm the inhibitory effects of oxyntomodulin and GLP-1, respectively, on GE and appetite scores observed previously, but by adding glucagon to the infusion of GLP-1 we found no additive effects. Unexpectedly, glucagon alone had no effect on GE and appetite scores, but inhibited food intake to the same extent as oxyntomodulin, GLP-1 and GLP-1 + glucagon. Both the GLP-1, oxyntomodulin and GLP-1 + glucagon infusions appeared to increase O

Topics: Animals; Appetite; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Oxyntomodulin; Peptide Fragments

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Global Health; Humans; Incidence; Incretins; Randomized Controlled Trials as Topic; Survival Rate

As type 2 diabetes mellitus progresses, most patients require treatment with basal insulin in combination with another agent to achieve recommended glycaemic targets. The purpose of this systematic review was to examine the evidence supporting the use of the available add-on treatments [rapid-acting insulin (RAI), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors] to basal insulin.. MEDLINE, EMBASE and EBSCOhost were searched for English-language articles, and all those captured were original articles (case studies and narrative reviews were omitted). Data on study design, population demographics, interventions and outcomes were tabulated. The extracted outcome data included changes in glycated haemoglobin (HbA. A total of 88 publications were deemed relevant. All treatments reduced HbA. The evidence supports effectiveness of the available add-on treatments to basal insulin. However, other factors, such as potential body-weight increases, convenience/compliance and adverse events, particularly hypoglycaemia, should be considered on a patient-by-patient basis to optimalize treatment outcomes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Routes; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Incretin-based agents, including dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 agonists (GLP-1As), work via GLP-1 receptor for hyperglycemic control directly or indirectly, but have different effect on cardiovascular (CV) outcomes. The present study is to evaluate and compare effects of incretin-based agents on CV and pancreatic outcomes in patients with type 2 diabetes mellitus (T2DM) and high CV risk.. Six prospective randomized controlled trials (EXMAINE, SAVOR-TIMI53, TECOS, ELIXA, LEADER and SUSTAIN-6), which included three trials for DPP-4Is and three trials for GLP-1As, with 55,248 participants were selected to assess the effect of different categories of incretin-based agents on death, CV outcomes (CV mortality, major adverse CV events, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization), pancreatic events (acute pancreatitis and pancreatic cancer) as well as on hypoglycemia.. When we evaluated the combined effect of six trials, the results suggested that incretin-based treatment had no significant effect on overall risks of CV and pancreatic outcomes compared with placebo. However, GLP-1As reduced all-cause death (RR = 0.90, 95% CI 0.82-0.98) and CV mortality (RR = 0.84, 95% CI 0.73-0.97), whereas DPP-4Is had no significant effect on CV outcomes but elevated the risk for acute pancreatitis (OR = 1.76, 95% CI 1.14-2.72) and hypoglycemia (both any and severe hypoglycemia), while GLP-1As lowered the risk of severe hypoglycemia.. GLP-1As decreased risks of all-cause and CV mortality and severe hypoglycemia, whereas DPP-4Is had no effect on CV outcomes but increased risks in acute pancreatitis and hypoglycemia.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Pancreatitis; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Recently, cardiovascular outcome trials with glucose-lowering drugs used in type 2 diabetes mellitus, namely glucagon-like peptide-1 receptor agonists (GLP-1RA), liraglutide and semaglutide, showed a reduction in cardiovascular events, which had not been observed in trials with other incretin-based drugs, such as lixisenatide or with dipeptidyl peptidase-4 inhibitors (DPP4i). Mechanisms underlying the observed cardiovascular differences between DPP4i and GLP1-RA, and across individual GLP1-RA are poorly understood. This review is aimed at collecting and summarizing available evidence from experimental and mechanistic studies on the action of GLP1-RA and DPP4i on the cardiovascular system, both deriving from clinical and pre-clinical sources. The results of cardiovascular outcome trials are interpreted on the basis of the experimental preclinical data available, paying particular attention to the heart failure results, and suggesting some novel intriguing hypotheses to explain some of the unexpected findings of cardioprotection of incretin-based drugs. In particular, we discuss the possible contribution to the incretin cardiovascular effects of a direct cardiac action of GLP-1 metabolites through GLP-1 receptor-independent pathways, and of DPP4 substrates other than GLP-1.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Incretins; Liraglutide; Treatment Outcome

In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the known incretin hormones in humans, released predominantly from the enteroendocrine K and L cells within the gut. Their secretion is regulated by a complex of integrated mechanisms involving direct contact for the activation of different chemo-sensors on the brush boarder of K and L cells and several indirect neuro-immuno-hormonal loops. The biological actions of GIP and GLP-1 are fundamental determinants of islet function and blood glucose homeostasis in health and type 2 diabetes. Moreover, there is increasing recognition that GIP and GLP-1 also exert pleiotropic extra-glycaemic actions, which may represent therapeutic targets for human diseases. In this review, we summarise current knowledge of the biology of incretin hormones in health and metabolic disorders and highlight the therapeutic potential of incretin hormones in metabolic regulation.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Liver; Obesity

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in Western societies. Despite its significance, there are no well-proven pharmacological treatments. Two novel classes of potential pharmacotherapies are the glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4I), collectively known as incretin-based therapies. These have several metabolic and anti-inflammatory actions that may be of benefit in NAFLD. The aim of this meta-analysis was to evaluate their efficacy via a structured retrieval and pooled analysis of relevant studies.. Studies were sourced from electronic databases and meeting abstracts. Main inclusion criteria were original studies investigating treatment of adults with NAFLD using GLP-1 RA/DPP-4I. Key outcomes were a change in serum alanine transaminase (ALT), as a marker of liver inflammation, and improvement in disease status measured by imaging or histology.. Initial searching retrieved 1357 peer-reviewed articles and abstracts. Four studies met all inclusion and exclusion criteria. There were a total of 136 participants with NAFLD and concomitant type 2 diabetes mellitus (T2DM). Meta-analysis (random-effects model) revealed a significant decrease in serum ALT following treatment (mean reduction 14.1 IU/L, 95% confidence intervals [CI] 8.3-19.8, P < 0.0001). In two studies with imaging and tissue data, treatment was found to significantly reduce steatosis, inflammation, and fibrosis.. The significant decrease in a key biochemical marker of hepatic inflammation following treatment with incretin-based therapies, as well as improvements in imaging and histology, suggests these agents may be effective options for managing NAFLD with comorbid T2DM.

Topics: Alanine Transaminase; Anti-Inflammatory Agents; Biomarkers; Comorbidity; Databases, Bibliographic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Non-alcoholic Fatty Liver Disease; Treatment Outcome

The two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1), were discovered 45 and 30 years ago. Initially, only their insulinotropic effect on pancreatic β cells was known. Over the years, physiological and pharmacological effects of GIP and GLP1 in numerous extrapancreatic tissues were discovered which partially overlap, but may also be specific for GIP or GLP1 in certain target tissues. While the insulinotropic effect of GIP was found to be blunted in patients with type 2 diabetes, the function of GLP1 is preserved and GLP1 receptor agonists and dipeptidyl-peptidase 4 (DPP4) inhibitors, which prolong the half-life of incretins, are widely used in diabetes therapy. Wild-type and genetically modified rodent models have provided important mechanistic insights into the incretin system, but may have limitations in predicting the clinical efficacy and safety of incretin-based therapies. This review summarizes insights from rodent and non-rodent models (pig, non-human primate) into physiological and pharmacological incretin effects, with a focus on the pancreas. Similarities and differences between species are discussed and the increasing potential of genetically engineered pig models for translational incretin research is highlighted.

Topics: Animals; Animals, Genetically Modified; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Liraglutide; Mice; Mice, Knockout; Primates; Receptors, Gastrointestinal Hormone; Rodentia; Swine

Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in β-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells

The objective of this review was to summarize and integrate specific clinical observations from the field of gastric bypass surgery and recent findings in beta cell biology. When considered together, these data sets suggest a previously unrecognized physiological mechanism which may explain how Roux-en-Y gastric bypass (RYGB) surgery mediates the early rapid reversal of hyperglycemia, observed before weight loss, in certain type 2 diabetes mellitus (T2DM) patients. The novel mechanism is based on a recently recognized inhibitory circuit of glucose stimulated insulin secretion driven by DA stored in β-cell vesicles and the gut. We propose that DA and glucagon-like peptide 1 (GLP-1) represent two opposing arms of a glucose stimulated insulin secretion (GSIS) regulatory system and hypothesize that dopamine represents the "anti-incretin" hypothesized to explain the beneficial effects of bariatric surgery on T2DM. These new hypotheses and the research driven by them may directly impact our understanding of: 1) the mechanisms underlying improved glucose homeostasis seen before weight loss following bariatric surgery; and 2) the regulation of glucose stimulated insulin secretion within islets. On a practical level, these studies may result in the development of novels drugs to modulate insulin secretion and/or methods to quantitatively asses in real time beta cell function and mass.

Topics: Diabetes Mellitus, Type 2; Dopamine; Gastric Bypass; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Obesity

The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches and falls below target levels. This may account for the sub-optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight-neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once-daily co-formulations of a basal insulin and a glucagon-like peptide-1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed-ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Peptides; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.

Topics: Adamantane; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Piperidines; Sitagliptin Phosphate; Uracil

In type 2 diabetes (T2D), treatment is optimised to minimise hyperglycaemia and the risk of microvascular complications. While there are a number of effective treatments, intensive treatment is associated with negative side effects such as increased hypoglycaemia and weight gain. With complementary modes of action, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and a basal insulin in combination offer an alternative to basal-bolus therapy in T2D. This review describes the rationale behind this treatment combination and presents clinical data available for IDegLira, the first basal insulin (insulin degludec) and GLP-1RA (liraglutide) co-formulation available in one pen for a single injection daily.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Injections; Insulin Resistance; Insulin, Long-Acting; Liraglutide; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, which affects millions of people worldwide. The disease is characterized by chronically elevated blood glucose concentrations (hyperglycaemia), which result in comorbidities and multi-organ dysfunction. This is due to a gradual loss of glycaemic control as a result of increasing insulin resistance, as well as decreasing β-cell function. The objective of T2DM drug interventions is, therefore, to reduce fasting and postprandial blood glucose concentrations to normal, healthy levels without hypoglycaemia. Several classes of novel antihyperglycaemic drugs with various mechanisms of action have been developed over the past decades or are currently under clinical development. The development of these drugs is routinely supported by the application of pharmacokinetic/pharmacodynamic modelling and simulation approaches. They integrate information on the drug's pharmacokinetics, clinically relevant biomarker information and disease progression into a single, unifying approach, which can be used to inform clinical study design, dose selection and drug labelling. The objective of this review is to provide a comprehensive overview of the quantitative approaches that have been reported since the 2008 review by Landersdorfer and Jusko in an increasing order of complexity, starting with glucose homeostasis models. Each of the presented approaches is discussed with respect to its strengths and limitations, and respective knowledge gaps are highlighted as potential opportunities for future drug-disease model development in the area of T2DM.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucokinase; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Models, Biological; Receptors, G-Protein-Coupled; Receptors, Glucagon; Sodium-Glucose Transporter 2 Inhibitors

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Kidney

Patients with type 2 diabetes mellitus are at risk for accelerated cognitive decline and dementia. Furthermore, their risk of stroke is increased and their outcome after stroke is worse than in those without diabetes. Incretin-based therapies are a class of antidiabetic agents that are of interest in relation to these cerebral complications of diabetes. Two classes of incretin-based therapies are currently available: the glucagon-like-peptide-1 agonists and the dipeptidyl peptidase-4 -inhibitors. Independent of their glucose-lowering effects, incretin-based therapies might also have direct or indirect beneficial effects on the brain. In the present review, we discuss the potential of incretin-based therapies in relation to dementia, in particular Alzheimer's disease, and stroke in patients with type 2 diabetes. Experimental studies on Alzheimer's disease have found beneficial effects of incretin-based therapies on cognition, synaptic plasticity and metabolism of amyloid-β and microtubule-associated protein tau. Preclinical studies on incretin-based therapies in stroke have shown an improved functional outcome, a reduction of infarct volume as well as neuroprotective and neurotrophic properties. Both with regard to the treatment of Alzheimer's disease, and with regard to prevention and treatment of stroke, randomized controlled trials in patients with or without diabetes are underway. In conclusion, experimental studies show promising results of incretin-based therapies at improving the outcome of Alzheimer's disease and stroke through glucose-independent pleiotropic effects on the brain. If these findings would indeed be confirmed in large clinical randomized controlled trials, this would have substantial impact.

Topics: Animals; Clinical Trials as Topic; Dementia; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Stroke

The incretin effect describes the phenomenon whereby oral glucose elicits higher insulin secretory responses than does intravenous glucose, despite inducing similar levels of glycaemia, in healthy individuals. This effect, which is uniformly defective in patients with type 2 diabetes, is mediated by the gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The importance of the incretin effect for the maintenance of glucose homoeostasis is clearly established, and incretin-based therapies are among the most promising new therapies for type 2 diabetes. However, despite the effectiveness of these therapies in many patients, the idea that they restore the incretin effect is a common misconception. In type 2 diabetes, the endocrine pancreas remains responsive to GLP-1 but is no longer responsive to GIP, which is the most likely reason for a reduced or absent incretin effect. Incretin-based drugs, including GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, stimulate GLP-1 receptors and thus augment insulin secretion in response to both oral and intravenous glucose stimulation, thereby abolishing any potential difference in the responses to these stimuli. These drugs therefore do not restore the defective incretin effect in patients. By contrast, some bariatric surgical procedures enhance GLP-1 responses and also restore the incretin effect in obese individuals with type 2 diabetes. Thus, not all biological actions elicited by the stimulation of GLP-1 receptors lead to quantitative changes to the incretin effect.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Insulin secretory defects are a key feature in the pathophysiology of type 2 diabetes (T2D). Classical insulin-secreting agents such as sulfonlyureas stimulate insulin secretion independent of glucose and cause hypoglycemia. Despite the advantages offered by incretin-based therapies, there is still a medical need for developing new insulin secretagogues for treating T2D.. This article discusses: the new advances in the field of incretin-based therapies, glucokinase (GK) activators, free fatty acid receptor (FFAR) or G protein-coupled receptor (GPR) agonists (GPR40, GPR119, GPR120), imeglimin and some other insulin secretagogues with diverse mechanisms of action still in preclinical development.. New insulin secretagogues should offer major advantages over sulfonylureas and gliptins. The challenge is to avoid uncontrolled insulin secretion and minimize the risk of hypoglycemia, to protect cells from progressive loss of mass and function for a better durability of glucose control, and to offer a good safety profile. Numerous approaches are in development. However, it is too early to decide whether one new pharmacological class will emerge as a clinically useful insulin secretagogue in the near feature.

Topics: Animals; Diabetes Mellitus, Type 2; Drugs, Investigational; Glucokinase; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Potassium Channel Blockers; Receptors, G-Protein-Coupled

This brief review describes the potential non-glycaemic effects and benefits of glucagon like peptide 1 receptor agonists (GLP1RA). It lists various indications in which this class of drugs has been used, and explains the rationale behind this use. The potential uses of GLP1RA extend across the entire spectrum of endocrinology and metabolism, from hypothalamic obesity to non-alcoholic steatohepatitis (NASH) to polycystic ovary syndrome (PCOS). The article also discusses and addresses endocrine-related concerns related to the GLP1RAs.

Topics: Bone and Bones; Central Nervous System; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Gonads; Humans; Hypothalamic Diseases; Incretins; Liraglutide; Liver; Male; Non-alcoholic Fatty Liver Disease; Obesity; Ovary; Peptides; Polycystic Ovary Syndrome; Psoriasis; Testis; Thyroid Gland; Venoms

Incretin-based therapies are effective glucose-lowering drugs that have an increasing role in the treatment of type 2 diabetes because of their efficacy, safety, and ease of use. Both glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used for glycemic control as adjuncts to metformin, other oral antiglycemic agents, or insulin. Glucagon-like peptide-1 receptor agonists may have additional effects, such as weight loss, that may be advantageous in obese patients. There is a large body of evidence from randomized controlled clinical trials supporting the cardiovascular safety of dipeptidyl peptidase-4 inhibitors and some glucagon-like peptide-1 receptor agonists, at least in the short term. However, concerns have been raised, particularly regarding their safety in patients with heart failure. In this review, the authors provide a brief but practical evidence-based analysis of the use of incretin-based agents in patients with diabetes, their efficacy, and cardiovascular safety.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Incretins; Practice Guidelines as Topic; Treatment Outcome

In the last couple of years incretin-based antidiabetic drugs became increasingly popular and widely used for treating patients with type 2 diabetes. Immediately after launching, case reports and small case series were published on the potential side effects of the new drugs, with special attention to pancreatic disorders such as acute pancreatitis or pancreatic cancer. As clinical observations accumulated, these side-effects were noted with nearly all drugs of this class. Although these side-effects proved to be rare, an intensive debate evolved in the literature. Opinion of diabetes specialists and representatives of pharmaceutical industry as well as position statements of different international scientific boards and health authorities were published. In addition, results of randomized clinical trials with incretin-based therapy and meta-analyses became available. Importantly, in everyday clinical practice, the label of the given drug should be followed. With regards to incretins, physicians should be cautious if pancreatitis in the patients' past medical history is documented. Early differential diagnosis of any abdominal pain during treatment of incretin-based therapy should be made and the drug should be discontinued if pancreatitis is verified. Continuous post-marketing surveillance and side-effect analysis are still justified with incretin-based antidiabetic treatment in patients with type 2 diabetes.

Topics: Abdominal Pain; Acute Disease; Diabetes Mellitus, Type 2; Diagnosis, Differential; Drug-Related Side Effects and Adverse Reactions; Humans; Hypoglycemic Agents; Incretins; Meta-Analysis as Topic; Pancreatic Neoplasms; Pancreatitis; Randomized Controlled Trials as Topic; Risk Factors

Recent cardiovascular outcome trials of incretin-based therapies (IBT) in type 2 diabetes have not demonstrated either benefit or harm in terms of major adverse cardiovascular events (MACE). Earlier meta-analyses showed conflicting results but were limited in methodology. We aimed to perform an updated meta-analysis of all available incretin therapies on the incidence of MACE plus arrhythmia and heart failure.. We identified studies published through November 2014 by searching electronic databases and reference lists. We included RCTs in which the intervention group received incretin-based therapies and the control group received placebo or standard treatment; enrolled >100 participants in each group; interventions lasted >24 weeks; and reported data on one or more primary major adverse cardiovascular events endpoints plus terms for arrhythmia and heart failure. We used the Peto method for each CV event for individual IBT treatment.. In this meta-analysis of 100 RCTs involving 54,758 incretin-based therapies users and 48,175 controls, exenatide was associated with increased risk of arrhythmia (OR 2.83; 95% CI, 1.06-7.57); saxagliptin was associated with an increased risk of heart failure (OR 1.23; 95% CI, 1.03-1.46), and sitagliptin was associated with a significantly decreased risk of all cause death compared to active controls (OR 0.39, 95% CI 0.18-0.82).. In type 2 diabetes, exenatide may increase the risk of arrhythmia, and sitagliptin may reduce the risk of all cause death; however, the subgroup of patients most likely to experience harm or benefit is unclear. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Arrhythmias, Cardiac; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Incretins; Prognosis; Randomized Controlled Trials as Topic

In the last ten years, knowledge on pathophysiology of type 2 diabetes (T2DM) has significantly increased, with multiple failures (decreased incretin effect, increased lipolysis, increased glucagon secretion, neurotransmitters dysfunction) recognized as important contributors, together with decreased insulin secretion and reduced peripheral glucose uptake. As a consequence, the pharmacologic therapy of T2DM has been progressively enriched by several novel classes of drugs, trying to overcome these defects. The last, intriguing compounds come into the market are SGLT2 inhibitors, framing the kidney in a different scenario, not as site of a harmful disease complication, but rather as the means to correct hyperglycemia and fight the disease. This review aims to offer a short, updated overview of the role of these compounds in the treatment of T2DM, focusing on efficacy, ancillary albeit relevant clinical effects, safety, potential cardiovascular protection, positioning in common therapeutic algorithms.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Kidney; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Several randomized, controlled clinical trials were initiated some years ago in order to evaluate the cardiovascular safety of the new antidiabetic drugs in patients with type 2 diabetes due to requirements from regulatory bodies. Four trials with incretin-based drugs (saxagliptin, alogliptin, sitagliptin and lixisenatide) have been completed so far. Based on the primary outcome endpoints of these trials no cardiovascular risks were found with incretins in patients with type 2 diabetes. As for saxagliptin, the hospitalization for heart failure was investigated as a secondary endpoint, and an increased risk was observed in the respective trial; however, this observation was widely debated later in the literature. Together with ongoing trials of other novel antihyperglycemic agents, these data will provide more robust evidence about the cardiovascular safety of incretin-based antidiabetic treatment in patients with type 2 diabetes.

Topics: Adamantane; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Evidence-Based Medicine; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Peptides; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Time Factors; Uracil

To assess the cardiovascular (CV) risk associated with the use of incretin-based therapy in adult patients with type 2 diabetes mellitus (T2DM) primary prevention group with low CV risks.. The clinical studies on incretin-based therapy published in medical journals until August 2014 were comprehensively searched using MEDLINE, EMBASE and CENTRAL with no language restriction. The studies were systemically reviewed and evaluated for CV risks using a meta-analysis approach and where they meet the following criteria: clinical trial, incidence of predefined CV disease, T2DM with no comorbidities, age > 18 years old, duration of at least 12 weeks, incretin-based therapy compared with other antihyperglycaemic agents or placebo. Statistical analyses were performed using a Mantel-Haenszel (M-H) test. The odds ratios (OR) and their 95% confidence interval (CI) were estimated and displayed for comparison.. A total of 75 studies comprising 45,648 patients with T2DM were selected. The pooled estimate demonstrated no significance in decreased CV risk with incretin-based therapy versus control (M-H OR, 0.90; 95% CI, 0.81-1.00).. This meta-analysis suggests that incretin-based therapy show no significant protective effect on CV events in T2DM primary prevention group with low CV risks. Prospective randomized controlled trials are required to confirm the results of this analysis.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Risk

Incretins are gastrointestinal-derived hormones released in response to a meal playing a key role in the regulation of postprandial secretion of insulin (incretin effect) and glucagon by the pancreas. Both incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), have several other actions by peripheral and central mechanisms. GLP-1 regulates body weight by inhibiting appetite and delaying gastric, emptying actions that are dependent on central nervous system GLP-1 receptor activation. Several other hormones and gut peptides, including leptin and ghrelin, interact with GLP-1 to modulate appetite. GLP-1 is rapidly degraded by the multifunctional enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 is involved in adipose tissue inflammation, which is associated with insulin resistance and diabetes progression, being a common pathophysiological mechanism in obesity-related complications. Furthermore, the incretin system appears to provide the basis for understanding the high weight loss efficacy of bariatric surgery, a widely used treatment for obesity, often in association with diabetes. The present review brings together new insights into obesity pathogenesis, integrating GLP-1 and DPP-4 in the complex interplay between obesity and inflammation, namely, in diabetic patients. This in turn will provide the basis for novel incretin-based therapeutic strategies for obesity and diabetes with promising benefits in addition to weight loss. © 2016 World Obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Obesity; Weight Loss

The gut incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion and regulate glucagon secretion. GLP-1 also slows gastric emptying and suppresses appetite, whereas GIP seems to affect lipid metabolism. The introduction of selective GLP-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has increased the scientific and clinical interest in incretins. Combining the body weight-lowering and glucose-lowering effects of GLP-1 with a more potent improvement of β cell function through additional GIP action could potentially offer a more effective treatment of diabetes and obesity, with fewer adverse effects than selective GLP-1R agonists; therefore, new drugs designed to co-activate both the GIP receptor (GIPR) and the GLP-1R simultaneously are under development. In the present review, we address advances in the field of GIPR and GLP-1R co-agonism and review in vitro studies, animal studies and human trials involving co-administration of the two incretins, as well as results from a recently developed GIPR/GLP-1R co-agonist, and highlight promising areas and challenges within the field of incretin dual agonists.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; In Vitro Techniques; Incretins; Insulin; Insulin-Secreting Cells; Obesity; Receptors, Gastrointestinal Hormone; Weight Loss

Incretin effect enhancers are drugs used in the treatment of Type 2 diabetes and include GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors (gliptins). Variants in several genes were shown to be involved in the physiology of incretin secretion. Only two gene variants have evidence also from pharmacogenetic studies. TCF7L2 rs7903146 C>T and CTRB1/2 rs7202877 T>G minor allele carriers were both associated with a smaller reduction in HbA1c after gliptin treatment when compared with major allele carriers. After replication in further studies, these observations could be of clinical significance in helping to identify patients with potentially lower or higher response to gliptin treatment.

Topics: Chymotrypsin; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; KCNQ1 Potassium Channel; Pharmacogenomic Testing; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Transcription Factor 7-Like 2 Protein

The alarming prevalence of type 2 diabetes mellitus (T2DM) stimulated the exploitation of new antidiabetic drugs with extended durability and enhanced safety. In this regard, the free fatty acid receptor 1 (FFA1) and FFA4 have emerged as attractive targets in the last decade. FFA1 has prominent advantages in promoting insulin and incretin secretion while FFA4 shows great potential in incretin secretion, insulin sensitization and anti-inflammatory effects.. Herein, the authors focus specifically on FFA1 and FFA4 agonists in clinical trials and preclinical development. LY2922470, P11187 and SHR0534 are currently active in clinical trials while the CNX-011-67, SAR1, DS-1558 and BMS-986118 are in preclinical phase. The information for this review is retrieved from Integrity, Scifinder, Espacenet and clinicaltrials.gov databases.. Current proof-of-concept in clinical trials suggests that FFA1 agonists have a significant improvement for T2DM without the risk of hypoglycemia. However, there are still several challenging problems including the mechanism of the receptor and the efficacy and safety of the ligands.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Design; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Receptors, G-Protein-Coupled

Agents introduced into therapy of type 2 diabetes in the last few years are still the subject of numerous clinical and experimental studies. Although many studies have been completed, we still do not know all aspects of these drugs' action, especially the long-term effects of their use. Most questionable is their impact on the processes of cell proliferation, on the cardiovascular and immune systems, on lipids and uric acid metabolism. A summary of the most important observations on the use of three groups of new drugs - analogs of glucagon-like peptide 1 (GLP-1), inhibitors of dipeptidyl peptidase IV (DPPIV) and inhibitors of sodium glucose cotransporters (SGLT1 and SGLT2) - has been made, based on a review of the literature over the past five years (2010-2014). The information included in the present review concerns the structure and activity relationship, therapeutic efficacy, side effects and the observed additional therapeutic effects, which can determine new standards in therapy of diabetes and also facilitate the development of better antidiabetic drugs.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Type 2 diabetes in East Asians is characterized primarily by β-cell dysfunction, and with less adiposity and less insulin resistance compared with that in Caucasians. Such pathophysiological differences can determine the appropriate therapeutics for the disease. Incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted in response to meal ingestion, and enhance insulin secretion glucose-dependently. Incretin-based drugs, dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists, that ameliorate β-cell dysfunction with limited hypoglycemia risk are now widely used in type 2 diabetes management. Recent meta-analyses of clinical trials on DPP-4i and glucagon-like peptide-1 receptor agonists found that the drugs were more effective in Asians, most likely because of amelioration of β-cell dysfunction. In addition, we found increased glycated hemoglobin-lowering effects of DPP-4i to be associated with intake of fish in type 2 diabetes, which suggests that dietary customs of East Asians might also underlie the greater efficacy of DPP-4i. Despite the limited risk, cases of severe hypoglycemia were reported for DPP-4i/sulfonylureas combinations. Importantly, hypoglycemia was more frequent in patients also receiving glibenclamide or glimepiride, which activate exchange protein directly activated by cyclic adenosine monophosphate 2, a critical mediator of incretin signaling, and was less frequent in patients receiving gliclazide, which does not activate exchange protein directly activated by cyclic adenosine monophosphate 2. Prevention of insulin-associated hypoglycemia by DPP-4i has gained attention with regard to the enhancement of hypoglycemia-induced glucagon secretion by insulinotropic polypeptide, but remains to be investigated in East Asians. Despite the safety issues, which are paramount and must be carefully monitored, the incretin-based drugs could have potential as a first choice therapy in East Asian type 2 diabetes patients.

Topics: Animals; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Mice; Rats; Risk Factors; Sulfonylurea Compounds; Treatment Outcome

Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes. Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target tissue sensitivity to GLP-1. The present article critically reviews the possible mechanisms by which metformin may affect GLP-1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose-lowering actions of metformin.

Topics: Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Metformin

Bariatric surgery has been found to be very useful in treating established type-2 diabetes in obese persons, as well as in borderline diabetics, besides giving a good weight loss. Various modifications of the primary bariatric procedures have been introduced, with differ advantages and better efficacy. Good incretin responses from the distal gut give the best results and combining medical treatment are helping patients to get very good glycemic control over a longer term.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Humans; Incretins; Obesity

Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer's disease (AD) and Parkinson's disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases.

Topics: Animals; Diabetes Mellitus, Type 2; Exenatide; Gastric Inhibitory Polypeptide; Humans; Hypoglycemic Agents; Incretins; Neurodegenerative Diseases; Peptides; Venoms

To review the current literature for the efficacy and safety of available treatments for type 2 diabetes (T2DM) in the pediatric population.. A search from January 1990 to April 2016 was conducted using PubMed and clinicaltrials.gov using the search terms diabetes mellitus, type 2; adolescent; child; and pediatric Bibliographies of chosen articles were reviewed.. Relevant articles and preliminary data from clinical trials on metformin, insulin, sulfonylureas, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and α-glucosidase inhibitors for the treatment of pediatric T2DM were reviewed. Studies included randomized controlled, observational, and open-label designs.. Metformin, studied in 4 of the reviewed trials, and premixed insulin appear to be safe and effective in pediatric patients with T2DM. TZDs were well tolerated and yielded favorable results, but may have limited applicability. A sulfonylurea had favorable hemoglobin A1C reduction, but was associated with significant weight gain. Studies of incretin-based agents also showed favorable results in the pediatric population but have limited safety and efficacy data. Several trials for other agents are reported on clinicaltrials.gov with unpublished results, but no statistical analyses are reported.. Metformin and insulin remain the mainstay of treatment for T2DM in pediatric patients. More robust studies are needed to assist in the provision of evidence-based guidance for the treatment of T2DM in youth.

Topics: Adolescent; Child; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Sulfonylurea Compounds; Thiazolidinediones; Weight Gain

Obesity and its associated complications like type 2 diabetes (T2D) are reaching epidemic stages. Increased food intake and lack of exercise are two main contributing factors. Recent work has been highlighting an increasingly more important role of gut microbiota in metabolic disorders. It's well known that gut microbiota plays a major role in the development of food absorption and low grade inflammation, two key processes in obesity and diabetes. This review summarizes key discoveries during the past decade that established the role of gut microbiota in the development of obesity and diabetes. It will look at the role of key metabolites mainly the short chain fatty acids (SCFA) that are produced by gut microbiota and how they impact key metabolic pathways such as insulin signalling, incretin production as well as inflammation. It will further look at the possible ways to harness the beneficial aspects of the gut microbiota to combat these metabolic disorders and reduce their impact.

Topics: Diabetes Mellitus, Type 2; Fatty Acids, Volatile; Gastrointestinal Microbiome; Gastrointestinal Tract; Gene Expression Regulation; Humans; Incretins; Inflammation; Insulin; Intestinal Absorption; Lipid Metabolism; Obesity; Signal Transduction

Controversy exists regarding the selection of second-line therapy for patients with type 2 diabetes mellitus (T2DM) who are unable to achieve glycemic control with metformin therapy alone. Newer pharmacologic treatments for T2DM include glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Both the classes of medication are efficacious, exhibit positive effects on weight, and are associated with minimal risk of hypoglycemia. The purpose of this review is to compare the clinical trial and real-world effectiveness data of glucagon-like peptide-1 receptor agonists versus sodium-glucose cotransporter 2 inhibitors related to A1c reduction, weight loss, cost-effectiveness, cardiovascular outcomes, and safety in patients with T2DM. This review summarizes comparative evidence for providers who are determining which of the two classes may be the most appropriate for a specific patient.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Costs; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Kidney Tubules, Proximal; Patient Selection; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome; Weight Loss

Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Diabetes treatments aim at preventing undesirable metabolic effects of hyperglycemia and at preventing/reducing tissue damage, including cardiovascular (CV) events. For approval, novel diabetes drugs undergo early systematic investigation to assess CV safety. This review provides an updated analysis of the results of recent studies examining novel diabetes medications and CV outcomes.. The new regulatory guidelines enforce adjudication of all CV events when testing novel diabetes drugs. Endpoints of CV mortality, myocardial infarction (MI), stroke and hospitalization for heart failure (HF) were included in the most recent clinical studies on novel antihyperglycemics. These are: the incretin mimetics glucagon-like peptide 1 (GLP-1) receptor agonists (GLP1-RA), the incretin enhancers dipeptidylpeptidase-4 (DPP-4) inhibitors (DPP4-I or gliptins), and the sodium-glucose cotransporter (SGLT2) inhibitors (SGLT2-I or gliflozins). The studies ELIXA and EXAMINE, testing lixisenatide and alogliptin, respectively, revealed non-inferiority versus placebo in terms of CV safety. The SAVOR-TIMI 53 results confirmed overall CV safety of saxagliptin, but raised a warning related to the increase in the risk of hospitalization for HF in the saxagliptin group. Recently, TECOS revealed a particularly favorable CV profile for sitagliptin while EMPA-REG showed a significant CV risk reduction in empagliflozin treated subjects. Ongoing studies will provide additional data on CV safety for other GLP1-RAs, DPP4-I and SGLT2-I.. Results of safety outcome studies focused on CV events, including HF and mortality for CV causes, are not homogeneous. A critical analysis of these studies may help cardiologists and diabetes specialists to adapt their therapeutic choices to individual patients.

Topics: Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucosides; Humans; Hypoglycemic Agents; Incretins; Patient Safety; Patient Selection; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Treatment Outcome

The increased risk of cardiovascular disease in patients with type 2 diabetes has been known for many years. However, until recently the cardiovascular (CV) impact of glucose lowering strategies has been inadequately understood. Major clinical trials have now investigated the impact of intensification of glycemic control upon CV outcomes, as well as the CV effects of glucose management with newer antihyperglycemic agents.. Key findings from recently completed CV outcomes trials of dipeptidyl peptidase-4 (DPP4) inhibitors, GLP-1 receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors completed thus far are reviewed and summarized.. Multiple trials designed to meet regulatory requirements for CV safety of antihyperglycemic medications have been initiated. The results of several completed CV outcomes trials clarify the risks and benefits associated with newer medications used to manage hyperglycemia in patients with type 2 diabetes, particularly in individuals at high CV risk. Important differences have been noted with respect to heart failure outcomes within the DPP4 inhibitor class, and thus far one agent in the SGLT2 inhibitor class has been found to significantly reduce rates of important CV outcomes. Robust safety related information from trials designed to assess the CV effects of diabetes therapies will permit the incorporation of outcomes-based evidence into the formulation of diabetes care guidelines.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Patient Safety; Patient Selection; Risk Assessment; Risk Factors; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.

Topics: Administration, Oral; Comorbidity; Diabetes Mellitus, Type 2; Genotype; Humans; Hypoglycemic Agents; Incretins; Mental Disorders; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Polymorphism, Genetic; Treatment Outcome

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials.

Topics: Algorithms; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Receptors, Glucagon; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

The. review gives data on the prognostic value of genetic markers when analyzing the risk of chronic kidney disease in diabetes mellitus, those on new possibilities of early diagnosis of diabetic nephropathy using urinary biomarkers (nephrinuria, podocinuria) and proteomic urinalysis at the stage of normoalbuminuria. The interpretation of the index mrcroalbuminuria in type 2 diabetesis critically analyzed. The nephroprotective properties of novel classes of glucose-lowering drugs, such as incretins and gliflozins, are considered.. В обзоре представлены данные о прогностической ценности генетических маркеров при анализе риска развития хронической болезни почек при сахарном диабете, о новых возможностях ранней диагностики диабетической нефропатии с использованием биомаркеров мочи (нефринурия, подоцинурия) и протеомного анализа мочи на стадии нормоальбуминурии. Дан критический анализ интерпретации показателя микроальбуминурии при сахарном диабете 2-го типа. Рассмотрены нефропротективные свойства новых классов сахароснижающих препаратов - икретинов и глифлозинов.

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Early Diagnosis; Humans; Hypoglycemic Agents; Incretins; Prognosis; Protective Agents; Proteomics

The effect of glucagon-like peptide-1 (GLP-1) treatment in patients with type 2 diabetes mellitus (T2DM) remains controversial. The purpose of this study was to compare the effect of GLP-1 and placebo/conventional antidiabetic agents on cardiovascular risk in T2DM patients. PubMed, EmBase and the Cochrane Library were searched to identify its eligible studies as well as manual searches for the reliability of this study. All eligible trials were performed in T2DM patients who received GLP-1 therapy or placebo/conventional antidiabetic agents. The reported outcomes included major cardiovascular events (MACE), and total mortality. Of 490 identified studies, we included 13 trials reporting data on 11,943 T2DM patients. Overall, the pooled results suggested that GLP-1 therapy has no or little effect on MACE (RR: 0.99; 95% CI: 0.88-1.12; P=0.872) and total mortality (RR: 0.90; 95% CI: 0.70-1.15; P=0.399). Furthermore, sensitivity analysis indicated that GLP-1 was associated with lower incidence of total mortality (RR: 0.28; 95% CI: 0.08-0.93; P=0.037). We concluded that GLP-1 therapy was not associated with MACE and total mortality compared with placebo or antidiabetic agents.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Global Health; Glucagon-Like Peptide 1; Humans; Incretins; Randomized Controlled Trials as Topic; Reproducibility of Results; Survival Rate

The pharmacokinetics and pharmacodynamics of antidiabetic therapies for patients with type 2 diabetes are often altered in the context of chronic kidney disease (CKD).. Systematic review and meta-analysis.. Patients with type 2 diabetes and CKD.. 2 reviewers independently screened studies identified through bibliographic databases (Cochrane Library, PubMed, Embase, International Pharmaceutical Abstracts), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Eligible studies included randomized controlled trials evaluating incretin-based therapy in adults with type 2 diabetes and estimated glomerular filtration rates < 60mL/min/1.73m. Incretin-based therapies (dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists) compared to placebo or active antidiabetic therapies.. Changes in glycated hemoglobin (HbA. Of 1,619 nonduplicate records screened, 13 studies were included. Compared to placebo, incretin-based therapies significantly reduced HbA. Variation among interventions, small number of studies, heterogeneity between studies, and high risk for attrition bias in 7 of the selected studies.. In patients with moderate or severe CKD, incretin-based therapies are effective in reducing HbA

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Incretins; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Treatment Outcome

Incretin based glucagon-like peptide-1 receptor (GLP-1R) agonists which target a G-protein coupled receptor (GPCR) are currently used in the treatment of type 2 diabetes. This review focuses on GPCRs from pancreatic β-cells, including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon, somatostatin, pancreatic polypeptide (PP), cholecystokinin (CCK), peptide YY (PYY), oxyntomodulin (OXM) and ghrelin receptors. In addition, fatty acids GPCRs are thought to have an increasing role in regulating peptide secretions namely short fatty acids GPCR (GPR41, GPR43), medium chain fatty acid GPCR (GPR84), long chain fatty acid GPCR (GPR40, GPR120) and cannabinoid-like GPCR (GPR55, GPR119). Several pre-clinical and clinical trials are currently ongoing in peptide GPCR based therapies, including dual and triple agonist peptides which activate two or more GPCRs simultaneously.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Design; Fatty Acids; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Ligands; Peptides; Receptors, G-Protein-Coupled

To identify the determinants of efficacy of glucagon-like peptide-1 receptor agonists (GLP-1A) and dipeptidyl peptidase-4 inhibitors (DPP-4I).. MEDLINE and EMBASE were searched between 01/01/2011 and 15/08/2014 for randomized controlled trials of 12-52weeks' duration, which reported the change in glycated hemoglobin (HbA1c) from baseline as the primary end point, and reported data about predictors of efficacy of incretins.. Among 4172 studies found, 77 studies reported data on baseline HbA1c, age, sex, ethnicity, body mass index (BMI), and history of diabetes in relation to change in HbA1c. For DPP-4I, 37 out of 47 studies reported a greater decrease in HbA1c among patients with higher baseline HbA1c. Most DPP-4I studies reported no variation in efficacy in regard to demographic characteristics or BMI. Among 17 studies reporting on GLP-1A, baseline higher HbA1c was reported as predictive of a greater response in 7 out of 9 studies; 13 studies reported data about other factors, without consistent findings.. Current evidence suggests that higher baseline HbA1c is associated with a greater efficacy of both DPP-4I and GLP-1A therapies in lowering HbA1c. The roles of other potential predictors are less consistent across studies and require further investigation.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Male; Treatment Outcome

In recent years, many studies have related gut microbiome to development of highly prevalent diseases such as type 2 diabetes and obesity. Obesity itself is associated to changes in the composition of gut microbiome, with a trend to an overgrowth of microorganisms more efficiently obtaining energy from diet. There are several mechanisms that relate microbiota to the onset of insulin resistance and diabetes, including changes in bowel permeability, endotoxemia, interaction with bile acids, changes in the proportion of brown adipose tissue, and effects associated to use of drugs like metformin. Currently, use of pro and prebiotics and other new techniques such as gut microbiota transplant, or even antibiotic therapy, has been postulated to be useful tools to modulate the development of obesity and insulin resistance through the diet.

Topics: Adipose Tissue, Brown; Bacterial Physiological Phenomena; Butyrates; Diabetes Mellitus, Type 2; Disease Susceptibility; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Metabolic Syndrome; Microbiota; Obesity; Prebiotics; Probiotics; Species Specificity

Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

Topics: Accidental Falls; Bone Density; Bone Remodeling; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fractures, Bone; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors

Type 2 diabetes (T2D) is a major worldwide public health concern. Despite a large armamentarium of T2D medications, a large proportion of patients fail to achieve recommended treatment goals for glycemic control. Weight loss has profound beneficial effects on the metabolic abnormalities involved in the pathogenesis of T2D. Accordingly, bariatric surgery, which is the most effective available weight loss therapy, is also the most effective therapy for treating patients with T2D. Surgical procedures that bypass the upper gastrointestinal (UGI) tract are particularly effective in achieving partial and even complete remission of T2D, suggesting that UGI bypass has weight loss-independent effects on glycemic control. Although a number of hypotheses (e.g. a role for multiorgan insulin sensitivity, β-cell function, incretin response, the gut microbiome, bile acid metabolism, intestinal glucose metabolism and browning of adipose tissue) have been proposed to explain the potential unique effects of UGI tract bypass surgery, none has yet been adequately evaluated to determine therapeutic importance in patients with T2D. Here, we review the efficacy of UGI bypass surgery in treating T2D and the mechanisms that have been proposed to explain its potential weight loss-independent therapeutic effects.

Topics: Adipose Tissue; Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Intestinal Mucosa; Microbiota; Obesity; Remission Induction; Weight Loss

Bariatric surgery (e.g. Roux-en-Y gastric bypass (RYGB)) has proven the most effective way of achieving sustainable weight losses and remission of type 2 diabetes (T2D). Studies indicate that the effectiveness of RYGB is mediated by an altered gastrointestinal tract anatomy, which in particular favours release of the gut incretin hormone glucagon-like peptide-1 (GLP-1). The EndoBarrier gastrointestinal liner or duodenal-jejunal bypass sleeve (DJBS) is an endoscopic deployable minimally invasive and fully reversible technique designed to mimic the bypass component of the RYGB. Not only GLP-1 is released when nutrients enter the gastrointestinal tract. Cholecystokinin (CCK), secreted from duodenal I cells, elicits gallbladder emptying. Traditionally, bile acids are thought of as essential elements for fat absorption. However, growing evidence suggests that bile acids have additional effects in metabolism. Thus, bile acids appear to increase GLP-1 secretion via activation of the TGR5 receptor on the intestinal L cell. Recently FXR receptors were postulated to contribute to GLP-1 secretion too. Furthermore, metformin has been shown to increase circulating GLP-1 levels but although the exact mechanism is not fully elucidated it may involve metformin-induced inhibition of bile acid reuptake from the small intestines. Small-sized studies reported varying degrees of weight loss and, in some, improvement of glucose metabolism. Therefore, the objectives of this thesis were to collect existing information on the DJBS in order to evaluate clinical efficacy and safety (study I and II). Furthermore, since the endocrine impact of the DJBS is not fully elucidated, and DJBS is expected to mimic RYGB, we investigated postprandial metabolic changes following 26 weeks of DJBS treatment in ten obese subjects with normal glucose tolerance (NGT) and nine matched patients with T2D (study III). Finally, we studied the single and combined effects of CCK induced gallbladder emptying and single-dose metformin on human GLP-1 secretion in ten healthy subjects (study IV). We hypothesized that metformin-induced GLP-1 secretion - at least partly - would be dependent on gallbladder emptying and the presence of bile acids in the gut. DJBS appears to lead to moderate weight losses in obese subjects compared to diet or lifestyle modifications (study II). DJBS had insignificant and small effects (compared to diet) on glycaemic regulation. Adverse events consisted mainly of mild-to-moderate tr

Topics: Animals; Bariatric Surgery; Bile Acids and Salts; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Incretins; Metformin; Obesity; Weight Loss

DPP-4 inhibitors are a class of compounds used for the treatment of type 2 diabetes. The drugs inhibit the degradation of GLP-1, thus amplifying the incretin effect. They have moderate glycemic efficacy, a low propensity of causing hypoglycaemia and are weight neutral. The drugs are often used as second line therapy after metformin. Areas covered: This review summarizes the available compounds in the market and discusses the novel compounds that are currently under development. Several large cardiovascular outcome trials with some of the compounds have been completed, and their results and implications are considered. Fixed dose combination pills are currently the main focus of research and the contribution of these to the care of patients with diabetes is further discussed. Expert opinion: The DPP-4 inhibitors have been a successful class in drug development for diabetes. Taken orally and available as fixed dose combinations with metformin or with SGLT-2 inhibitors, they have reached a large market share of over 7 billion dollars. Other than retagliptin, it does not appear that any additional compound will be launched soon. Currently, the main focus is on the development of additional fixed dose combinations with SGLT-2 inhibitors, but the success of these combinations remains to be seen.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Metformin; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug's pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users.

Topics: Acidosis, Lactic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Kidney Transplantation; Metformin; Renal Insufficiency; Sulfonylurea Compounds; Thiazolidinediones

Concerns raised by several animal studies, case reports, and pharmacovigilance warnings over incretin-based therapy potentially exposing type two diabetes patients to an elevated risk of pancreatitis have cast a shadow on the overall safety of this class of drugs. This systematic review evaluates the data from observational studies that compared treatment with or without incretins and the risk of pancreatitis. We searched PubMed for publications with the key terms incretins or GLP-1 receptor agonists or DPP-4 inhibitors or sitagliptin or vildagliptin or saxagliptin or linagliptin or alogliptin or exenatide or liraglutide AND pancreatitis in the title or abstract. Studies were evaluated against the following criteria: design (either cohort or case-control); outcome definition (incidence of pancreatitis); exposure definition (new or current or past incretins users); and comparison between patients receiving incretins or not for type 2 diabetes. Two authors independently selected the studies and extracted the data. Six studies meeting the inclusion criteria were reviewed. No difference was found in the overall risk of pancreatitis between incretin users and non-users (odds ratio 1.08; 95 % CI [0.84-1.40]). A risk increase lower than 35 % cannot be excluded according to the power calculation. This systematic review and meta-analysis suggests that type 2 diabetes patients receiving incretin-based therapy are not exposed to an elevated risk of pancreatitis. Limitations of this analysis are the low prevalence of incretin users and the lack of a clear distinction by the studies between therapy with DPP-4 inhibitors or with GLP-1 receptor agonists.

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Observational Studies as Topic; Pancreatitis

The increasing prevalence of obesity and type 2 diabetes mellitus (T2DM) has led to a growing interest in the investigation of new therapies. Treatment of T2DM has focused on the insulinopenia and insulin resistance. However, in the last 10 years, new lines of research have emerged for the treatment of T2DM and preclinical studies appear promising. The possibility of using these drugs in combination with other currently available drugs will enhance the antidiabetic effect and promote weight loss with fewer side effects. The data provided by post-marketing monitoring will help us to better understand their safety profile and potential long-term effects on target organs, especially the cardiovascular risk.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diacylglycerol O-Acyltransferase; Dipeptidyl Peptidase 4; Drug Therapy, Combination; Drugs, Investigational; Enzyme Inhibitors; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucokinase; Gluconeogenesis; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Insulin, Long-Acting; Molecular Targeted Therapy; Obesity; Phosphofructokinase-2; Sodium-Glucose Transport Proteins; Weight Loss

To investigate the real-world incidence of acute pancreatitis (AP) associated with incretin-based therapy (IBT).. We carried out a systematic review and meta-analysis of observational studies using Medline, PubMed, Embase, the Cochrane Database, ClinicalTrials.gov and conference proceedings. We included: those studies in which AP was a pre-defined clinical outcome; longitudinal studies (case-control, cohort); studies that adjusted for confounders; studies that reported on a population exposed to IBT; studies in which non-IBT users or past users (who received IBTs >90 days before the index date) were used as the control group; studies that reported risk estimates [relative risks, odds ratios (ORs) or hazard ratios] with 95% confidence intervals (CIs) for AP event with IBT use, or that reported sufficient data to estimate these; and publications in the English language. Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study-specific ORs from seven cohort studies and two case-control studies were meta-analysed using random-effects models. Associations were tested in subgroups representing different patient characteristics and study quality.. A total of nine studies that included 1,324,515 patients and 5195 cases of AP were included in our meta-analysis. The summary estimate of OR for an association between IBT and AP was 1.03 (95% CI 0.87-1.20).. The present meta-analysis of real-world data does not suggest that IBT is associated with AP. Although we should continue to remain vigilant, IBTs should be regarded as reasonable options to consider adding to the regimen of a patient with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Observational Studies as Topic; Pancreatitis; Receptors, Glucagon; Risk Factors

The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Receptors, Glucagon; Renal Insufficiency, Chronic

Incretin-based therapies offer another treatment option for patients with type 2 diabetes. Agents that provide glycaemic control in addition to attenuating cardiovascular disease (CVD) risk factors are important for diabetes management. This review will focus on the off-target effects of incretin-based therapies on CVD risk factors [body weight, blood pressure (BP), lipid profile and albuminuria], major adverse cardiovascular events (MACE), heart failure (HF) and beta-cell preservation.. A literature search was conducted to identify English-language publications for incretin-based therapies evaluating the following off-target end-points: body weight, BP, lipid profile, albuminuria, MACE, HF and beta-cell function. Randomised controlled trials (RCTs) were prioritised as the primary source of information.. Overall, incretin-based therapies have shown beneficial effects on CVD risk factors, and glucagon-like peptide 1 (GLP-1) receptor agonists appear to have a more pronounced effect compared with dipeptidyl peptidase-4 inhibitors. RCTs are being conducted to determine if these positive effects on CVD risk factors translate to a reduction in MACE. To date, these studies have not shown an increase in MACE. A signal of increased hospitalisations for HF was observed with saxagliptin, warranting continued evaluation and vigilance in high-risk patients. In addition, incretin-based therapies have shown positive effects on measures of beta-cell function supporting their durability in the management of diabetes.. Incretin-based therapies are an important treatment option for patients with type 2 diabetes, offering beneficial effects on CVD risk factors without increasing MACE.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Treatment Outcome

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a new class of drugs used in the treatment of type 2 diabetes mellitus (T2DM). Gastrointestinal (GI) adverse events (AEs) are the most frequently reported treatment-related AEs for GLP-1 RAs. We aim to evaluate the effect of GLP-1 RAs on the incidence of GI AEs of T2DM.. The overview of the GI events of GLP-1 RAs has been performed on relevant publications through the literature search, such as MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov The manufacturer was contacted regarding unpublished data. We analyzed direct and indirect comparisons of different treatments using Bayesian network meta-analysis.. Taspoglutide 30 mg once weekly (TAS30QW) and lixisenatide 30 μg twice daily (LIX30BID) were ranked the top two drugs in terms of GI AEs versus placebo. The odds ratios of nausea and vomiting for TAS30QW were 11.8 (95% confidence interval [CI], 2.89, 46.9) and 51.7 (95% CI, 7.07, 415), respectively, and that of diarrhea was 4.93 (95% CI, 1.75, 14.7) for LIX30BID.. Our study found all GLP-1 RA dose regimens significantly increased the incidence of GI AEs, compared with placebo or conventional treatment. The occurrence of GI AEs was different with diverse dose regimens of GLP-1 RAs. TAS30QW had the maximum probability to occur nausea and vomiting, whereas LIX30BID had the maximum probability to cause development of diarrhea versus other treatments.

Topics: Diabetes Mellitus, Type 2; Diarrhea; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Middle Aged; Nausea; Peptides; Receptors, Glucagon; Vomiting

The role of incretins in glucose homeostasis is well known. Yet, in recent years, the sustained weight loss and rapid glycemic control following bariatric surgery has challenged our understanding of the intestinal-pancreatic interaction. This in turn led to the introduction of metabolic surgery, an innovative medical discipline in which a surgical manipulation of the gastrointestinal tract (e. g., through a Roux-en-Y gastric bypass, RYGB, or Bilio-Pancreatic-Diversion, BPD) yields a sustained remission of diabetes mellitus. The pathophysiological background of this metabolic effect is, amongst other things, based on the anti-incretin theory. This theory postulates that in addition to the well-known incretin effect, nutrient passage through the GI-tract could also activate negative feedback mechanisms (anti-incretins) to balance the effects of incretins and other postprandial glucose-lowering mechanisms (i. e., suppression of ghrelin, glucagon, and hepatic glucose production via activation of nutrient sensing). This in turn prevents postprandial hyperinsulinemic hypoglycemia. The bypass of the duodenum, the entire jejunum and the first portion of the ileum by BPD induce normalization of peripheral insulin sensitivity, while the bypass of a shorter intestinal tract by RYGB mainly improves the hepatic insulin sensitivity. In addition, RYGB greatly increases insulin secretion. Therefore, metabolic surgery highlights the important role of the small intestine in glucose homeostasis, while until few years ago, it was only the pancreas and the liver that were thought to represent the regulatory organs for glucose disposal.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin; Insulin Secretion; Intestinal Mucosa; Models, Biological; Pancreas

Non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and is more prevalent in patients with type 2 diabetes mellitus (T2DM). Incretin-based antidiabetic agents (glucagonlike peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors) are used in the treatment of T2DM but it is unclear whether they may also play a role in the management of NAFLD. We systematically reviewed the PubMed and Scopus database up to October 2014 and also hand-searched the references of the retrieved articles for studies evaluating the effects of these agents on NAFLD. In animal studies, both GLP-1 receptor agonists and DPP-4 inhibitors reduced transaminase activity and steatosis but their effects on liver inflammation were inconsistent and fibrosis was not assessed. In clinical studies, both agents consistently reduced transaminase activity and steatosis as assessed non-invasively. There are very limited data on the effects of incretin-based treatments on liver histology. In conclusion, GLP-1 receptor agonists and DPP-4 inhibitors appear to hold promise in patients with NAFLD but larger controlled studies with histological and clinical endpoints are needed to evaluate their effects in this population.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Non-alcoholic Fatty Liver Disease

Incretin-based therapies are steadily gaining clinical popularity, with many more products in the developmental pipeline. Current treatment recommendations incorporate GLP-1 RAs and DPP-4 inhibitors as important agents for consideration in the treatment of T2DM owing to their low hypoglycemia risk, ability to address postprandial hyperglycemia (DPP-4 inhibitors and short-acting GLP-1 RAs), and potential for weight reduction (GLP-1 RAs). These properties may likewise prove advantageous in older adults in whom hypoglycemia is particularly undesirable, although older adults may be more prone to the nausea and vomiting associated with GLP-1 RA therapy. Other safety issues for incretin-based therapies, such as pancreatitis, C-cell hyperplasia, and renal failure, should be considered when choosing an appropriate patient to receive such therapies. Ongoing CV outcome studies will further inform the health care community regarding the CV safety of incretin-based therapies. The availability of both short-acting and long-acting GLP-1 RAs currently allows practitioners to consider individualized blood glucose trends and therapeutic needs when choosing an optimal agent.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Monitoring; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Receptors, Glucagon; Treatment Outcome; Weight Loss

Hyperglycemia in patients with and without a prior history of diabetes is an independent marker of morbidity and mortality in critically and noncritically ill patients. Improvement of glycemic control with insulin therapy has been shown to reduce hospital complications in patients with diabetes, but also results in increased rates of hypoglycemia, which have been linked to poor outcomes. Thus, alternative treatment options that can normalize blood glucose levels without undue hypoglycemia are being sought. Incretin-based therapies, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, stimulate insulin secretion in a glucose-dependent fashion, thus not causing hypoglycemia. Alternative points of view exist regarding insulin versus incretin therapy for the care of these patients. We have brought together the authors on the opposite sides of this discussion with the objective of providing a rational synthesis on how to achieve the best possible control of glycemia in the hospital, using both standard insulin approaches and incretin-based therapies to improve patient outcomes. This review examines the benefits of incretin-based therapy in improving glycemic control in hospitalized patients with stress-induced diabetes and in diabetic patients in critical care and non-critical care settings.

Topics: Diabetes Mellitus, Type 2; Hospitalization; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin

The goal of this study was to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on lipid profiles in patients with type 2 diabetes.. The MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched from inception through October 31, 2013. Randomized controlled trials with available data were selected if they compared GLP-1 RAs with placebo and traditional antidiabetic drugs with a duration ≥8 weeks. The weighted mean difference for changes in lipid profiles was estimated by using the random effects model, and a network meta-analysis was performed to supplement direct comparisons.. Thirty-five trials with 13 treatments were included in the analysis. GLP-1 RAs decreased HDL-C with a range of -0.06 mmol/L (95% CI, -0.11 to -0.01) to -0.13 mmol/L (95% CI, -0.17 to -0.10) compared with thiazolidinediones, whereas thiazolidinediones were associated with a significant increase in HDL-C compared with placebo (0.09 mmol/L [95% CI, 0.06 to 0.12]). A significant reduction in LDL-C was detected for all GLP-1 RAs versus placebo (range, -0.08 to -0.16 mmol/L), insulin (range, -0.10 to -0.19 mmol/L), and thiazolidinediones (range, -0.16 to -0.24 mmol/L). Exenatide, liraglutide 1.8 mg once daily, and taspoglutide decreased total cholesterol with a range of -0.16 mmol/L (95% CI, -0.26 to -0.06) to -0.27 mmol/L (95% CI, -0.41 to -0.12) versus placebo and thiazolidinediones (range, -0.26 to -0.37 mmol/L). The decreased effect was more evident in exenatide long-acting release and liraglutide 1.8 mg once daily. A significant reduction in triglyceride levels was observed with liraglutide 1.8 mg once daily (-0.30 mmol/L [95% CI, -0.49 to -0.11]) and taspoglutide 20 mg once weekly (-0.17 mmol/L [95% CI, -0.31 to -0.01]) versus placebo.. GLP-1 RAs were associated with modest reductions in LDL-C, total cholesterol, and triglycerides but no significant improvement in HDL-C. Further evidence is needed to determine if improvements in lipid profiles might translate into reductions in cardiovascular outcomes.

Topics: Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Incretins; Insulin; Lipids; Liraglutide; Peptides; Thiazolidinediones; Venoms

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures despite increased body weight and normal or higher bone mineral density. The mechanisms by which T2DM increases skeletal fragility are unclear. It is likely that a combination of factors, including a greater risk of falling, regional osteopenia, and impaired bone quality, contributes to the increased fracture risk. Drugs for the treatment of T2DM may also impact on the risk for fractures. For example, thiazolidinediones accelerate bone loss and increase the risk of fractures, particularly in older women. In contrast, metformin and sulfonylureas do not appear to have a negative effect on bone health and may, in fact, protect against fragility fracture. Animal models indicate a potential role for incretin hormones in bone metabolism, but there are only limited data on the impact of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 agonists on bone health in humans. Animal models also have demonstrated a role for amylin in bone metabolism, but clinical trials in patients with type 1 diabetes with an amylin analog (pramlintide) have not shown a significant impact on bone metabolism. The effects of insulin treatment on fracture risk are inconsistent with some studies showing an increased risk and others showing no effect. Finally, although there is limited information on the latest class of medications for the treatment of T2DM, the sodium-glucose co-transporter-2 inhibitors, these drugs do not seem to increase fracture risk. Because diabetes is an increasingly common chronic condition that can affect patients for many decades, further research into the effects of agents for the treatment of T2DM on bone metabolism is warranted. In this review, the physiological mechanisms and clinical impact of diabetes treatments on bone health and fracture risk in patients with T2DM are described.

Topics: Bone and Bones; Bone Density; Bone Remodeling; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fractures, Bone; Hip Fractures; Humans; Hypoglycemic Agents; Incretins; Insulin; Islet Amyloid Polypeptide; Metformin; Sulfonylurea Compounds; Thiazolidinediones

To summarize evidence from and assess the quality of published systematic reviews evaluating the safety, efficacy and effectiveness of incretin-based medications used in the treatment of type 2 diabetes.. We identified systematic reviews of randomized controlled trials or observational studies published in any language that evaluated the safety and/or effectiveness of glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl-peptidase-4 (DPP-4) inhibitors. Data sources used include the Cochrane Library, PubMed, EMBASE, Web of Science, International Pharmaceutical Abstracts, table of contents of diabetes journals, and hand-searching of reference lists and clinical practice guidelines. The methodological quality of systematic reviews was independently assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Our study protocol was registered with PROSPERO (2013:CRD42013005149). The primary outcomes were pooled treatment effect estimates for glycaemic control, macrovascular and microvascular complications, and hypoglycaemic events.. We identified 467 unique citations of which 84 systematic reviews met our inclusion criteria. There were 51 reviews that evaluated GLP-1 receptor agonists and 64 reviews that evaluated DPP-4 inhibitors. The median (interquartile range) AMSTAR score was 6 (3) out of 11 for quantitative and 1 (1) for non-quantitative reviews. Among the 66 quantitative systematic reviews, there were a total of 718 pooled treatment effect estimates reported for our primary outcomes and 1012 reported pooled treatment effect estimates for secondary outcomes.. Clinicians and policy makers, when using the results of systematic reviews to inform decision-making with regard to round clinical care or healthcare policies for incretin-based medications, should consider the variability in quality of reviews.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Observational Studies as Topic; Randomized Controlled Trials as Topic; Review Literature as Topic

Owing to advances in transplant science, increasing numbers of patients are receiving solid organ transplantation. New onset diabetes after transplantation (NODAT) frequently develops in transplant patients and requires acute and often ongoing management of hyperglycemia. The metabolic derangements of NODAT are similar to those of classic type 2 diabetes, and treatment has typically followed diabetes standards of care. Best practices for NODAT management remain to be developed.. The mechanistic suitability of incretins to treat NODAT pathogenesis has been hitherto underappreciated. This review details the specific mechanistic value of incretins in patients with immunosuppression-associated hyperglycemia.. Corticosteroids have long been known to exert their effects on glucose metabolism by decreasing glucose utilization and enhancing hepatic gluconeogenesis. Corticosteroids also significantly and directly reduce insulin secretion, as do calcineurin inhibitors (CNIs), another commonly used group of immunosuppressive drugs that cause hyperglycemia and NODAT. The ability of incretins to counteract immunosuppressant-induced disruptions in insulin secretion suggest that the insulinotropic, glucagonostatic, and glucose-lowering actions of incretins are well suited to treat immunosuppressant-induced hyperglycemia in NODAT. Additional benefits of incretins include decreased glucagon levels and improved insulin resistance. In the case of glucagon-like peptide-1 (GLP-1) receptor agonists, weight loss is another benefit, countering the weight gain that is a common consequence of both hyperglycemia and transplantation. These benefits make incretins very attractive and deserving of more investigation.. Among diabetes treatment options, incretin therapies uniquely counteract immunosuppressant drugs' interference with insulin secretion. We propose an incretin-based treatment paradigm for NODAT management.

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Organ Transplantation

Sulfonylurea compounds have been basic elements of antidiabetic treatment in type 2 diabetes for a long time. However, with the introduction of incretin type insulin secretagogues it is often arises, whether is still there a place for sulfonylureas in the today's therapy. To answer this question the author overviews general pharmaceutical characteristics of the sulfonylurea compounds as well as individual particularities of the second generation derivatives used at present in Hungary. The author details also the most important differences between incretin type drugs - first of all dipeptidyl peptidase-4 inhibitors - and sulfonylureas. On the basis of available data it can be concluded in accordance with the latest international guidelines, that sulfonylureas have still role in the blood glucose lowering therapy of type 2 diabetes, though they became somewhat pushed back among insulin secretagogue type drugs. If a sulfonylurea compound is the drug of choice, it is important to select the appropriate molecule (in case of normal renal function gliclazide or glimepiride). It is also important to re-educate the patient, as well as to apply the minimal dose providing the desired glycaemic effect.. A szulfanilureavegyületek hosszú ideje a 2-es típusú diabetes vércukorcsökkentő kezelésének alapgyógyszerei. Az inkretin mechanizmusú antidiabetikumok megjelenésével azonban időről időre felmerül, van-e helye továbbra is e gyógyszercsoportnak napjaink terápiájában. A szerző áttekinti a szulfanilureák általános hatástani jellemzőit, s a Magyarországon forgalomban lévő második generációs származékok főbb sajátosságait. Kitér az inkretin hatású szerek, elsősorban a dipeptidil-peptidáz-gátlók és a szulfanilureák különbségeire. Megállapítja, hogy amint azt a legújabb kezelési irányelvek is tükrözik, a szulfanilureáknak ma is helye van a vércukorcsökkentő kezelésben, bár az inzulinszekretagóg szerek között a korábbinál hátrébb szorultak. Rendelésük esetén fontos a megfelelő készítményválasztás – rendezett vesefunkció esetén elsősorban gliclazid vagy glimepirid adása −, a cukorbeteg megfelelő edukálása, valamint a kívánt anyagcserehatást biztosító legkisebb dózis választása. Orv. Hetil., 2015, 156(13), 511–515.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gliclazide; Humans; Hungary; Hypoglycemic Agents; Incretins; Insulin; Sulfonylurea Compounds

Incretin-based therapies, including the use of incretin mimetics of glucagon-like peptide-1 receptor (GLP-1R) agonists and incretin enhancers of dipeptidyl-peptidase 4 (DPP-4) inhibitors, are widely used by clinicians for glucose lowering in patients with type 2 diabetes mellitus. These agents have benefits of a lower risk of hypoglycemia, being neutral for body weight for DPP-4 inhibitors and having a potential for weight reduction with GLP-1R agonists. They may also have a neutral or beneficial cardiovascular effect. Despite these benefits, an increased risk of cancer (especially pancreatic cancer and thyroid cancer) associated with incretin-based therapies has been reported. In this article, we reviewed related literature of experimental animal and observational human studies, clinical trials, and meta-analyses published until December 15, 2014. Current studies suggested a probable role of GLP-1R activation on the development of pancreatic cancer and thyroid cancer in rodents, but such an effect in humans is not remarkable due to the lower or lack of expression of GLP-1R on human pancreatic ductal cells and thyroid tissues. Findings in human studies are controversial and inconclusive. In the analyses of the US Food and Drug Administration adverse events reporting system, a significantly higher risk of pancreatic cancer was observed for GLP-1R agonists and DPP-4 inhibitors, but a significantly higher risk of thyroid cancer was only observed for GLP-1R agonists. Such a higher risk of pancreatic cancer or thyroid cancer could not be similarly demonstrated in other human observational studies or analyses of data from clinical trials. With regards to cancers other than pancreatic cancer and thyroid cancer, available studies supported a neutral association in humans. Some preliminary studies even suggested a potentially beneficial effect on the development of other cancers with the use of incretins. Based on current evidence, continuous monitoring of the cancer issues related to incretin-based therapies is required, even though the benefits may outweigh the potential cancer risk in the general patients with type 2 diabetes mellitus.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Neoplasms; Pancreatic Neoplasms; Risk Factors; Thyroid Neoplasms

Chronic hyperglycemia and its associated metabolic products are key factors responsible for the development and progression of diabetic chronic kidney disease (CKD). Endocrinologists are tasked with detection and management of early CKD before patients need referral to a nephrologist for advanced CKD or dialysis evaluation. Primary care physicians are increasingly becoming aware of the importance of managing hyperglycemia to prevent or delay progression of CKD. Glycemic control is an integral part of preventing or slowing the advancement of CKD in patients with diabetes; however, not all glucose-lowering agents are suitable for this patient population. The availability of the latest information on treatment options may enable physicians to thwart advancement of serious renal complication in patients suffering from diabetes. This review presents clinical data that shed light on the risk/benefit profiles of three relatively new antidiabetes drug classes, the dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 analogs, and sodium glucose co-transporter 2 inhibitors, particularly for patients with diabetic CKD, and summarizes the effects of these therapies on renal outcomes and glycemic control for endocrinologists and primary care physicians. Current recommendations for screening and diagnosis of CKD in patients with diabetes are also discussed.

Topics: Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Cardiovascular (CV) disease is the leading cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). However, improving glycaemic control alone has not decreased CV events. Therapies that improve glycaemic control, CV disease risk factors and CV function are more likely to be successful. Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent breakdown of incretin hormones glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic peptide and improve glycaemic control in patients with T2DM. DPP-4 acts on other substrates, many associated with cardioprotection. Thus, inhibition of DPP-4 may lead to elevations in these potentially beneficial substrates. Data from animal studies and small observational studies in humans suggest that DPP-4 inhibitors may potentially reduce CV risk. However, recently completed CV outcome trials in patients with T2DM and CV disease or at high risk of adverse CV events have shown that the DPP-4 inhibitors saxagliptin and alogliptin neither increased nor decreased major adverse CV events.

Topics: Adamantane; Animals; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Piperidines; Protective Factors; Risk Assessment; Risk Factors; Treatment Outcome; Uracil

Over the past few years, substantial clinical data have been presented showing that incretin-based therapies are effective glucose-lowering agents. Specifically, glucagon-like peptide 1 receptor agonists demonstrate an efficacy comparable to insulin treatment with minimal hypoglycemia and have favorable effects on body weight. Thus, many of the unmet clinical needs noted from prior therapies are addressed by these agents. However, even after many years of use, many continue to raise concerns about the long-term safety of these agents and, in particular, the concern with pancreatitis. This clearly remains a complicated topic. Thus, in this issue of Diabetes Care, we continue to update our readers on this very important issue by presenting two studies evaluating incretin-based medications and risk of pancreatitis. Both have undergone significant revisions based on peer review that provided significant clarification of the data. We applaud both author groups for being extremely responsive in providing the additional data and revisions requested by the editorial team. As such, because of the critical peer review, we feel both articles achieve the high level we require for Diabetes Care and are pleased to now present them to our readers. In keeping with our aim to comprehensively evaluate this topic, we asked for additional commentaries to be prepared. In the narrative outlined below, Dr. Laurent Azoulay provides a commentary about the remaining uncertainty in this area and also discusses the results from a nationwide population-based case-control study. In the narrative preceding Dr. Azoulay's contribution, Prof. Edwin A.M. Gale provides a commentary on the report that focuses on clinical trials of liraglutide in the treatment of diabetes. From the journal's perspective, both of the articles on pancreatitis and incretin-based therapies reported in this issue have been well vetted, and we feel both of the commentaries are insightful.

Topics: Body Weight; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Pancreas; Pancreatitis

Nutrient-specific sensor systems in enteroendocrine cells detect intestinal contents and cause gut hormone release upon activation. Among these peptide hormones, the incretins glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 are of particular interest by their role in glucose homeostasis, metabolic control and for proper ß-cell function. This review focuses on intestinal nutrient-sensing processes and their role in health and disease.. All macronutrients, respectively, their digestion products can cause incretin release by targeting specific sensors. Luminal glucose is the strongest stimulant for incretin release with the Na-dependent glucose transporter as the prime sensor. For peptides, the H-dependent peptide transporter together with calcium-sensing-receptor act as a sensing system. That transporters can function as nutrient-sensing 'transceptors' is conceptually new as G-protein coupled receptors so far were thought to be the sensing entities. This still holds true for GPR40 and GPR120 as sensors for medium/long-chain fatty acids and GPR41 and GPR43 for microbiota-derived short-chain fatty acids. Synthetic agonists for these receptors show impressive effects on glucagon-like peptide 1 output and glycemic control. Moreover, the remarkable and immediate antidiabetic effects of bariatric surgery/gastric bypass put intestinal nutrient sensing into focus of new strategies for metabolic control.. Targeting the intestinal nutrient-sensing machinery by dietary and/or pharmacological means holds promises in particular for treatment of type 2 diabetes. This interest may help to better understand the nutrient-sensing processes and the involvement of the intestine in overall endocrine, neuronal and metabolic control.

Topics: Animals; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fiber; Dietary Proteins; Disease Models, Animal; Enteroendocrine Cells; Fatty Acids, Volatile; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Incretins; Intestinal Mucosa; Intestines

Since diabetes mellitus (DM) is the most common cause of heart failure (HF), it is critically important to clarify whether incretin hormones including glucagon-like peptide-1 (GLP-1), which play an important role in blood glucose control, mediate cardioprotection. There are many lines of basic research evidence indicating that GLP-1 improves the pathophysiology of HF: In murine and canine HF models, either GLP-1 analogues or DPP-IV inhibitors improved cardiac functions. The first question that arises is how either GLP-1 analogues or DPP-IV inhibitors mediate cardioprotection. Cardiovascular diseases are tightly linked to impaired glucose tolerance (IGT): IGT is not only one of the causes of cardiovascular events but also the result of HF. Indeed, the treatment of IGT improved HF, showing that one of the mechanisms attributable to DPP-IV inhibitors is related to the improvement of IGT. Intriguingly, either DPP-IV inhibitors or GLP-1 analogues mediate cardioprotection even without IGT, suggesting two possible explanations: One is that GLP-1 analogues directly activate the prosurvival kinases, such as Akt and Erk1/2, and another is that DPP-IV inhibition increases cardioprotective peptides such as BNP and SDF-1α. The next question is whether cardioprotection is translated to clinical medicine. Small scale clinical trials proved their cardioprotective effects; however, several large scale clinical trials have not proved the beneficial effects of DPP-IV inhibitors. Taken together, GLP-1 analogues or DPP-IV inhibitors can mediate cardioprotection, however, what needs to be clarified is who mainly receives their benefits among the patients with cardiovascular diseases and/or DM.

Topics: Animals; Blood Glucose; Cardiotonic Agents; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dogs; Glucagon-Like Peptide 1; Heart Failure; Humans; Incretins; Mice; Translational Research, Biomedical

Individuals with metabolic syndrome and frank type 2 diabetes are at increased risk of atherosclerotic cardiovascular disease, partially due to the presence of lipid and lipoprotein abnormalities. In these conditions, the liver and intestine overproduce lipoprotein particles, exacerbating the hyperlipidemia of fasting and postprandial states. Incretin-based, antidiabetes therapies (i.e., glucagon-like peptide [GLP]-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) have proven efficacy for the treatment of hyperglycemia. Evidence is accumulating that these agents also improve fasting and postprandial lipemia, the latter more significantly than the former. In contrast, the gut-derived peptide GLP-2, cosecreted from intestinal L cells with GLP-1, has recently been demonstrated to enhance intestinal lipoprotein release. Understanding the roles of these emerging regulators of intestinal lipoprotein secretion may offer new insights into the regulation of intestinal lipoprotein assembly and secretion and provide new opportunities for devising novel strategies to attenuate hyperlipidemia, with the potential for cardiovascular disease reduction.

Topics: Animals; Apolipoprotein B-48; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Intestinal Mucosa; Lipoproteins; Receptors, Glucagon; Triglycerides

Type 2 diabetes mellitus (T2DM) has become one of the most prevalent noncommunicable diseases in the past years. It is undoubtedly associated with atherosclerosis and increased risk for cardiovascular diseases. Incretins, which are intestinal peptides secreted during digestion, are able to increase insulin secretion and its impaired function and/or secretion is involved in the pathophysiology of T2DM. Dipeptidyl peptidase 4 (DPP4) is an ubiquitous enzyme that regulates incretins and consequently is related to the pathophysiology of T2DM. DPP4 is mainly secreted by endothelial cells and acts as a regulatory protease for cytokines, chemokines, and neuropeptides involved in inflammation, immunity, and vascular function. In T2DM, the activity of DPP4 seems to be increased and there are a growing number of in vitro and in vivo studies suggesting that this enzyme could be a new link between T2DM and atherosclerosis. Gliptins are a new class of pharmaceutical agents that acts by inhibiting DPP4. Thus, it is expected that gliptin represents a new pharmacological approach not only for reducing glycemic levels in T2DM, but also for the prevention and treatment of atherosclerotic cardiovascular disease in diabetic subjects. We aimed to review the evidences that reinforce the associations between DPP4, atherosclerosis, and T2DM.

Topics: Atherosclerosis; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Inflammation

Type 2 diabetes (T2D), one of the major common human health problems, is growing at an alarming rate around the globe. Alpha-glucosidase and dipeptidyl peptidase IV (DPP-IV) enzymes play a significant role in development of T2D. Hence, reduction or inhibition of their activity can be one of the important strategies in management of T2D. Studies in the field of bioactive peptides have shown that dietary proteins could be natural source of alpha-glucosidase and DPP-IV inhibitory peptides.. The purpose of this review is to provide an overview of food protein-derived peptides as potential inhibitors of alpha-glucosidase and DPP-IV with major focus on milk proteins.. Efforts have been made to review the available information in literature on the relationship between food protein-derived peptides and T2D. This review summarizes the current data on alpha-glucosidase and dipeptidyl peptidase IV inhibitory bioactive peptides derived from proteins and examines the potential value of these peptides in the treatment and prevention of T2D. In addition, the proposed modes of inhibition of peptide inhibitors are also discussed.. Studies revealed that milk and other food proteins-derived bioactive peptides play a vital role in controlling T2D through several mechanisms, such as the satiety response, regulation of incretin hormones, insulinemia levels, and reducing the activity of carbohydrate degrading digestive enzymes.. The bioactive peptides could be used in prevention and management of T2D through functional foods or nutraceutical supplements. Further clinical trials are necessary to validate the findings of in vitro studies and to confirm the efficiency of these peptides for applications.

Topics: alpha-Glucosidases; Amino Acid Sequence; Animals; Blood Glucose; Carbohydrate Metabolism; Cultured Milk Products; Diabetes Mellitus, Type 2; Dietary Proteins; Digestion; Dipeptidyl-Peptidase IV Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Incretins; Milk Proteins; Molecular Sequence Data; Peptides; Postprandial Period; Satiation

The once-weekly glucagon-like peptide 1 receptor agonists (QW GLP1RA) represent a major advancement in diabetes pharmaco-therapeutics. This review describes the basic, clinical, and comparative pharmacology of this novel class of drugs. It highlights the clinical placement and posology of these drugs.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Peptides; Recombinant Fusion Proteins; Venoms

Who never had a type 2 obese diabetic patient, treated by several oral antidiabetic drugs and insulin, with consequent weight gain associated with the therapeutic escalation and uncontrolled diabetes? The arrival of GLP-1 agonists and SGLT-2 inhibitors allows to reevaluate the management of these patients, with their favorable effects on glycemic control, weight and the risk of hypoglycemia and their complementary mechanisms to conventional treatments. The vicious cycle of weight gain and increased need of insulin is limited. The choice between these two molecules must be based on several factors (glycemic target, weight, comorbidities, route of administration, side effects, etc.), and the balanced enthusiasm of these new treatments with the insufficient data regarding their long-term safety and their impact on micro- and macrovascular complications.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Obesity; Practice Guidelines as Topic; Receptors, Glucagon; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

GPR120 receptor functions as a receptor for ω-3 fatty acid, involving regulating the secretion of gastrointestinal peptide hormone, adipogenesis, adipogenic differentiation and anti-inflammatory process and the like in the aspect of biological functions. In view that the dysfunction of GPR120 receptor is closely correlated with metabolic disorders, GPR120 may act as a novel potential therapeutic target for the treatment of obesity, insulin resistance, Type 2 diabetes and so on. Therefore, mounting scientists devote themselves to probing the molecular mechanism of the biological function of GPR120 receptor and their ligands for the treatment of impaired metabolic health. Herein, we summarize the mechanisms of signal transduction through GPR120 receptor, and discovery and development of GPR120 agonists thereof.

Topics: Amino Acid Sequence; Animals; Appetite Regulation; Diabetes Mellitus, Type 2; Drug Discovery; Fatty Acids, Omega-3; Humans; Incretins; Insulin Resistance; Metabolic Diseases; Molecular Sequence Data; Obesity; Receptors, G-Protein-Coupled; Sequence Alignment

Albiglutide is a glucagon-like peptide-1 receptor agonist, a new class of drugs used to treat type 2 diabetes. We did a prospective meta-analysis of the cardiovascular safety of albiglutide as stipulated by the US Food and Drug Administration recommendations for the assessment of new treatments for diabetes.. We did a meta-analysis of eight phase 3 trials and one phase 2b trial in which patients were randomly assigned to albiglutide, placebo, or active comparators (glimepiride, insulin glargine, insulin lispro, liraglutide, pioglitazone, or sitagliptin). The safety population included 5107 patients, of whom 2524 took albiglutide (4870 person-years) and 2583 took comparators (5213 person-years). Possible major cardiovascular events were recorded prospectively and adjudicated by an independent endpoint committee masked to treatment allocation. The primary endpoint was a composite of first occurrence of major adverse cardiovascular events (ie, cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) or hospital admission for unstable angina. Secondary endpoints were major adverse cardiovascular events alone, all-cause mortality, silent myocardial infarction, hospital admission for heart failure, chest pain, other angina, and subdural or extradural haemorrhage. The occurrence of all other adverse events classified by the investigators as cardiovascular events were documented, but these were not adjudicated.. The primary endpoint was not significantly different between albiglutide and all comparators (58 events vs 58 events; hazard ratio [HR] 1·00, 95% CI 0·68-1·49, p=0·0019 for non-inferiority). Major adverse cardiovascular event alone was also not significantly different (52 events vs 53; HR, 0·99; 95% CI, 0·65-1·49). When albiglutide was compared separately with placebo or active comparators, we noted no significant differences. We detected no significant differences in the other secondary endpoints. More patients had atrial fibrillation or atrial flutter in the albiglutide group (35 [1·4%] of 2524 patients; 8·6 events per 1000 patient-years) than in the all-comparators group (16 [0·6%] of 2583 patients; 3·4 events per 1000 patient-years).. Cardiovascular events were not significantly more likely to occur with albiglutide than with all comparators. Because the upper bound of the 95% CI for major adverse cardiovascular event plus hospital admission for unstable angina was greater than 1·3, a dedicated study with a cardiovascular endpoint is underway to confirm the safety of albiglutide.. GlaxoSmithKline.

Topics: Aged; Cardiovascular Diseases; Cardiovascular System; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Incretins; Male; Middle Aged; Randomized Controlled Trials as Topic

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are injectable glucose-lowering medications approved for the treatment of adult patients with type 2 diabetes mellitus (T2DM). This article provides practical information to guide primary care physicians on the use of GLP-1RAs in patients with T2DM. Two short-acting (once- or twice-daily administration; exenatide and liraglutide) and three long-acting (weekly administration; albiglutide, dulaglutide and exenatide) GLP-1RAs are currently approved in the US. These drugs provide levels of GLP-1 receptor agonism many times that of endogenous GLP-1. The GLP-1RAs have been shown to significantly improve glycemic parameters and reduce body weight. These agents work by activating GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release-responses that are both glucose-dependent-with a consequent low risk for hypoglycemia. Effects on GLP-1 receptors in the CNS and the gastrointestinal tract cause reduced appetite and delayed glucose absorption due to slower gastric emptying. The most common adverse effects are gastrointestinal, which are transient and less common with the long-acting drugs. GLP-1RAs are recommended as second-line therapy in combination with metformin, sulfonylureas, thiazolidinediones or basal insulin, providing a means of enhancing glucose control while offsetting the weight gain associated with insulin and some oral agents. GLP-1RAs represent a useful tool that the primary care physician can use to help patients with T2DM achieve their therapeutic goals.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Energy Intake; Gastric Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Medication Adherence; Metformin; Pancreas; Primary Health Care; Weight Loss

To assess the efficacy and safety of recently approved once-weekly glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes.. We conducted a systematic review and meta-analysis of randomized controlled trials comparing any GLP-1 RA licensed for once-weekly dosing (albiglutide, dulaglutide or exenatide extended release) with placebo or other antidiabetic agents. We searched Medline, Embase, the Cochrane Library and grey literature for articles published up to December 2014 and extracted data in duplicate.. In our systematic review we included 33 trials with a total of 16 003 participants. Compared with placebo the change in glycated haemoglobin (HbA1c) concentration was -0.66% [six studies; 95% confidence interval (CI) -1.14 to -0.19; I(2)  = 88%] with albiglutide, and -1.18% (seven studies; 95% CI -1.34 to -1.02; I(2)  = 65%) with dulaglutide. Based on data from placebo-controlled trials, we did not detect statistically significant weight-sparing benefits for albiglutide or dulaglutide. Compared with other antidiabetic agents, once-weekly GLP-1 RAs outperformed sitagliptin, daily exenatide and insulin glargine in terms of HbA1c-lowering (mean differences -0.40%; 95% CI -0.66 to -0.14; I(2)  = 85%, -0.44%; 95% CI -0.58 to -0.29; I(2)  = 40% and -0.28; 95% CI -0.45 to -0.10; I(2)  = 81%, respectively). The main adverse effects of treatment included gastrointestinal and injection site reactions.. Given their dosing scheme and overall efficacy and safety profile, once-weekly GLP-1 RAs are a convenient therapeutic option for use as add-on to metformin.

Topics: Adult; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Male; Metformin; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Venoms

The purpose of this review is to discuss the clinical evidence for dipeptidyl peptidase-4 (DPP-4) inhibitors and to better define their use in treating type 2 diabetes mellitus (T2DM), including in special populations, such as the elderly. DPP-4 inhibitors are incretin-based therapies that can be used as monotherapy or in combination with other antidiabetes medications to treat T2DM. As monotherapy, DPP-4 inhibitors have demonstrated a modest and comparable glycated hemoglobin-lowering effect. As initial dual therapy with other antidiabetes agents, DPP-4 inhibitors significantly improved glycated hemoglobin when compared with monotherapy arms. Similarly, in triple combinations, DPP-4 inhibitors consistently provided additive glycemic benefits. In patients who were continuing insulin, glycemic parameters were improved with the addition of a DPP-4 inhibitor, and they required less insulin uptitration. In clinical trials, the overall occurrence of adverse events was similar between DPP-4 inhibitor groups and controls, and a low occurrence of hypoglycemia was observed, except when used in combination with a sulfonylurea. A neutral effect on weight was maintained, even in combination with insulin. Similar to outcomes observed in younger patients, DPP-4 inhibitors significantly improved glycemic efficacy in older patients, without increasing the risk for hypoglycemia. Efficacy and safety in patients with renal insufficiency are also documented.. DPP-4 inhibitors are therapeutically beneficial for a diverse population of patients with T2DM, including elderly patients, based on demonstrated efficacy, tolerability, and a low risk for hypoglycemia.

Topics: Age Factors; Aged; Aged, 80 and over; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Kidney; Metformin

Previous studies have offered weak and conflicting evidence regarding the impact of incretin-based oral antihyperglycemic agents on risk of acute pancreatitis. This meta-analysis of three recent mega-trials found an 82% increase in the odds of acute pancreatitis with the use of these agents compared to usual care (95% CI, 1.17-2.82).

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Pancreatitis; Randomized Controlled Trials as Topic; Risk

The hormone glucagon-like peptide-1 (GLP-1) is released from the gut in response to food intake. It acts as a satiety signal, leading to reduced food intake, and also as a regulator of gastric emptying. Furthermore, GLP-1 functions as an incretin hormone, stimulating insulin release and inhibiting glucagon secretion from the pancreas in response to food ingestion. Evidence suggests that the action or effect of GLP-1 may be impaired in obese subjects, even in those with normal glucose tolerance. GLP-1 impairment may help explain the increased gastric emptying and decreased satiety signalling seen in obesity. Incretin impairment, probably associated with reduced insulinotropic potency of GLP-1, is also characteristic of type 2 diabetes (T2D). Therefore, it is possible that incretin impairment may contribute to the pathophysiological bridge between obesity and T2D. This review summarises current knowledge about the pathophysiology and consequences of GLP-1 and incretin impairment in obesity, and examines the evidence for an incretin-related link between obesity and T2D. It also considers the current literature surrounding the novel use of GLP-1 receptor agonists as a treatment for obesity in patients with normoglycaemia, prediabetes and T2D.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Emptying; Gastrointestinal Motility; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Obesity; Receptors, Glucagon; Satiation

The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long-term limitation being the eventual need for insulin replacement therapy (Table 1). Since 2007, drugs targeting the glucagon-like peptide-1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterized even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand-dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary for future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Protein Conformation; Receptors, Glucagon

Glucagon-like (GLP-1) is a peptide hormone secreted from the small intestine in response to nutrient ingestion. GLP-1 stimulates insulin secretion in a glucose-dependent manner, inhibits glucagon secretion and gastric emptying, and reduces appetite. Because of the short circulating half-life of the native GLP-1, novel GLP-1 receptor (GLP-1R) agonists and analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors have been developed to facilitate clinical use. Emerging evidence indicates that GLP-1-based therapies are safe and may provide cardiovascular (CV) benefits beyond glycemic control. Preclinical and clinical studies are providing increasing evidence that GLP-1 therapies may positively affect CV function and metabolism by salutary effects on CV risk factors as well as via direct cardioprotective actions. However, the mechanisms whereby the various classes of incretin-based therapies exert CV effects may be mechanistically distinct and may not necessarily lead to similar CV outcomes. In this review, we will discuss the potential mechanisms and current understanding of CV benefits of native GLP-1, GLP-1R agonists and analogs, and of DPP-4 inhibitor therapies as a means to compare their putative CV benefits.

Topics: Animals; Blood Glucose; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

The aim of this review is to examine the evidence on the role of antidiabetic agents in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). In particular, metformin does not seem to have significant effects on liver histology. Glitazones improve steatosis and necro-inflammation, delay progression of fibrosis, and ameliorate glucose and lipid metabolism and subclinical inflammation. However, there is now evidence that prolonged treatment with these agents may offer no additional histological benefit and that metabolic improvement does not necessarily parallel histological improvement. Moreover, the long-term safety and efficacy of glitazones is an issue of continuing concern. Injectable glucagon-like peptide 1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are more recent antidiabetic agents with some promising preliminary resulst in NFLD. However, experience with their use is still very limited. In conclusion, no antidiabetic agent has hitherto been shown to exert a beneficial effect on hepatic fibrosis. However, pharmacological treatment could be considered in patients with non-alcoholic steatohepatitis (NASH) not responding to lifestyle intervention. Finally, larger long-term studies are needed to shed more light on the effect of antidiabetic treatment on NAFLD.

Topics: Administration, Oral; Biomimetic Materials; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Non-alcoholic Fatty Liver Disease

Insulin and incretin agents (dipeptidyl peptidase-4 inhibitors [DPP4is] and glucagon-like peptide-1 receptor agonists [GLP1 RAs]) are second-line treatment options in patients with type 2 diabetes (T2D) not achieving glycemic targets with metformin. Combinations of insulin with incretin agents have been explored in randomized controlled trials (RCTs) and retrospective studies. However, the optimal approach is still elusive; numerous combination regimens can be envisioned, differing in composition and in order of addition.. A systematic survey was conducted of RCTs testing insulin/DPP4i or insulin/GLP1 RA regimens. PubMed and other online databases were queried using 'insulin' and the names of all incretin agents available in Canada, along with 'combination', 'concomitant', 'concurrent', and 'add-on'. Web of Science and clinicaltrials.gov were searched to identify unpublished trials.. Fifteen placebo-controlled or active-comparator RCTs were identified, reporting outcomes for regimens combining insulins and incretin agents available in Canada. DPP4i add-on to insulin therapy (six trials) leads to modest A1c lowering, with weight neutrality. GLP1 RA and insulin combination therapy (GLP1 RA add-on, five trials; insulin add-on, two trials) is associated with significant A1c lowering, with beneficial effects on body weight. A single proof-of-concept trial compared GLP1 RA to DPP4i add-on to insulin, and only one RCT examined simultaneous introduction of an incretin agent with insulin. Adding an incretin agent to established basal insulin therapy may represent a useful alternative to insulin intensification with prandial or premixed insulin. Initial introduction of an incretin agent, with subsequent introduction of insulin, offers potential practical advantages. No study directly comparing order of addition has yet been reported.. Insulin/incretin combination therapy comprises a variety of efficacious, weight-sparing regimens and may be considered for many patients who do not achieve glycemic targets when treated with insulin or an incretin agent.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Incretins; Insulin

Incretin-based therapy with glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is considered a promising therapeutic option for type 2 diabetes mellitus. Cumulative evidence, mainly from preclinical animal studies, reveals that incretin-based therapies also may elicit beneficial effects on kidney function. This review gives an overview of the physiology, pathophysiology, and pharmacology of the renal incretin system.. Activation of GLP-1R in the kidney leads to diuretic and natriuretic effects, possibly through direct actions on renal tubular cells and sodium transporters. Moreover, there is evidence that incretin-based therapy reduces albuminuria, glomerulosclerosis, oxidative stress, and fibrosis in the kidney, partially through GLP-1R-independent pathways. Molecular mechanisms by which incretins exert their renal effects are understood incompletely, thus further studies are needed.. The GLP-1R and DPP-4 are expressed in the kidney in various species. The kidney plays an important role in the excretion of incretin metabolites and most GLP-1R agonists and DPP-4 inhibitors, thus special attention is required when applying incretin-based therapy in renal impairment. Preclinical observations suggest direct renoprotective effects of incretin-based therapies in the setting of hypertension and other disorders of sodium retention, as well as in diabetic and nondiabetic nephropathy. Clinical studies are needed in order to confirm translational relevance from preclinical findings for treatment options of renal diseases.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Kidney; Receptors, Glucagon; Treatment Outcome

Incretin therapies such as glucagon-like peptide 1 (GLP-1) agonists are commonly used for the treatment of type 2 diabetes mellitus. GLP-1 mimetics, besides improving glycemic control, have been shown to influence multiple pathways regulating blood pressure (BP). We investigated the GLP-1 analogs effects on BP from published randomized studies using a meta-analytic approach.. Thirty-three trials (12,469 patients) that assessed the efficacy of GLP-1 analogs on glycemic control (HbA1C) over 12-56 weeks that met additional criteria, including the availability of standardized sitting BP assessment and weight parameters, were identified. Comparator therapy included oral antiglycemic drugs or placebo. The weighted mean difference (WMD) in systolic BP (SBP) change was calculated using a random-effects model after performing a test for heterogeneity.. Forty-one percent of patients were treated with liraglutide (0.3-3mg once daily), whereas 59% were treated with exenatide (5-10 µg twice daily or 2mg weekly). GLP-1 treatment achieved a greater SBP reduction than comparator therapy (WMD = 2.22mm Hg; 95% confidence interval (CI) = -2.97 to -1.47). In the pooled analysis, GLP-1 had beneficial effects on weight loss (WMD = -2.56kg; 95% CI = -3.12 to -2.00), HbA1c reduction (WMD = -0.41%; 95% CI = -0.78 to -0.04) but was associated with a heart rate increase (WMD = 1.30 bpm; 95% CI = 0.26-2.33). In a separate meta-regression analysis, the degree of SBP change was not related to baseline BP, weight loss, or improvement in HbA1C.. This meta-analysis provides evidence that GLP-1 analogs reduce sitting SBP. These findings may support potentially favorable long-term cardiovascular outcomes.

Topics: Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Time Factors; Treatment Outcome; Venoms; Weight Loss

Incretin peptides are a group of gastrointestinal hormones that play a prominent role in the regulation of glucose metabolism. Incretin-based therapies (IBTs) have recently emerged as an important treatment option for patients with type 2 diabetes mellitus (T2DM). These pharmaceutical agents may be specially well suited for patients who are overweight or obese with primarily post-meal glucose peaks, and in whom traditional first-line oral agents have failed to maintain adequate glycemic control. There are 2 classes of IBTs: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide 1 (GLP-1) receptor agonists. The ultimate effect of both types of agents is to augment GLP-1 signaling, which results in enhanced glucose-dependent insulin secretion, inhibition of glucagon secretion and decreased appetite. This leads to improved regulation of glucose homeostasis accompanied by either no increase in body weight (with DPP-4 inhibitors) or a reduction (with GLP-1 receptor agonists). GLP-1 inhibits food intake and the increased GLP-1 response may contribute as a satiety signal. Although data regarding the effect of GLP-1 agonists and DPP-4 inhibitors on levels of peptides involved in the regulation of food intake in T2DM are few, an indirect effect of IBT on weight loss is possible (e.g. Exendin-4 induces adiponectin secretion in vitro). Results from animal models indicate reduction of food intake and body weight by GLP-1 agonists, but follow-up studies are required. A growing amount of evidence suggests that these peptides may also impact the cardiovascular system, including beneficial effects on myocardial cells, lipid profiles and blood pressure as well as reduced markers of systemic inflammation and improved endothelial dysfunction. The potential role of these agents in improving components of the metabolic syndrome and retardation of atherosclerosis needs to be fully elucidated. Although IBTs are currently recommended only for use in the early treatment of T2DM, the 'non-glycemic' actions of these drugs may have far reaching therapeutic implications. It is hoped that future studies will elucidate their potential strengths and weaknesses for use in various metabolic conditions.

Topics: Animals; Atherosclerosis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Incretins; Inflammation; Lipoproteins; Metabolic Syndrome

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta-cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP-1 receptors are also expressed in extra-pancreatic tissues and trial data suggest that GLP-1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP-1 or GLP-1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP-1RAs in both people with type 2 diabetes and obese people without diabetes. GLP-1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP-1RA-induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP-1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra-pancreatic effects of GLP-1RAs could provide multi-factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP-1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP-1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future.

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Neuropathies; Evidence-Based Medicine; Exenatide; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Peptides; Receptors, Glucagon; Venoms

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, and is associated with a high risk of cardiovascular morbidity and mortality. Intensive control of glucose levels and blood pressure is currently the mainstay of both prevention and treatment of diabetic nephropathy. However, this strategy cannot fully prevent the development and progression of diabetic nephropathy, and an unmet need remains for additional novel therapies. The incretin-based agents--agonists of glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades glucagon-like peptide 1--are novel blood-glucose-lowering drugs used in the treatment of type 2 diabetes mellitus (T2DM). Therapeutic agents from these two drug classes improve pancreatic islet function and induce extrapancreatic effects that ameliorate various phenotypic defects of T2DM that are beyond glucose control. Agonists of GLP-1R and inhibitors of DPP-4 reduce blood pressure, dyslipidaemia and inflammation, although only GLP-1R agonists decrease body weight. Both types of incretin-based agents inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in rodents and humans. In rodents, incretin-based therapies also prevent onset of the morphological abnormalities of diabetic nephropathy.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hypoglycemic Agents; Incretins

A post hoc pooled analysis was undertaken to evaluate the safety of saxagliptin in patients with type 2 diabetes mellitus, with attention to events of special interest for dipeptidyl peptidase-4 inhibitors.. Pooled analyses were performed for 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy, and a subset of 11 saxagliptin + metformin studies. Adverse events and events of special interest (gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin lesions, lymphopenia, thrombocytopenia, hypoglycaemia, bone fracture, severe cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, worsening renal function, and specific laboratory events) were assessed; incidence rates (events/100 person-years) and incidence rates ratios (saxagliptin/control) were calculated (Mantel-Haenszel method).. In both pooled datasets, the incidence rates for deaths, serious adverse events, discontinuations due to adverse events, pancreatitis, malignancy, and most other events of special interest, excepting bone fractures and hypersensitivity, were similar between treatments, with 95% confidence intervals (CIs) for incidence rates ratios including 1. In the 20-study pool, the incidence rates per 100 person-years was higher with saxagliptin versus control for bone fractures [1.1 vs 0.6; incidence rates ratio (95% CI), 1.81 (1.04-3.28)] and hypersensitivity adverse events [1.3 vs 0.8; 1.67 (1.01-2.87)].. Pooled data from 20 studies confirm that saxagliptin has a favourable safety and benefit-risk profile.

Topics: Adamantane; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Incretins; Male; Middle Aged; Randomized Controlled Trials as Topic; Risk Assessment; Treatment Outcome

Incretin-based therapies appear to offer many advantages over other approaches for treating type 2 diabetes. Some preclinical studies have suggested that chronic activation of glucagon-like peptide 1 receptor (GLP1R) signalling in the pancreas may result in the proliferation of islet β-cells and an increase in β-cell mass. This provided hope that enhancing GLP1 action could potentially alter the natural progression of type 2 diabetes. However, to date, there has been no evidence from clinical trials suggesting that GLP1R agonists or dipeptidyl peptidase-4 (DPP4) inhibitors can increase β-cell mass. Nevertheless, while the proliferative capacity of these agents remains controversial, some studies have raised concerns that they could potentially contribute to the development of pancreatitis and hence increase the risk of pancreatic cancer. Currently, there are very limited clinical data to directly assess these potential benefits and risks of incretin-based therapies. However, a review of the preclinical studies indicates that incretin-based therapies probably have only a limited capacity to regenerate pancreatic β-cells, but may be useful for preserving any remaining β-cells in type 2 diabetes. In addition, the majority of preclinical evidence does not support the notion that GLP1R agonists or DPP4 inhibitors cause pancreatitis.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Pancreas

An impaired endothelial function has been recognized in the early stage of atherosclerosis, and is a major factor affecting the future development of cardiovascular events. Type 2 diabetes mellitus (T2DM) is widely prevalent, and is one of the most important risk factors for cardiovascular disease. T2DM is associated with increases in both morbidity and mortality, particularly from cardiovascular disease.New therapies based on the incretin hormone and its actions are now becoming widely used, and appear to offer advantages over conventional therapies by keeping the body weight steady and limiting hypoglycemia, while also achieving attractive glycemic control. However, there is little data available about the effects of incretins on the cardiovascular system.This review will focus on the effects of incretin therapies, including glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase (DPP)-4 inhibitors, on the endothelial function, and will discuss the potential mechanisms underlying these effects.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Risk Factors

As type 2 diabetes mellitus progresses, multiple antihyperglycemic agents are needed to maintain adequate glycemic control. Consensus guidelines recommend combining agents with complementary mechanisms of action. Given that hypoglycemic events increase the risk of cardiovascular disease and that weight gain affects mortality in obese individuals, it is important to control hyperglycemia without inducing hypoglycemia or weight gain. Peer-reviewed clinical trial data from patients requiring insulin-containing combination therapy suggest that insulin may be more effective at controlling hyperglycemia when given with appropriate combination therapy, but insulin is associated with weight gain and hypoglycemia. Some agents should not be combined with insulin because of associated weight gain and edema (ie, thiazolidinediones) or hypoglycemia (ie, sulfonylureas). Conversely, the lack of weight gain and hypoglycemia associated with metformin, glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors and suppression of glucagon secretion by both classes of incretin-based therapies suggest that these agents are well suited to combination therapy with insulin.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycemic Index; Humans; Hypoglycemic Agents; Incretins; Insulin

Studies designed to evaluate the short-term effects of incretin-related drugs in subjects with cardiac disease are still preliminary. In patients with heart failure, two of five studies showed that glucagon-like peptide-1 (GLP-1) infusion was associated with an absolute increase in left ventricular ejection fraction (LVEF) by 6-10 %, whereas no significant benefit was observed in the remaining three studies. In patients with coronary artery disease, single infusion of the GLP-1 receptor analog, exenatide, did not increase LVEF, but this drug may decrease infarct size in patients with myocardial infarction presenting with short duration of ischemic symptoms. Single dose of GLP-1 and the dipeptidyl-peptidase-IV (DPP-IV) inhibitor, sitagliptin, may improve left ventricular function, predominantly in ischemic segments, and attenuate post-ischemic stunning. Nausea, vomiting and hypoglycemia were the most common adverse effects associated with GLP-1 and exenatide administration. Increased heart rate was also observed with exenatide in patients with heart failure. Large randomized trials including diabetic patients with preexisting heart failure and myocardial infarction showed that chronic therapy with the DPP-IV inhibitors saxagliptin and alogliptin did not reduce cardiovascular events or mortality. Moreover, saxagliptin use was associated with significant increase in frequency of heart failure requiring hospitalization, hypoglycemia and angioedema. Overall, short-term preliminary data suggest potential cardioprotective effects of exenatide and sitagliptin in patients with heart failure and myocardial infarction. Meanwhile, long-term randomized trials suggest no benefit of alogliptin, and increased harm associated with the use of saxagliptin.

Topics: Animals; Cardiotonic Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Myocardial Infarction; Peptides; Venoms

Antidiabetic drugs for type 2 diabetes receive marketing authorization if they show efficacy in reducing levels of HbA(1c). However, efficacy on this biological criterion does not necessarily reflect clinical benefit to patients. Several randomized clinical trials have shown that antidiabetic drugs reduce HbA(1c) without a corresponding reduction in clinical events. This suggests a need to focus on the clinical effectiveness (morbimortality criteria) of our available antidiabetic drugs. In this non-extensive review of the literature, it was found that none of the current antidiabetic drugs have clearly proven their superiority over placebo in the gold standard double-blind randomized clinical trials. Thus, in 2013, the level of evidence for the clinical efficacy of antidiabetic drugs is disappointing and does not support the millions of prescriptions being written for them.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Evidence-Based Medicine; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Randomized Controlled Trials as Topic; Sulfonylurea Compounds

Overproduction of hepatic apoB100-containing VLDL particles has been well documented in animal models and in humans with insulin resistance such as the metabolic syndrome and type 2 diabetes, and contributes to the typical dyslipidemia of these conditions. In addition, postprandial hyperlipidemia and elevated plasma concentrations of intestinal apoB48-containing chylomicron and chylomicron remnant particles have been demonstrated in insulin resistant states. Intestinal lipoprotein production is primarily determined by the amount of fat ingested and absorbed. Until approximately 10 years ago, however, relatively little attention was paid to the role of the intestine itself in regulating the production of triglyceride-rich lipoproteins (TRL) and its dysregulation in pathological states such as insulin resistance. We and others have shown that insulin resistant animal models and humans are characterized by overproduction of intestinal apoB48-containing lipoproteins. Whereas various factors are known to regulate hepatic lipoprotein particle production, less is known about factors that regulate the production of intestinal lipoprotein particles. Monosacharides, plasma free fatty acids (FFA), resveratrol, intestinal peptides (e.g. GLP-1 and GLP-2), and pancreatic hormones (e.g. insulin) have recently been shown to be important regulators of intestinal lipoprotein secretion. Available evidence in humans and animal models strongly supports the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of chylomicrons in fed and fasting states. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors contribute to the enhanced formation and secretion of TRL. Understanding the regulation of intestinal lipoprotein production is imperative for the development of new therapeutic strategies for the prevention and treatment of dyslipidemia. Here we review recent developments in this field and present evidence that intestinal lipoprotein production is a process with metabolic plasticity and that modulation of intestinal lipoprotein secretion may be a feasible therapeutic strategy in the treatment of dyslipidemia and possibly prevention of atherosclerosis.

Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Atherosclerosis; Bile Acids and Salts; Cholesterol; Chylomicrons; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Dyslipidemias; Exenatide; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Resistance; Intestine, Small; Lipoproteins; Microbiota; Peptides; Receptors, Glucagon; Resveratrol; Secretory Rate; Stilbenes; Triglycerides; Venoms

DPP4 inhibitors and GLP-1 receptor agonists used in incretin-based strategies treat Type 2 diabetes with different modes of action. The pharmacological blood GLP-1R agonist concentration targets pancreatic and some extrapancreatic GLP-1R, whereas DPP4i favors the physiological activation of the gut-brain-periphery axis that could allow clinicians to adapt the management of Type 2 diabetes, according to the patient's pathophysiological characteristics.

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

Suboptimal blood glucose control among patients with type 2 diabetes continues to support the need for new pharmacologic approaches.. The purpose of this commentary was to highlight newly available and soon-to-be available agents that are promising tools for targeting specific pathophysiologic pathways in the management of diabetes.. Published evidence to support the application of novel incretin-based therapies, dipeptidyl peptidase (DPP)-4 inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, other oral agents and insulins for managing specific aspects of type 2 diabetes, as well as disadvantages associated with those novel medications, are discussed.. Several new glucagon-like peptide (GLP)-1 receptor agonists with different time frames of action, although each has unique advantages and disadvantages, have been through clinical trials. Examples of these are lixisenatide and albiglutide. Currently available DPP-4 inhibitor agents, important for inhibiting the breakdown of endogenous GLP-1, have not been associated with weight gain or hypoglycemia. SGLT-2 inhibitors, which do not depend on insulin secretion or insulin action, may be advantageous in that they appear to be broadly efficacious at all stages of diabetes. New insulin analogues, such as degludec and U-500, improve glycemic control without contributing to hypoglycemia.. Advances in pharmacologic options offer the promise of improving glycemic control for longer periods, with limited glycemic fluctuations, hypoglycemia, and weight gain. However, the effectiveness of these agents ultimately depends on their availability to providers managing the health care of patients at high risk for poor diabetes outcomes and patients' use of them as directed. Long-term effectiveness and safety trials are ongoing.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin, Long-Acting; Male; Peptides

Hyperglycaemia occurs frequently in the critically ill, even in those patients without a history of diabetes. The mechanisms underlying hyperglycaemia in this group are complex and incompletely defined. In health, the gastrointestinal tract is an important modulator of postprandial glycaemic excursions and both the rate of gastric emptying and the so-called incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are pivotal determinants of postprandial glycaemia. Incretin-based therapies (that is, glucagon-like peptide- 1 agonists and dipeptidyl-peptidase-4 inhibitors) have recently been incorporated into standard algorithms for the management of hyperglycaemia in ambulant patients with type 2 diabetes and, inevitably, an increasing number of patients who were receiving these classes of drugs prior to their acute illness will present to ICUs. This paper summarises current knowledge of the incretin effect as well as the incretin-based therapies that are available for the management of type 2 diabetes, and provides suggestions for the potential relevance of these agents in the management of dysglycaemia in the critically ill, particularly to normalise elevated blood glucose levels.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Incretins

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and inhibits glucagon secretion in the pancreatic islets of Langerhans under hyperglycaemia. In type 2 diabetes (T2DM), GLP-1 improves glycaemic control without a hypoglycaemia risk. GLP-1 receptors have also been found in extra-pancreatic tissues, e.g., the cardiovascular system, the gastrointestinal system, and the central nervous system. Since cardiovascular comorbidities and degenerative neurological changes are associated with T2DM, the interest in the extrapancreatic effects of GLP-1 has increased. GLP-1-based therapies with either GLP-1 receptor agonists (GLP-1 RA) or DPP-4 inhibitors (that delay the degradation of endogenous GLP-1) have become widely used therapeutic options in T2DM. In clinical studies, GLP-1 RA have demonstrated a significant lowering of blood pressure that is independent of body weight changes. Preclinical data and small short-term studies with GLP-1 and GLP-1 RA have shown cardioprotective effects in ischaemia models. GLP-1 as well as a treatment with GLP-1 RA also induces a stable body weight loss by affecting GLP-1 signaling in the hypothalamus and by slowing gastric emptying. Regarding neuroprotective actions in degenerative neurological disease models for Parkinson's- or Alzheimer's disease or neurovascular complications like stroke, animal studies have shown positive results. In this article, a summary of the extrapancreatic effects of GLP-1 and GLP-1-based therapies is presented.

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Emptying; Humans; Hypoglycemic Agents; Incretins; Neuroprotective Agents; Receptors, Glucagon; Weight Loss

Type 2 diabetes mellitus (T2DM) is widely prevalent and a critical risk factor for cardiovascular disease that increases both morbidity and mortality. Recently, new therapies based on the actions of the incretin hormones have become widely used, offering advantages over conventional treatments by limiting hypoglycemia and achieving glycemic control. Moreover, many experimental studies have suggested that GLP-1 and related drugs exert cardioprotective effects on atherosclerosis and cardiac dysfunction both in vitro and in vivo. However, there is thus far little clinical evidence supporting the efficacy of incretin therapy in patients with cardiovascular disease. This review focuses on the effects of GLP-1-related therapy on cardiac function from the bench to the bed, with a discussion of possible underlying mechanisms.  

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Heart Failure; Humans; Incretins

Atherothrombotic cardiovascular events are a leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). A number of factors beyond hyperglycemia contribute to this increased risk of cardiovascular events in T2D, including elevated blood pressure, dyslipidemia, inflammation, endothelial dysfunction, and enhanced platelet activation. Importantly, most currently available antihyperglycemic treatments for T2D do not address these additional mechanisms. Indeed, we posit that this may explain why more intensive treatment of hyperglycemia has not contributed to a reduced incidence of cardiovascular events in subjects with T2D. Incretin-targeted therapies, such as dipeptidyl peptidase 4 inhibitors, are a relatively new class of antidiabetic treatments, and preclinical as well as small mechanistic clinical studies suggest that they exert beneficial cardiovascular effects. This review focuses specifically on the potential antiatherothrombotic effects of dipeptidyl peptidase 4 inhibitors.

Topics: Animals; Blood Pressure; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins

Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose-lowering effect in patients with type 2 diabetes remain unclear. This article offers a review of the mechanisms behind the glucose-lowering effect of BASs, and the efficacy of BASs in the treatment of type 2 diabetes.

Topics: Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Epichlorohydrin; Female; Gastric Emptying; Glycated Hemoglobin; Humans; Hypercholesterolemia; Hypoglycemic Agents; Imidazoles; Incretins; Lipid Metabolism; Male; Resins, Synthetic; Signal Transduction; Treatment Outcome

Incretin-based therapy became recently available as antihyperglycemic treatment for patients with type 2 diabetes (T2DM). Incretin therapy comprises glucagon-like peptide receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 inhibitors (DPP4-I): these classes of drugs not only have the ability to reduce blood glucose, but also can exert several cardioprotective effects. They have been shown to positively influence some risk factors for cardiovascular disease (CVD), to improve endothelial function, and to directly affect cardiac function. For these reasons incretins are considered not only antidiabetic drugs, but also cardiovascular effective. The first clinical trials aimed to demonstrate the safety of DPP4 inhibitors have been recently published: their clinical significance will be discussed in light of the prior experimental findings.

Topics: Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Inflammation; Lipid Metabolism; Male; Myocytes, Cardiac; Receptors, Glucagon

The question whether antidiabetes drugs can cause acute pancreatitis dates back to the 1970s. Recently, old concerns have re-emerged following claims that use of incretins, a new class of drugs for type 2 diabetes, might increase the relative risk of acute pancreatitis up to 30-fold. Given that diabetes is per se a potent risk factor for acute pancreatitis and that drug-related acute pancreatitis is rare and difficult to diagnose, we searched the medical databases for information linking acute pancreatitis and type 2 diabetes drugs. Among the biguanides, both phenformin and metformin (the latter in patients with renal insufficiency) have been cited in case reports as a potential cause of acute pancreatitis. Sulphonylureas, as both entire class and single compound (glibenclamide), have also been found in cohort studies to increase its risk. No direct link was found between pancreatic damage and therapy with metaglinide, acarbose, pramlintide or SGLT-2 inhibitors. In animal models, thiazolinediones have demonstrated proprieties to attenuate pancreatic damage, opening perspectives for their use in treating acute pancreatitis in humans. Several case reports and the US Food and Drug Administration pharmacovigilance database indicate an association between acute pancreatitis and incretins, dipeptidyl peptidase-4 (DPP-4) inhibitors, and GLP-1 receptor agonists. To date, however, a clear-cut odds ratio for this association has been reported in only one of eight pharmacoepidemiological studies. Finally, none of the intervention trials investigating these compounds, including two large randomized controlled trials with cardiovascular endpoints, confirmed the purportedly increased risk of acute pancreatitis with incretin use.

Topics: Biguanides; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hypoglycemic Agents; Incretins; Pancreatitis; Randomized Controlled Trials as Topic; Risk Factors; Sulfonylurea Compounds

Bariatric surgery has emerged as the most durably effective treatment of type 2 diabetes (DM). However, the mechanisms governing improvement in glucose homeostasis have yet to be fully elucidated. In this review we discuss the various types of surgical interventions and the multitude of factors that potentially mediate the effects on glycemia, such as altered delivery of nutrients to the distal ileum, duodenal exclusion, gut hormone changes, bile acid reabsorption, and amino acid metabolism. Accumulating evidence that some of these changes seem to be independent of weight loss questions the rationale of using body mass index as the major indication for surgery in diabetic patients. Understanding the complex mechanisms and interactions underlying improved glycemic control could lead to novel therapeutic targets and would also allow for greater individualization of therapy and optimization of surgical outcomes.

Topics: Bariatric Surgery; Body Mass Index; Caloric Restriction; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Homeostasis; Humans; Incretins; Insulin Resistance; Male; Obesity, Morbid; Peptide YY; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome; Weight Loss

To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus.. Systematic review and meta-analysis.. Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov.. Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs.. Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis.. 60 studies (n=353,639), consisting of 55 randomised controlled trials (n=33,350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320,289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13).. The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Pancreatitis; Randomized Controlled Trials as Topic; Receptors, Glucagon

Chronic diseases have become one of the most important public health problems, due to their high costs for treatment and prevention. Until now, researchers have considered that the etiology of Type 2 diabetes mellitus (T2DM) is multifactorial. Recently, the study of the innate immune system has offered an explanation model of the pathogenesis of T2DM. On the other hand, there is evidence about the beneficial effect of polyunsaturated fatty acids (PUFA) n-3 and n-6 in patients with chronic inflammatory diseases including diabetes. Furthermore, high vitamin D plasmatic concentrations have been associated with the best performance of pancreatic β cells and the improving of this disease. In conclusion, certain fatty acids in the adequate proportion as well as 25-hydroxivitamin D can modulate the inflammatory response in diabetic people, modifying the evolution of this disease.

Topics: Adipokines; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Gene Expression; Humans; Immunity, Innate; Incretins; Inflammation; Insulin; Insulin-Secreting Cells; Vitamin D

Management of recent-onset diabetes offers osteopathic physicians the opportunity to work with patients to set treatment goals and expectations for this progressive yet manageable disease, as well as intervene early to reduce the risk of diabetes-related complications. Starting effective therapy early--and intensifying therapy appropriately--to achieve and maintain glycemic goals has been shown to reduce microvascular risks and produce legacy effects that may have macrovascular benefits. Metformin remains a cornerstone of therapy for those patients who can tolerate it. Early combination therapy that is well tolerated reduces risks of hypoglycemia or unwanted weight gain, improves patient adherence, and addresses the multifactoral pathophysiology of even recent-onset diabetes. Incretin-based therapies have been shown to be effective across the spectrum of type 2 diabetes mellitus, including recent-onset diabetes. The present article reviews the use of incretin-based therapies early in the disease process of type 2 diabetes mellitus.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Metformin; Receptors, Glucagon

Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment of type 2 diabetes mellitus. Activation of GLP-1R signaling or inhibition of DPP-4 activity produces a broad range of overlapping and unique cardiovascular actions. Native GLP-1 regulates cardiovascular biology via activation of the classical GLP-1R, or through GLP-1(9-36), a cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved GLP-1R agonists are not cleaved to GLP-1(9-36) and produce the majority of their actions through the classical GLP-1R. The cardiovascular mechanisms engaged by DPP-4 inhibition are more complex, encompassing increased levels of intact GLP-1, reduced levels of GLP-1(9-36), and changes in levels of numerous cardioactive peptides. Herein we review recent experimental and clinical advances that reveal how GLP-1R agonists and DPP-4 inhibitors affect the normal and diabetic heart and coronary vasculature, often independent of changes in blood glucose. Improved understanding of the complex science of incretin-based therapies is required to optimize the selection of these therapeutic agents for the treatment of diabetic patients with cardiovascular disease.

Topics: Animals; Blood Glucose; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl Peptidase 4; Disease Models, Animal; Enzyme Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Lipid Metabolism; Mice; Receptors, Glucagon; Treatment Outcome

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Receptors, Glucagon; Risk Factors

Cardiovascular (CV) disease remains the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV disease in T2DM is complex and multifactorial, and includes abnormalities in endothelial cells, vascular smooth muscle cells, myocardium, platelets, and the coagulation cascade. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of agents that act by potentiating the action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. This review summarizes CV disease pathophysiology in T2DM and the potential effect of DPP-4 inhibitors on CV risk in patients with T2DM. Preclinical and small observational studies and post hoc analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Some effects of DPP-4 inhibitors are GLP-1 dependent, whereas others may be due to GLP-1-independent actions of DPP-4 inhibitors. Analyses of major adverse CV events occurring during clinical development of DPP-4 inhibitors found no increased risk of CV events or mortality and even a potential reduction in CV events. Two large CV outcome trials have been completed and report that saxagliptin and alogliptin did not increase or decrease adverse CV outcomes in patients with T2DM and CV disease or at high risk for adverse CV events. More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure, and there was a similar numerically increased risk of hospitalization for heart failure with alogliptin; however, the risk was not significantly greater compared with placebo. Dipeptidyl peptidase-4 inhibitors may affect some of the pathologic processes involved in the increased CV risk inherent in T2DM.

Topics: Animals; Blood Platelets; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Endothelial Cells; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Lipoproteins; Muscle, Smooth, Vascular; Myocardium; Risk Factors

The incretin class of anti-hyperglycemic agents, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-inhibitors, is an important addition to the therapeutic armamentarium for the management of appropriate patients with type 2 diabetes mellitus as an adjunct to diet and exercise and/or with the agents metformin, sulfonylureas, thiazolidinediones, or any combination thereof. More recently, US Food and Drug Administration (FDA)-approved indications for incretins were expanded to include use with basal insulin. This review article takes an evidence-based practice approach in discussing the importance of aggressive treatment for diabetes, the principles of incretin physiology and pathophysiology, use of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, and patient types and contexts where incretin therapy has been found beneficial, from metabolic syndrome to overt diabetes.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Evidence-Based Medicine; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Practice Guidelines as Topic; Receptors, Glucagon

As cardiovascular (CV) disease remains the major cause of mortality and morbidity in type 2 diabetes mellitus, reducing macrovascular complications has been a major target of antiglycemic therapies. Emerging evidence suggests that incretin-based therapies are safe and may provide CV and cerebrovascular (CBV) benefits beyond those attributable to glycemic control, making the class an attractive therapeutic option. However, the mechanisms whereby the various classes of incretin-based therapies exert CV and CBV benefits may be distinct and may not necessarily lead to similar outcomes. In this chapter, we will discuss the potential mechanisms and current understanding of CV and CBV benefits of native glucagon-like peptide (GLP)-1, GLP-1 receptor agonists and analogues, and of dipeptidyl peptidase-4 inhibitor therapies as a means to better understand differences in safety and efficacy.

Topics: Blood Glucose; Blood Pressure; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Incretins; Peptide Fragments; Receptors, Glucagon

Therapies targeting the action of incretin hormones have been under close scrutiny in recent years. The incretin effect has been defined as postprandial enhancement of insulin secretion by gut-derived factors. Likewise, incretin mimetics and incretin effect amplifiers are the two different incretin-based treatment strategies developed for the treatment of diabetes. Although, incretin mimetics produce effects very similar to those of natural incretin hormones, incretin effect amplifiers act by inhibiting dipeptidyl peptidase-4 (DPP-4) enzyme to increase plasma concentration of incretins and their biologic effects. Because glucagon-like peptide-1 (GLP-1) is an incretin hormone with various anti-diabetic actions including stimulation of glucose-induced insulin secretion, inhibition of glucagon secretion, hepatic glucose production and gastric emptying, it has been evaluated as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM). GLP-1 also manifests trophic effects on pancreas such as pancreatic beta cell growth and differentiation. Because DPP-4 is the enzyme responsible for the inactivation of GLP-1, DPP-4 inhibition represents another potential strategy to increase plasma concentration of GLP-1 to enhance the incretin effect. Thus, anti-diabetic properties of these two classes of drugs have stimulated substantial clinical interest in the potential of incretin-based therapeutic agents as a means to control glucose homeostasis in T2DM patients. Despite this fact, clinical use of GLP-1 mimetics and DPP-4 inhibitors have raised substantial concerns owing to possible side effects of the treatments involving increased risk for pancreatitis, and C-cell adenoma/carcinoma. Thus, controversial issues in incretin-based therapies under development are reviewed and discussed in this manuscript.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Glargine; Insulin Secretion; Insulin-Secreting Cells; Insulin, Long-Acting; Peptides; Receptors, Glucagon; Venoms

Type 2 diabetes mellitus is a progressive and heterogeneous disease. The decrease in insulin secretion by pancreatic beta cells and the increase of glucagon secretion by pancreatic beta cells, are the two major pathophysiologic characteristics. The majority of type 2 diabetics will therefore require insulin in the evolution of their disease, with weight gain and hypoglycaemia as side effects. GLP-1 analogs are effective therapeutic alternatives due to their actions on glucagon and insulin secretion, on satiety and gastric emptying. For patients inadequately controlled with conventional antidiabetics, GLP-1 analogs, introduced as an alternative or in combination with insulin, can prevent or reduce the side effects associated with insulin. Indeed, the risk of hypoglycaemia is reduced and the vicious circle of weight gain secondary to insulin/need to increase insulin doses is limited.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Molecular Targeted Therapy

Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Liver; Liver Diseases; Receptors, Glucagon

Hyperglycemia is common in hospitalized patients with and without prior history of diabetes and is an independent marker of morbidity and mortality in critically and noncritically ill patients. Tight glycemic control using insulin has been shown to reduce cardiac morbidity and mortality in hospitalized patients, but it also results in hypoglycemic episodes, which have been linked to poor outcomes. Thus, alternative treatment options that can normalize blood glucose levels without undue hypoglycemia are being sought. Incretin-based therapies, such as glucagon-like peptide (GLP)-1 receptor agonists (RAs) and dipeptidyl peptidase (DPP)-4 inhibitors, may have this potential.. A PubMed database was searched to find literature describing the use of incretins in hospital settings. Title searches included the terms "diabetes" (care, management, treatment), "hospital," "inpatient," "hypoglycemia," "hyperglycemia," "glycemic," "incretin," "dipeptidyl peptidase-4 inhibitor," "glucagon-like peptide-1," and "glucagon-like peptide-1 receptor agonist.". The preliminary research experience with native GLP-1 therapy has shown promise, achieving improved glycemic control with a low risk of hypoglycemia, counteracting the hyperglycemic effects of stress hormones, and improving cardiac function in patients with heart failure and acute ischemia. Large, randomized controlled clinical trials are necessary to determine whether these favorable results will extend to the use of GLP-1 RAs and DPP-4 inhibitors.. This review offers hospitalist physicians and healthcare providers involved in inpatient diabetes care a pathophysiologic-based approach for the use of incretin agents in patients with hyperglycemia and diabetes, as well as a summary of benefits and concerns of insulin and incretin-based therapy in the hospital setting.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins

Recently, incretin-based therapy was introduced for the treatment of type 2 diabetes (T2D). In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin) play an increasing role in the management of T2D.. An extensive literature search was performed to analyze the pharmacological characteristics of DPP-4i and their clinical implications.. DPP-4i present significant pharmacokinetic differences. They also differ in chemical structure, in the interaction with distinct subsites of the enzyme and in different levels of selectivity and potency of enzyme inhibition. Moreover, disparities in the effects on glycated hemoglobin, glucagon-like peptide-1 and glucagon levels and on glucose variability have been observed. However, indirect comparisons indicate that all DPP-4i have a similar safety and efficacy profiles. DPP-4i are preferred in overweight/obese and elderly patients because of the advantages of minimal or no influence on weight gain and low risk of hypoglycemia. For the same reasons, DPP-4i can be safely combined with insulin. However, currently cardiovascular outcomes related to DPP-4i are widely debated and the available evidence is controversial. Today, long-term studies are still in progress and upcoming results will allow us to better define the strengths and limits of this therapeutic class.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Weight Gain

Signals from the FDA Adverse Event Reporting System (AERS) and pre-clinical and human pancreata obtained from organ donors have suggested that incretin-based therapies used to treat type 2 diabetes mellitus, such as glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, may increase the risk of acute pancreatitis (AP) and pancreatic cancer (PC). However, data from observational studies and randomized trials have been conflicting. We conducted a literature review to identify and summarize all observational data published assessing the pancreatic safety of incretins.. Searches were conducted in MEDLINE via PubMed and Embase using the key terms for the time period of 1 January 2005, to 12 February 2014. A total of 180 articles were screened in abstract form and 49 were subsequently reviewed in full text for inclusion. Data from 12 articles are included in this report.. Data from the FDA AERS database suggest increased risk of AP and PC with GLP-1 receptor agonist and DPP-4 inhibitor use. These findings are not supported by population-based observational studies for either AP or PC; however, studies assessing the relationship between PC and incretin-based therapies are limited.. Current evidence is conflicting and inadequate to conclude whether use of incretin-based therapies increases the risk of AP and PC. Further studies, with the ability to provide long term follow-up, are needed.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incidence; Incretins; Observational Studies as Topic; Pancreatic Neoplasms; Pancreatitis; Receptors, Glucagon

Type 2 diabetes mellitus (T2DM) is mainly associated with impaired insulin secretion by the pancreatic β-cells, insulin resistance and elevated hepatic gluconeogenesis. Incretin based treatments for T2DM are now widely investigated and used. The incretin based therapies mainly include incretin hormones which are glucose-dependent insulinotropic peptides (GIP) and glucagon like peptide-1 (GLP-1) released from the endocrinal cells in the small intestine in response to food intake. The main function of GLP-1 is to induce insulin secretion and suppress glucagon secretion. This review describes the different formulation approaches for oral delivery of incretins and the limitations associated with this route of administration. We highlight the use of micro and nanosystems to efficiently deliver the incretins orally. Furthermore, we present several examples of the significant potential of these systems in pharmaceutical applications.

Topics: Administration, Oral; Animals; Blood Glucose; Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Drug Delivery Systems; Gastrointestinal Tract; Humans; Hypoglycemic Agents; Incretins; Microspheres; Nanoparticles

The dramatic rise in the prevalence of obesity and type 2 diabetes mellitus (T2DM) is associated with increased mortality, morbidity as well as public health care expenses worldwide. The need for effective and long-lasting pharmaceutical treatment is obvious. The record of anti-obesity drugs has been poor so far and the only efficient treatment today is bariatric surgery. Research has indicated that appetite inhibiting hormones from the gut may have a therapeutic potential in obesity. The gut incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral and central pathways mediating satiety. Clinical trials have shown that two GLP-1 receptor agonists exenatide and liraglutide have a weight-lowering potential in non-diabetic obese individuals. Furthermore, they may also hold a potential in preventing diabetes as compared to other weight loss agents.. The purpose of this review is to cover the background for the GLP-1-based therapies and their potential in obesity and pre-diabetes. Up-to-date literature on incretin-based therapies will be summarized with a special mention of their weight-lowering properties. The literature updated to August 2014 from PubMed was identified using the combinations: GLP-1, GLP-1 receptor agonists, incretins, obesity and pre-diabetes.. The incretin impairment, which seems to exist in both obesity and diabetes, may link these two pathologies and underlines the potential of GLP-1-based therapies in the prevention and treatment of these diseases.

Topics: Anti-Obesity Agents; Appetite; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Peptides; Prediabetic State; Receptors, Glucagon; Venoms

Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are new options in the treatment of type 2 diabetes mellitus. However, due to accumulating reports on the occurrence of acute pancreatitis (AP), a suspicion of an association between incretin-based therapies and pancreatic disease has arisen.. A review of the literature on the safety of incretin-based therapies in regard to AP and pancreatic cancer was undertaken with discussion of potential mechanisms as well as limitations.. Until now, several preclinical and clinical studies have been published; however, they present conflicting results. Common risk factors, low incidence rates, long latency periods (in regard to pancreatic malignancy), lack of availability of human pancreatic tissues during lifetime among others hamper the confirmation or exclusion of a causal association. The results of the ongoing large randomized controlled trials will add further data. In line with current recommendations by European Medicines Agency and FDA, incretin-based therapies should be discontinued in patients with suspicion of AP, and incretin mimetics should not be administered to patients with a history of AP. However, based on current knowledge, there is no sound reason for depriving type 2 diabetic patients in general of a beneficial and effective therapy. However, this conclusion cannot be final and should be subject to constant reevaluation and, if necessary, change.

Topics: Animals; Blood Glucose; Cell Transformation, Neoplastic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Pancreatic Neoplasms; Pancreatitis; Receptors, Glucagon; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Glucagon-like peptide-1 receptor (GLP-1) agonists and dipeptidyl-peptidase-4 (DPP-4) inhibitors are therapies that are used to treat hyperglycemia in patients with type 2 diabetes mellitus. Although both of these medication types primarily lower prandial and fasting blood glucose levels by enhanced GLP-1 receptor signalling, they have distinct mechanisms of action. Whereas DPP-4 inhibitors boost patient levels of endogenously produced GLP-1 (and glucose-dependent insulinotropic peptide) by preventing its metabolism by DPP-4 enzymatic activity, GLP-1 receptor agonists are either synthetic analogues of human GLP-1 or exendin-4 based molecules. They are tailored to resist hydrolysis by DPP-4 activity and to provide longer durability in the circulation compared with native GLP-1. Several roles for incretin-based diabetes therapies beyond the endocrine pancreas and their glycemic-lowering properties have now been described, including attenuation of cardiac myocyte injury and reduction in post-ischemic infarction size after cardiovascular insult. Favourable outcomes have also been observed on systolic blood pressure reduction, postprandial intestinal lipoprotein metabolism, endothelial cell function, modulation of innate immune-mediated inflammation and surrogate markers of renal function. As hypertension is an independent risk factor for premature death in patients with type 2 diabetes, potential favourable extrapancreatic actions, particularly within the heart, blood vessels and kidney, for this drug class are of considerable clinical interest. Herein, we highlight and provide critical appraisal of the clinical data supporting the antihypertensive effects of GLP-1 receptor agonists and DPP-4 inhibitors and link possible mechanisms of action to clinical outcomes reported for this drug class.

Topics: Antihypertensive Agents; Blood Glucose; Blood Pressure; Canada; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hyperglycemia; Incretins; Treatment Outcome

Type 2 diabetes increases the risk of developing cardiovascular (CV) complications such as myocardial infarction, heart failure, stroke, peripheral vascular disease, and CV-associated mortality. Strict glycemic control in diabetics has shown improvement in microvascular complications related to diabetes but has been unable to demonstrate major effects on macrovascular complications including myocardial infarction and stroke. Conventional therapies for diabetes that include insulin, metformin, sulfonylureas (SU), and alpha-glucosidase inhibitors have limited and/or controversial data on CV safety based on observational studies not designed or powered to assess CV safety of these medications. In 2008, the US Food and Drug Administration (FDA) revised regulations for the approval of medications for type 2 diabetes by requiring that enough CV events are accrued prior to approval to rule out an upper 95 % confidence interval (95 % CI) for HR of 1.8 for CV events, followed by ruling out an upper 95 % CI for HR of 1.3 in the post-approval period. To date, novel diabetes therapies including peroxisome proliferator-activated receptor (PPAR) gamma agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP 1) analogs, and sodium-glucose transporter-2 (SGL2) inhibitors have been evaluated in CV safety trials. Results from the first major CV outcome studies in type 2 diabetes, SAVOR-TIMI 53 and EXAMINE, have shown that neither saxagliptin nor alogliptin had increases in major CV events relative to placebo in high-risk patients. Ongoing and future trials will elucidate the CV safety for other DPP-4 inhibitors compared to SUs and the GLP-1 agonists versus placebo.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Practice Guidelines as Topic; Risk Assessment; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Corticosteroid-induced hyperglycemia is a common medical problem which can cause frequent hospitalizations and therefore relates to an increase in morbidity. Metformin, sulfonylureas, thiazolidinediones and insulin are well known available therapies for the treatment of steroid induced hyperglycemia. Incretin based therapies are a newly developing strategies with a considerable importance in the treatment regimen as well. This review aims at discussing the pathophysiology of steroid induced hyperglycemia in addition to the available therapies used for treatment, focusing on incretin therapies.

Topics: Adrenal Cortex Hormones; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Hospitalization; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Treatment Outcome

Type II diabetes (T2D) is a progressive condition affecting approximately 350 million adults worldwide. Whilst skeletal muscle insulin resistance and beta-cell dysfunction are recognised causes of T2D, progressive loss of lean muscle mass (reducing surface area for glucose disposal area) in tandem with ageing-related adiposity (i.e. sarcopenic obesity) also plays an important role in driving hyperglycaemia progression. The anabolic effects of nutrition on the muscle are driven by the uptake of amino acids, into skeletal muscle protein, and insulin plays a crucial role in regulating this. Meanwhile glucagon-like peptide (GLP-1) and glucose- dependent insulinotropic peptide (GIP) are incretin hormones released from the gut into the bloodstream in response to macronutrients, and have an established role in enhancing insulin secretion. Intriguingly, endocrine functions of incretins were recently shown to extend beyond classical insulinotropic effects, with GLP-1/GIP receptors being found in extra-pancreatic cells i.e., skeletal muscle and peripheral (muscle) microvasculature. Since, incretins have been shown to modulate blood flow and muscle glucose uptake in an insulin-independent manner, incretins may play a role in regulating nutrient-mediated modulation of muscle metabolism and microvascular tone, independently of their insulinotropic effects. In this review we will discuss the role of skeletal muscle in glucose homeostasis, disturbances related to insulin resistance, regulation of skeletal muscle metabolism, muscle microvascular abnormalities and disturbances of protein (PRO) metabolism seen in old age and T2D. We will also discuss the emerging non-insulinotropic role of GLP-1 in modulating skeletal muscle metabolism and microvascular blood flow.

Topics: Blood Flow Velocity; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Microcirculation; Muscle, Skeletal

The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin

Modulation of the incretin effect has opened up a new strategy in the treatment of diabetes mellitus type 2 (DM2). To date, this physiological mechanism has been boosted in two ways: firstly, by pharmacological inhibition of the enzyme that physiologically degrades glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP4); secondly, through the development of GLP-1 agonists (GLP-1a) that are resistant to the action of DPP-4. Several clinical trials have shown the clinical superiority of GLPa, which seems to be linked to higher circulating levels of GLP-1. On the other hand, this higher efficacy also seems to be associated with the higher rate of adverse effects associated with aGLP-1 therapy compared with DPP-4 inhibition. These and other differentiating characteristics of the two drug families will determine the choice of drug therapy in the personalized treatment of hyperglycemia in patients with DM2.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. Moreover slows gastric emptying -reducing postprandial glycemic excursions-, reduces body weight, systolic blood pressure and has beneficial effects in the cardiovascular and central nervous systems. Since the 1990s, the efficacy of GLP-1 in reducing blood glucose levels in type 2 diabetes (DM2) was well known. However, GLP-1 should be administered by chronic subcutaneous infusion because of the rapid cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4). Hence, DPP-4 inhibitors -which increase pseudo-physiologically endogenous GLP-1 levels- were developed. In addition, several GLP-1 receptor agonists have been designed to avoid DPP-4-breakdown and/or rapid renal elimination and, therefore, induce a pharmacologic effect in the GLP-1 receptor: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different structural, pharmacodynamic and clinical properties and could be administered in different therapeutical regimens giving us the opportunity to individualize the therapy of DM2.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Compounding; Exenatide; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Peptides; Treatment Outcome; Venoms

The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

Topics: Alzheimer Disease; Brain Ischemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liver Diseases; Parkinson Disease; Patient Care Planning

Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials.

Topics: Animals; Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Hepatitis; Humans; Incretins; Lipids; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Obesity; Receptors, Glucagon; Risk Factors; Signal Transduction; Treatment Outcome

The glucagon-like peptide-1 (GLP-1) mimetics are an established therapeutic option for patients with type 2 diabetes. However, the properties of the GLP-1 mimetics go beyond the strict metabolic control of the patients with diabetes. The neuroprotective effects of GLP-1 have been shown in recent studies opening new areas of research in neurodegenerative diseases such as Alzheimer's disease (AD), among others. AIM. Systematic review including experimental studies and human clinical trials demonstrating the neuroprotective properties of GLP-1 mimetics in AD.. The experimental studies that have been conducted in rodent models of AD have demonstrated the neuroprotective properties of GLP-1 in the central nervous system reducing beta-amyloid plaques, the oxidative stress and the inflammatory brain response. Clinical trials in patients with cognitive impairment and AD testing the effects of GLP-1 analogs have recently started.. The GLP-1 analogs have neuroprotective properties. Considering that type 2 diabetes is a risk factor for cognitive impairment and dementia, the benefits of GLP-1 mimetics on cognition must be considered. Likewise, the GLP-1 mimetics represent a promising treatment for neurodegenerative diseases such as AD.. Analogos del glucagon-like peptide-1 (GLP-1): una nueva estrategia de tratamiento para la enfermedad de Alzheimer?. Introduccion. Los analogos del glucagon-like peptide-1 (GLP-1) son una opcion terapeutica establecida en los pacientes con diabetes tipo 2. Sin embargo, las propiedades de los analogos del GLP-1 van mas alla del control estrictamente metabolico del paciente diabetico. Los efectos neuroprotectores de los analogos del GLP-1 se han puesto de manifiesto en estudios recientes y han abierto nuevos campos de investigacion en trastornos neurodegenerativos como la enfermedad de Alzheimer (EA), entre otros. Objetivo. Revision sistematica de los estudios experimentales y ensayos clinicos en humanos que demuestran las propiedades neuroprotectoras de los analogos del GLP-1 en la EA. Desarrollo. Los estudios experimentales que se han llevado a cabo en modelos de roedores con EA demuestran las propiedades neuroprotectoras de los analogos del GLP-1 sobre el sistema nervioso central que reducen las placas de beta-amiloide, el estres oxidativo y la respuesta inflamatoria cerebral. Recientemente se han puesto en marcha estudios con analogos del GLP-1 en humanos con deterioro cognitivo y EA. Conclusiones. Los analogos del GLP-1 presentan propiedades neuroprotectoras. Al considerarse la diabetes tipo 2 un factor de riesgo para el deterioro cognitivo y la demencia, deben considerarse los beneficios de los analogos del GLP-1 sobre la cognicion. Del mismo modo, los analogos del GLP-1 suponen un tratamiento prometedor en la EA.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Brain Chemistry; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Models, Neurological; Neuroprotective Agents; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Factors; Venoms

Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. Moreover slows gastric emptying -reducing postprandial glycemic excursions-, reduces body weight, systolic blood pressure and has beneficial effects in the cardiovascular and central nervous systems. Since the 1990s, the efficacy of GLP-1 in reducing blood glucose levels in type 2 diabetes (DM2) was well known. However, GLP-1 should be administered by chronic subcutaneous infusion because of the rapid cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4). Hence, DPP-4 inhibitors -which increase pseudo-physiologically endogenous GLP-1 levels- were developed. In addition, several GLP-1 receptor agonists have been designed to avoid DPP-4-breakdown and/or rapid renal elimination and, therefore, induce a pharmacologic effect in the GLP-1 receptor: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different structural, pharmacodynamic and clinical properties and could be administered in different therapeutical regimens giving us the opportunity to individualize the therapy of DM2.

Topics: Amino Acid Sequence; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Forecasting; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Half-Life; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Infusions, Subcutaneous; Kidney; Molecular Sequence Data; Multicenter Studies as Topic; Precision Medicine; Proteolysis; Receptors, Glucagon

GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Exenatide; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Male; Metformin; Peptides; Pioglitazone; Receptors, Glucagon; Thiazolidinediones; Venoms; Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer.

Topics: Animals; Antibody Formation; Blood Pressure; Carcinoma, Medullary; Cardiotonic Agents; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Gastrointestinal Motility; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Lipids; Meta-Analysis as Topic; Nausea; Pancreatitis; Receptors, Glucagon; Rodentia; Species Specificity; Thyroid Neoplasms; Vomiting

Type 2 diabetes (T2D) is a complex, progressive disease with life-threatening complications and one of the most serious public-health problems worldwide. The two main mechanisms of T2D pathogenesis are pancreatic beta cell dysfunction and insulin resistance. It is now recognized that pancreatic beta cell dysfunction is a necessary factor for T2D development. Traditional therapies for controlling blood glucose are suboptimal as they fail to meet target goals for many patients. Glucagon-like peptide-1 receptor agonists (GLP1RA) and dipeptidyl peptidase-4 inhibitors (DPP4I) are an attractive class of therapy because they reduce blood glucose by targeting the incretin hormone system and, in particular, have the potential to positively affect pancreatic beta cell biology. This review outlines our current understanding of pancreatic beta cell incretin system dysfunction in T2D and summarizes recent evidence of the effect of incretin-based therapies on beta cell function and mass. Incretin-based therapies have shown strong evidence for beneficial effects on beta cell function and mass in animal studies. In humans, incretin-based therapies are effective glucose-lowering agents, but further study is still required to evaluate their long-term effects on beta cell function and safety as well as beta cell mass expansion.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin-Secreting Cells

To evaluate the effectiveness and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors versus intermediate-acting insulin for adults with type 2 diabetes mellitus (T2DM) and poor glycaemic control despite treatment with two oral agents.. Studies were multicentre and multinational.. Ten studies including 2967 patients with T2DM.. Studies that examined DPP-4 inhibitors compared with each other, intermediate-acting insulin, no treatment or placebo in patients with T2DM.. Primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes were healthcare utilisation, body weight, fractures, quality of life, microvascular complications, macrovascular complications, all-cause mortality, harms, cost and cost-effectiveness.. 10 randomised clinical trials with 2967 patients were included after screening 5831 titles and abstracts, and 180 full-text articles. DPP-4 inhibitors significantly reduced HbA1c versus placebo in network meta-analysis (NMA; mean difference (MD) -0.62%, 95% CI -0.93% to -0.33%) and meta-analysis (MD -0.61%, 95% CI -0.81% to -0.41%), respectively. Significant differences in HbA1c were not observed for neutral protamine Hagedorn (NPH) insulin versus placebo and DPP-4 inhibitors versus NPH insulin in NMA. In meta-analysis, no significant differences were observed between DPP-4 inhibitors and placebo for severe hypoglycaemia, weight gain, cardiovascular disease, overall harms, treatment-related harms and mortality, although patients receiving DPP-4 inhibitors experienced less infections (relative risk 0.72, 95% CI 0.57 to 0.91).. DPP-4 inhibitors were superior to placebo in reducing HbA1c levels in adults with T2DM taking at least two oral agents. Compared with placebo, no safety signals were detected with DPP-4 inhibitors and there was a reduced risk of infection. There was no significant difference in HbA1c observed between NPH and placebo or NPH and DPP-4 inhibitors.. PROSPERO # CRD42013003624.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin, Isophane; Treatment Outcome

Incretin-based therapies exploit the insulinotropic actions of the gut hormones gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) for the treatment of diabetes and include GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 (DPP-4), the enzyme that inactivates the incretin hormones in the body. Both drug classes improve metabolic control in type 2 diabetes (T2DM), with GLP-1 receptor agonists also lowering body weight. Pharmacotherapy using DPP-4 inhibitors has few side effects and is weight neutral. Animal studies support their use in prediabetes; however, human data are scarce. GLP-1 receptor agonist effects are also apparent in non-diabetic obese individuals. Therefore, incretin-based therapies, if safe, may be effective in preventing progression of prediabetes; and GLP-1 receptor agonists may have potential for use in the treatment of obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity; Prediabetic State; Receptors, Glucagon

Most physicians are comfortable with initiating basal insulin replacement therapy in their patients with type 2 diabetes who are no longer meeting treatment goals with oral antidiabetic agents. What is more challenging is what to do when treatment goals are no longer being met despite adequate titration of basal insulin. Both fasting plasma glucose and postprandial glucose contribute to hemoglobin A1C levels. Addressing postprandial glucose levels can be accomplished by several approaches. Traditionally this has meant moving to basal bolus insulin, which is considered the gold standard. Premixed insulin may also be used. Data is also emerging for basal "plus" strategies, that is, incremental addition of prandial insulin injections. Newer approaches also reviewed in this article included premixed formulations containing ultra-long acting basal insulin with rapid-acting insulin analogs, inhaled insulin and insulin jet injectors, as well as the use of incretin-based therapies.

Topics: Administration, Inhalation; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Design; Fasting; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Injections, Jet; Insulin; Insulin, Long-Acting; Insulin, Short-Acting; Postprandial Period; Randomized Controlled Trials as Topic

Psoriasis is a chronic inflammatory skin disease with a global prevalence of 2-3%. In recent years it has been established that patients with psoriasis carry an increased risk of type 2 diabetes, but the underlying pathophysiological mechanisms remain unclear. The association is most likely due to a combination of shared genes, immunoinflammatory mechanisms and a number of diabetes risk factors in patients with psoriasis. The current review summarises the evidence in the field and calls for attention on diabetes risk assessment, preventive measures and treatment in patients with psoriasis.

Topics: Alcohol Drinking; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucocorticoids; Humans; Incretins; Metabolic Syndrome; Obesity; Psoriasis; Risk Factors; Smoking

Type 2 diabetes and obesity are intimately linked; reduction of bodyweight improves glycemic control, mortality and morbidity. Treating obesity in the diabetic is hampered as some diabetic treatments lead to weight gain. Bariatric surgery is currently the most effective antiobesity treatment and causes long-term remission of diabetes in many patients. However, surgery has a high cost and is associated with a significant risk of complications, and in practical terms only limited numbers can undergo this therapy. The choice of pharmacological agents suitable for treatment of diabetes and obesity is currently limited. The glucagon-like peptide-1 receptor agonists improve glycemia and induce a modest weight loss, but there are doubts over their long-term safety. New drugs such as lorcaserin and phentermine/topiramate are being approved for obesity and have modest, salutary effects on glycemia, but again long-term safety is unclear. This article will also examine some future avenues for development, including gut hormone analogues that promise to combine powerful weight reduction with beneficial effects on glucose metabolism.

Topics: Anti-Obesity Agents; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Obesity; Receptors, Glucagon; Weight Loss

The present short review summarizes and updates clinical experience with two classes of drugs introduced for the management of type 2 diabetes mellitus over the past 8 years: (i) the glucagon-like peptide-1 receptor agonists; and (ii) the dipeptidyl peptidase 4 inhibitors. Both classes of agents address the so called "incretin defect" in patients with T2DM.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Molecular Structure; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms

Incretins (gastric inhibitory polypeptide and glucagon-like peptide 1 [GLP-1]) are hormones released from the gastrointestinal tract during food intake that potentiate insulin secretion. Native GLP-1 is quickly degraded by the enzyme dipeptidylpeptidase-4 (DPP-4), which has led to the development of GLP-1 agonists with resistance to degradation and to inhibitors of DPP-4 activity as therapeutic agents in humans with type 2 diabetes. In healthy cats, GLP-1 agonists and DPP-4 inhibitors have produced a substantial increase in insulin secretion. Although results of clinical studies are not yet available, incretin-based therapy promises to become an important new research area in feline diabetes.

Topics: Animals; Cat Diseases; Cats; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Treatment Outcome

The gut derived peptides, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), are secreted following nutrient ingestion. GLP-1 and another gut peptide, glucose-dependent insulinotropic polypeptide (GIP) are collectively referred to as 'incretin' hormones, and play an important role in glucose homeostasis. Incretin secretion shares a complex interdependent relationship with both postprandial glycemia and the rate of gastric emptying. GLP-1 based therapies are now well established in the management of type 2 diabetes, while recent literature has suggested potential applications to treat obesity and protect against cardiovascular and neurological disease. The mechanism of action of GLP-2 is not well understood, but it shows promise as an intestinotropic agent.

Topics: Animals; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Gastric Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Incretins; Pancreas; Postprandial Period; Receptors, Glucagon

Insulin therapy has been the mainstay of therapy for patients with type 2 diabetes mellitus for the past 90 years. This trend is likely to continue as new formulations are developed to more closely mimic physiologic insulin secretion and to provide patients who have diabetes with more convenient options for integrating this therapy into their lifestyle. The present article reviews how the role of insulin continues to evolve, from its earlier use in the treatment paradigm (even at first diagnosis) to its role in combination therapy with incretin-based therapies, as well as new formulations that provide more-convenient forms of insulin replacement therapy.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin

To discuss the controversy surrounding selection of second-line type 2 diabetes mellitus (T2DM) therapy by reviewing available data regarding secondary effects of glucagon-like peptide-1 receptor (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, which include low hypoglycemia risk, weight loss, and cardiovascular (CV) and β-cell function benefits.. A MEDLINE search (1966-March 2013) was conducted using the following key terms: β-cell protection, blood pressure, DPP-4 inhibitors, exena tide, exenatide extended-release, GLP-1 agonists, hypoglycemia, lina glip tin, lipid, liraglutide, pancreatitis, saxagliptin, sitagliptin, and type 2 diabetes.. Identified articles published in English were evaluated for inclusion, with priority given to randomized controlled trials in humans receiving incretin monotherapy or incretin combination therapy with metformin. References identified in these articles were reviewed for additional trials.. Most patients with T2DM use combination therapy; however, determination of the second-line agent that is most appropriate is debatable. Prior to the use of incretin therapies, traditional second-line agents included sulfonylureas, thiazolidinediones, and basal insulin, all of which demonstrate undesirable adverse effects. In addition to improving glycemic control, incretin therapies have demonstrated benefits concerning hypoglycemic risk and weight loss in addition to potential improvements in CV risk factors and β-cell function. While there are risks associated with using incretins, most patients with T2DM are good candidates for incretins and could benefit from their potential secondary effects. Cost remains a barrier to initiating these agents.. Demonstrated secondary benefits in addition to efficacy may make GLP-1 agonists and DPP-4 inhibitors a more favorable option than other second-line T2DM therapies.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Metformin; Randomized Controlled Trials as Topic

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

The incretin effect refers to the augmentation of insulin secretion after oral administration of glucose compared with intravenous glucose administration at matched glucose levels. The incretin effect is largely due to the release and action on beta-cells of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This system has in recent years had considerable interest due to the success of incretin therapy as a glucose-lowering strategy in type 2 diabetes. In non-diabetic subjects, the incretin effect is responsible for 50-70% of insulin release during oral glucose administration. In type 2 diabetes patients, the incretin effect is impaired and contributes to only 20-35% of the insulin response to oral glucose. The reason for the defective incretin effect in type 2 diabetes has been the subject of many studies. Although the reports in the literature are mixed, most studies of GIP and GLP-1 secretory responses to oral glucose or a mixed meal have shown fairly normal results in type 2 diabetes. In contrast, the insulinotropic effects of both GIP and GLP-1 are impaired in type 2 diabetes with greater suppression of insulin secretion augmentation with GIP than with GLP-1. The suggested causes of these defects are a defective beta-cell receptor expression or post-receptor defects secondary to the diabetes milieu, defective beta-cell function in general resulting in defective incretin effect and genetic factors initiating incretin hormone resistance. Identifying the mechanisms in greater detail would be important for understanding the strengths, weaknesses and efficacy of incretin therapy in individual patients to more specifically target this glucose-lowering therapy.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion

Once lifestyle measures implemented, if hyperglycemia persists, above individual HbA1c targets, a medication should be started in type 2 diabetic patients (T2DM). First, unless exception, an oral antidiabetic drug. Except in case of intolerance, the initial monotherapy, metformin remains the strengthening treatment. Latter, combination of two oral drugs, now offers several options, mainly the choice to associate a "conventional insulin-secretor", sulfonylureas, glinide, or a "new one" belonging the class of "incretin", more readily a gliptine (DPP-4 inhibitors) rather than injectable GLP-1 analogue which can also be sometimes chosen at this stage. These options are mostly new and have the advantage a neutral or favourable (for GLP-1) effect on body weight in obese type 2 DM patient and the absence of any hypoglycaemic risk in both classes of incretins. But this risk varies depending on the patient profile, much higher if the target HbA1c is low (6 to 6.5 or 7%), or in the elderly, fragile and/or in case of renal insufficiency. These two different situations with a high risk of hypoglycaemia, define best indications of this new class. If dual oral therapy does not achieve the goals we are faced with three options: triple oral therapy: metformin-sulfonylurea-gliptine or one of two approaches with injections, insulin or GLP-1 analogues. The use of GLP-1 analogues is often delayed today and put wrongly in balance with the transition to insulin, a use already delayed in France and insufficient. The use of incretins is new and needs to be validated by studies of sustainability on glycemic control, prevention of microvascular and macrovascular complications and after years on the market security of use, primarily on the exocrine pancreas. In short, individualization of strategies and HbA1c targets are required, the new molecules can help us in this process. This individualization can easily be done through the handy guide proposed by the experts ADA EASD statement, endorsed by the SFD, abandoning the complex algorithm recently again proposed by HAS and ANSM in 2013. A recommendation that prioritizes the costs of the strategies. An absolutely critical issue, while admitting not to have the tools to measure them in all their dimensions. Finally, we must reconsider every treatment after a maximum of 6 months of use, if the results are deemed inadequate substitute rather than adding drugs.

Topics: Administration, Oral; Body Weight; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Management; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Goals; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Kidney; Metformin; Obesity; Practice Guidelines as Topic; Risk; Societies, Medical; Sulfonylurea Compounds

Pancreatic beta-cell mass expands through beta-cell proliferation and neogenesis while it decreases mainly via apoptosis. The loss of balance between beta-cell death and regeneration leads to a reduction of beta-cell functional mass, thus contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). The pathogenetic mechanisms causing T2DM are complex, and also include a significant reduction of the incretin effect. A better understanding of the role of incretin hormones in glucose homeostasis has led to the development of incretin-based therapies. Recently, incretin hormones have been shown to stimulate the beta-cell growth and differentiation from pancreas-derived stem/progenitor cells, as well as to exert cytoprotective, antiapoptotic effects on beta-cells. However, the role and the molecular mechanisms by which GLP-1 and its agonists regulate beta-cell mass have not been fully investigated. This review focuses the current findings and the missing understanding of the effects of incretin hormones on beta-cell mass expansion.

Topics: Animals; Cell Count; Cell Death; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin-Secreting Cells

Therapy based on incretins presents a new group of medicinal substances designated for an intervention in patients with type 2 diabetes. It includes a therapy that is efficient, safe and effective. Its advantage is a low risk of hypoglycaemia and a positive effect on body weight. The analyses that have been published so far consistently indicate a positive impact on cardiovascular risk factors. The first studies conducted on animal models prove a favourable influence ofincretin therapy on the pathophysiology of diabetic retinopathy.

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Incretins

The purpose of this review is to examine recently published literature in the areas of incretins and amylin in the management of pediatric diabetes.. Recent studies have begun to explore the use of longer-acting GLP-1 analogues that can be given once daily, such as liraglutide, and the use of DPP-IV inhibitors in the management of type 2 diabetes. In addition, recent studies have been published on the use of exenatide in the management of pediatric obesity and newly diagnosed type 1 diabetes.. Very few medications are approved for management of type 2 diabetes in youth. In addition, monotherapy of type 1 diabetes in youth with insulin does not achieve HbA1c targets in the majority of youth despite the use of rapid-acting insulin analogues, insulin pump therapy, and continuous glucose monitoring. Novel therapies that target physiologic modalities other than enhancing or replacing insulin secretion or improving insulin sensitivity have shown efficacy in adults. Studies with these drugs are being done in the pediatric population and should provide additional treatment options for these patients.

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Management; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Islet Amyloid Polypeptide; Pediatric Obesity

The dramatic rise in the prevalence of obesity and type 2 diabetes mellitus (T2DM) has become a major global public health issue. There is increasing evidence that metabolic surgery is more effective than diet and exercise for diabetes remission and weight loss. Moreover, the rapid time course and disproportional degree of T2DM improvement after metabolic procedures compared with equivalent weight loss with conservative treatment, suggest surgery-specific, weight-independent effects on glucose homeostasis. Gut hormones has been proposed as one of the potential mechanisms for the weight-independent diabetes remission and long-term weight loss after these procedures. In this review we discuss the available current metabolic procedures and we review the current human data on changes in gut hormones after each metabolic procedure.. El espectacular aumento de la prevalencia de la obesidad y la diabetes mellitus tipo 2 (DMT2) se ha convertido en un importante problema de salud pública mundial. Hay evidencias crecientes de que la cirugía metabólica es más eficaz que la dieta y el ejercicio para remisión de la diabetes y la pérdida de peso. Por otra parte, el inmediato y elevado grado de mejora de la DM2 tras los procedimientos metabólicos en comparación con la equivalente pérdida de peso mediante el tratamiento conservador, sugieren efectos específicos de la cirugía, peso-independientes en la homeostasis de la glucosa. Se han propuesto a las hormonas intestinales como uno de los posibles mecanismos para la remisión de la diabetes peso-independiente y la pérdida de peso a largo plazo la después de estos procedimientos. En esta revisión se discuten los procedimientos metabólicos actuales disponibles y se revisan los datos humanos actuales sobre los cambios en las hormonas intestinales después de cada procedimiento metabólico.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Hormones; Humans; Incretins

Insulin resistance has been associated with the development of type 2 diabetes, obesity, hypertension, dyslipidemia, atherosclerosis, and thus with increased cardiovascular morbidity and mortality. Insulin resistance precedes the onset of type 2 diabetes by many years. Targeting the pathophysiologic defects that characterize the onset of diabetes is more likely to achieve a durable glucose control and to delay disease progression. Incretins are gut-derived peptides that stimulate in a glucose-dependent mechanism insulin secretion and action. Glucose-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors both decrease fasting and postprandial glucose levels. In addition, GLP-1 analogues promote weight loss and exert a favorable effect on several cardiovascular risk factors. Data from human and experimental studies implicate that GLP-1 analogues and to a less extend DPP-4 inhibitors enhance insulin sensitivity. This review summarizes the current knowledge regarding the impact of GLP-1 analogues and DPP-4 inhibitors on insulin resistance.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance

An important role in the regulation of glucose homeostasis is played by incretins, which are gut-derived hormones released in response to nutrient ingestion. In humans, the major incretin hormones are glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), and together they fully account for the incretin effect (that is, higher insulin release in response to an oral glucose challenge compared to an equal intravenous glucose load). Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, and the loss of incretin effect is likely to contribute importantly to the postprandial hyperglycaemia in type 2 diabetes. However, the specific cause-effect relationship between disease and incretins is still unclear. This review focuses on several key studies elucidating the association of defective incretin action with obesity and T2DM and the effects of metformin and other anti-diabetic agents on the incretin system.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Obesity

The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological responses to the incretin hormone glucagon-like peptide-1 and is a major therapeutic target for the treatment of type 2 diabetes, owing to the broad range of effects that are mediated upon its activation. These include the promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin action, and promotion of weight loss. Regulation of GLP-1R function is complex, with multiple endogenous and exogenous peptides that interact with the receptor that result in the activation of numerous downstream signaling cascades. The current understanding of GLP-1R signaling and regulation is limited, with the desired spectrum of signaling required for the ideal therapeutic outcome still to be determined. In addition, there are several single-nucleotide polymorphisms (used in this review as defining a natural change of single nucleotide in the receptor sequence; clinically, this is viewed as a single-nucleotide polymorphism only if the frequency of the mutation occurs in 1% or more of the population) distributed within the coding sequence of the receptor protein that have the potential to produce differential responses for distinct ligands. In this review, we discuss the current understanding of GLP-1R function, in particular highlighting recent advances in the field on ligand-directed signal bias, allosteric modulation, and probe dependence and the implications of these behaviors for drug discovery and development.

Topics: Allosteric Regulation; Amino Acid Sequence; Diabetes Mellitus, Type 2; Drug Discovery; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Incretins; Insulin; Insulin Secretion; Molecular Sequence Data; Polymorphism, Single Nucleotide; Receptors, Glucagon; Signal Transduction

Comorbid obesity, dyslipidemia, and hypertension place patients with type 2 diabetes (T2DM) at greatly increased risk of cardiovascular (CV) disease-related morbidity and mortality. An urgent need exists for effective treatment for patients with T2DM that encompasses glycemic control, weight loss, and reduction in CV risk factors. The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide are incretin-based antidiabetes agents. This review examines CV-associated effects of liraglutide and exenatide in animal models and clinical trials with patients with T2DM. Studies support the effectiveness of GLP-1 RAs in reducing hyperglycemia. Further, GLP-1 RAs represent a significant advance in T2DM treatment because they uniquely affect a broad array of CV risk factors through significant weight and systolic blood pressure reduction, improved lipid levels, and possibly, as shown in in vitro studies and animal models, through direct effects on cardiac myocytes and endothelium.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Receptors, Glucagon; Risk Factors; Treatment Outcome; Venoms

The use of natural products is very common among non-industrialized societies because these remedies are more accessible and affordable than modern pharmaceuticals. In developed countries, use of herbal products has recently increased as scientific evidence about their effectiveness has become broadly available. For the past two decades many research articles in the field of ethno-pharmacology have focused on the anti-diabetic effects of some natural products. This dramatic increase of interest was partly due to the fact that type 2 diabetes mellitus (T2DM) was considered as becoming a global epidemic health problem which imposed high cost to national health services around the world. We have no intention to advocate for replacing conventional pharmacotherapy with natural products to prevent and control T2DM. However, the fact that a lack of highly effective drug-therapy with existing synthetic agents and their resulting adverse effects motivated further search into traditional medicine in order to re-evaluate old remedies as well as screening to find new natural entities to be used as anti-diabetic products cannot be ignored. Some recent reports on the natural products with anti-diabetic effects have provided evidence for possible mechanisms of action. Nonetheless, the majority of investigators only speculated on a wide range of possible mechanisms or simply demonstrated an anti-hyperglycemic effect for the crude plant extracts or the isolated compounds of interest. A few reviews with less attention paid to mechanisms of action have been published on medicinal plants and diabetes. This article reviews publications on anti-diabetic natural products that have appeared in PUBMED or other research-related literature found on the Internet (from 1990 to present) to categorize them based on their mechanisms of action. We hope that this communication will be beneficial as a starting point to consider the discussed products for further investigations to identify and develop new remedies with potential alternative or complementary use in controlling T2DM.

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Complementary Therapies; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Signal Transduction

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Insulin; Treatment Outcome

Treating patients with diabetes is one of the most challenging and important activities a physician (primary care physician or specialist) can undertake. A key to successful therapy for type 2 diabetes is the insight that this condition is progressive and that the need for additional agents over time is normative. The ability to individualize therapy by patient and medication characteristics comes from experience and knowledge of pertinent clinical studies. However, guidelines from expert bodies such as the American Diabetes Association/European Association for the Study of Diabetes and American Association of Clinical Endocrinologists/American College of Endocrinology can help clinicians of all levels of expertise to approach therapy choices more rationally. There is unity across these guidelines about the role and benefits of metformin as first-line pharmacological treatment, probability of good efficacy, low risk of hypoglycemia, modest weight loss, and overall long-term data. Unfortunately, this unity does not extend to recommendations for subsequent pharmacological agents and their use in combination to intensify treatment when insulin is not (yet) appropriate. Across both statements, some drug classes seem more prominent, and looking at their benefit-risk profile, it is clear why this is the case. The most profound recent change in diabetes therapy has been the introduction of incretin therapies. Incretin therapies minimize 2 important adverse effects seen with many other therapies: hypoglycemia and weight gain. These agents have increased the range of options available for early intensification of treatment of type 2 diabetes. In combination with more established therapies, there are more opportunities than ever to accommodate patient preferences while improving glycemic control and harnessing extraglycemic benefits of a second (or third) agent.

Topics: Algorithms; Carbamates; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Metformin; Peptides; Piperidines; Practice Guidelines as Topic; Receptors, Glucagon; Sulfonylurea Compounds; Thiazolidinediones; Venoms

The aim of this review article is to discuss the epidemiological links between diabetes and cancer; the potential biological mechanisms linking diabetes, obesity and cancer; the risk of cancer associated with antidiabetic medications.. The data discussed in this review were obtained from the American Association of Clinical Endocrinologists Consensus Conference on Diabetes and Cancer, held in New York, NY, USA, September 2012.. The results of these studies demonstrate a significant association between diabetes and the risk of multiple cancers, including hepatocellular, pancreatic, endometrial, colorectal, breast, kidney, bladder, gastric, and ovarian cancer, non-Hodgkin lymphoma, T cell lymphoma and leukemia. There are multiple potential biological mechanisms that may link type 2 diabetes, obesity and cancer. Insulin resistance and hyperinsulinemia may lead to direct activation of the insulin receptors on tumor cells and promote tumor growth. Other potential mechanisms include increased circulating, local or bioavailable insulin-like growth factor 1, hyperglycemia, dyslipidemia, increased circulating or local estrogen, adipokines and direct and indirect effects of inflammatory cytokines. Epidemiological studies have had conflicting results regarding the associations between various classes of antidiabetic medication and cancer development. Animal studies have demonstrated increased tumor growth with certain medications, but their relevance to humans is uncertain. Metformin may, however, have protective effects on cancer development and may improve survival in patients with cancer.. We describe the current understanding of the links among diabetes, antidiabetic medication and cancer risk. We highlight some of the issues that should be addressed in the future to prevent cancer development and death in those with diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Neoplasms; Obesity; Risk Factors; Thiazolidinediones

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in people with diabetes and therefore managing cardiovascular (CV) risk is a critical component of diabetes care. As incretin-based therapies are effective recent additions to the glucose-lowering treatment armamentarium for type 2 diabetes mellitus (T2D), understanding their CV safety profiles is of great importance. Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with beneficial effects on CV risk factors, including weight, blood pressure and lipid profiles. Encouragingly, mechanistic studies in preclinical models and in patients with acute coronary syndrome suggest a potential cardioprotective effect of native GLP-1 or GLP-1 receptor agonists following ischaemia. Moreover, meta-analyses of phase 3 development programme data indicate no increased risk of major adverse cardiovascular events (MACE) with incretin-based therapies. Large randomized controlled trials designed to evaluate long-term CV outcomes with incretin-based therapies in individuals with T2D are now in progress, with the first two reporting as this article went to press.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Risk Factors; Time Factors; Treatment Outcome

Recent suggestions that glucagon-like peptide-1 (GLP-1)-based therapies could cause pancreatitis, and even pancreatic cancer, are based on:. The worrying histological changes are not reproduced in all studies and are unexpectedly variable with different GLP-1-based therapies.. Singh's findings that pancreatitis is doubled with GLP-1-based therapies could relate to their use in obese patients who are prone to pancreatitis risk factors--gallstones and hypertriglyceridaemia. The other observational studies do not find an association between GLP-1-based therapies and pancreatitis.. The increased reports of pancreatitis and pancreatic cancer are likely to be attributable to 'notoriety bias'.. Butler's findings for those on GLP-1-based therapies vs. those not, could have other explanations. Meanwhile: META ANALYSIS: Randomized control trials with GLP-1-based therapies do not find increased pancreatitis risk. Meta-analysis of 53 randomized controlled trials including 20 212 dipeptidyl peptidase-4 inhibitor-treated patients found a significantly reduced risk of major adverse cardiovascular events [odds ratio 0.689 (0.528-0.899), P = 0.006] for dipeptidyl peptidase-4 inhibitors compared with control subjects.. The evidence suggests that there is more than a possibility that some of the GLP-1 receptor agonists, and possibly also some dipeptidyl peptidase-4 inhibitors, may be associated with reduced cardiovascular events. Eight ongoing long-term cardiovascular randomized controlled trials will report from September 2013 onwards. These trials should resolve the issue of pancreatitis risk and substantiate the extent of benefit.. Whilst we should remain vigilant, currently the balance of evidence is strongly in support of GLP-1-based therapy, with benefits far outweighing potential risks.

Topics: Adverse Drug Reaction Reporting Systems; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Liraglutide; Male; Pancreatic Neoplasms; Pancreatitis; Patient Selection; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Assessment; Risk Factors; Venoms

Obesity is a chronic disease, and it requires chronic therapy. Hypertension, dyslipidemia, diabetes and cardiovascular diseases are leading causes of mortality in the modern world. All of them are strongly linked to obesity. While treating obesity, those conditions are also managed. Obese patients should always be treated through lifestyle interventions, though the results of such interventions are modest. Pharmacotherapy is a second step in the treatment of obesity, approved only when weight loss targets were not reached through lifestyle intervention. During the history of antiobesity drugs, many of them were withdrawn because of their side effects. Various guidelines recommend prescribing drug therapy for obesity through consideration of the potential benefits and limitations. Orlistat deactivates intestinal lipase and inhibits intestinal fat lipolysis. It is actually the only drug on the European market approved for the treatment of obesity. Orlistat therapy reduces weight to a modest extent, but it reduces the incidence of diabetes beyond the result achieved with lifestyle changes. Recently, some effective antiobesity drugs like sibutramine and rimonabant have been removed from the market due to their side effects. The new combination of topimarate and fentermine is approved in the US but not in Europe. The cost effectiveness of long-term pharmacotherapy of obesity is still an unresolved question.

Topics: Anti-Obesity Agents; Appetite; Combined Modality Therapy; Comorbidity; Cost-Benefit Analysis; Cyclobutanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Drug Combinations; Exercise Therapy; Fructose; Gastrointestinal Hormones; Humans; Incretins; Insulin; Insulin Secretion; Intestines; Lactones; Leptin; Life Style; Models, Biological; Neuropeptides; Obesity; Orlistat; Phentermine; Phytotherapy; Piperidines; Plant Preparations; Pyrazoles; Rimonabant; Topiramate

Type 2 Diabetes Mellitus (T2D) and osteoporosis have been found recently to be tightly correlated. In fact, T2D can result in bone loss through different mechanisms resulting in alteration of bone matrix and inhibition of bone formation. Fracture risk also increases significantly. New antidiabetic agents, dipeptidyl peptidase-4 inhibitors and glucagon like peptide -1 agonists have shown promise in many fields beyond glycemic control. Benefits on the skeletal system are multiple through direct stimulation of osteoblasts, inhibition of advanced glycation end products and inhibition of bone resorption. However, clinical evidence in humans is still not enough to allow definitive conclusions.

Topics: Animals; Blood Glucose; Bone Density; Bone Density Conservation Agents; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Osteoporosis

Topics: Diabetes Mellitus, Type 2; Fatty Liver; Humans; Incretins; Liver; Non-alcoholic Fatty Liver Disease

The ADA/EASD and AACE guidelines emphasize the importance of individualizing treatment to best meet each patient's situation. Metformin remains the preferred choice as initial therapy for most patients. The 2009 AACE algorithm elevated the role of incretin-based therapies (GLP-1R agonists and DPP-4 inhibitors) relative to previous algorithms and this has been endorsed by subsequent algorithms and guidelines. The incretin-based therapies and insulin therapy should be considered with very high priority. Either incretin-based therapy or insulin therapy can be used as monotherapy or in combination with other agents. The GLP-1R agonists are especially useful when attempting to reduce the risk of hypoglycemia and when assisting the patient to achieve weight loss. Insulin therapy is especially useful when the HbA1c level is >9.0% or when symptoms of glucotoxicity are present. Insulin is the recommended treatment when other agents fail to achieve the desired target levels for HbA1c, FPG, and PPG. The combination of a GLP-1R agonist with basal insulin can provide better glycemic control than either agent alone, with less weight gain and glycemic outcomes for combined therapy with a long-acting basal insulin analog and a glucagon-like peptide-1 receptor agonist a markedly lower incidence of hypoglycemia than with use of basal insulin alone.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Receptors, Glucagon; Treatment Outcome

Recent years have seen an enormous increase in the number of therapeutic agents available for lowering blood glucose levels in people with type 2 diabetes. Among these agents, the incretin mimetics glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors have received particular attention for the potential of these interventions to positively impact on cardiovascular outcomes. Although the results of large-scale cardiovascular outcome trials eagerly are anticipated, an increasing body of literature from preclinical and early phase clinical studies has indicated that both GLP-1R agonists and DPP4 inhibitors may exert glucose-independent cardiovascular effects. Despite its role in glucose homeostasis, the GLP-1R is surprisingly widely distributed throughout the body, including in the heart. GLP-1 may exert its effects through both receptor-dependent and receptor-independent mechanisms and through the actions of both the intact peptide and its metabolites. In addition, DPP4 inhibition not only augments the circulating levels of incretin hormones, but it also holds the capacity to augment the activity of other biologically important substrates, most notably the small protein stromal cell-derived factor 1 alpha. Whether these collective functions will act to reduce cardiovascular events in patients remains to be determined.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Myocytes, Cardiac; Peptides; Treatment Outcome; Venoms

Our research focuses on the molecular mechanisms controlling glycemia in healthy and diabetic individuals. Diabetes is now considered as a worldwide epidemic by WHO, and is predicted to affect several hundred million people in the near future. Current therapies have failed to prevent or control hyperglycemia, as well as the deleterious cardiovascular consequences of the disease have increased. New paradigms are thus needed to develop novel therapeutic strategies. Over the last 15 years, we have been studying the intestine as a major regulator of the integrated cross-talk between the brain, liver, pancreas, muscles and blood vessels required for glycemic control. As a first example, we identified that during a meal the glucose transporter GLUT2 and the intestinal hormone glucagon-like peptide-1 (GLP-1) are involved in glucose detection by the entero-portal system. This was done using highly innovative experimental techniques in the awake free moving mouse. We then found that the enteric-vagal nervous system transmits this nutritional information towards the brain stem and hypothalamus, where leptin, neuropeptide Y and GLP-1 relay the enteric signal to control the endocrine pancreas (insulin-glucagon secretion), the liver (glycogen metabolism), the vascular system (vasodilation, arterial flow), and muscle metabolism. This "anticipatory metabolic reflex " is altered during diabetes and might thus represent a new pharmacological target. Subsequently, while investigating the molecular mechanisms responsible for regulating this new physiological pathway, we discovered that a fat-rich diabetogenic diet alters the intestinal microbiota and permeability. This leads to an increase in the concentration of plasma lipopolysaccharides (LPS), which causes metabolic endotoxemia responsible for the induction of low-grade inflammation that characterizes type 2 diabetes, insulin resistance, adipose tissue development and hepatic lipid storage. We then showed that bacteria can be translocated from the intestine towards tissues and the bloodstream. Bacterial DNA present in blood was found to be predictive of diabetes, 6-9 years before disease onset (patent), presenting new molecular targets in the microbiota-host relationship. This should enable the scientific community to discover new functional relationships between the genome and metagenome and thus to develop original preventive and therapeutic strategies for metabolic diseases. Four biotechnology companies have already b

Topics: Adipocytes; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Humans; Incretins; Intestinal Mucosa; Intestines; Mice; Microbiota

Type 2 Diabetes Mellitus is most common form of diabetes. Oral agents are the main stay of pharmacological treatment for type 2 diabetes mellitus. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a new therapeutic approach for type 2 diabetes. Sitagliptin is highly selective DPP-4 inhibitor that has been approved for type 2 diabetes therapy. It acts by increasing the levels of incretins by inhibiting their degradation by DPP-4. Sitagliptin has been shown to be effective, well tolerated and safe in the treatment of type 2 diabetes in monotherapy or in combination with metformin or thiozolidinediones with minimal side effects.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Hypoglycemic Agents; Incretins; Pyrazines; Sitagliptin Phosphate; Triazoles

Diabetes is a metabolic disease and is a major cause of mortality and morbidity in epidemic proportions. A type I diabetic patient is dependent on daily injections of insulin, for survival and also to maintain a normal life, which is uncomfortable, painful and also has deleterious effects. Extensive efforts are being made worldwide for developing noninvasive drug delivery systems, especially via oral route. Oral route is the most widely accepted means of administration. However it is not feasible for direct delivery of peptide and protein drugs. To overcome the gastro-intestinal barriers various types of formulations such as polymeric micro/nanoparticles, liposomes, etc. are investigated. In the recent years lot of advances have taken place in developing and understanding the oral peptide delivery systems. Simultaneously, the development and usage of other peptides having anti-diabetic potentials are also considered for diabetes therapy. In this review we are focusing on the advances reported during the past decade in the field of oral insulin delivery along with the possibility of other peptidic incretin hormones such as GLP-1, exendin-4, for diabetes therapy.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 2; Exenatide; Gastrointestinal Hormones; Humans; Hypoglycemic Agents; Incretins; Insulin; Peptides; Venoms

Consumption of milk and dairy products has been associated with reduced risk of metabolic disorders and cardiovascular disease. Milk contains two primary sources of protein, casein (80%) and whey (20%). Recently, the beneficial physiological effects of whey protein on the control of food intake and glucose metabolism have been reported. Studies have shown an insulinotropic and glucose-lowering properties of whey protein in healthy and Type 2 diabetes subjects. Whey protein seems to induce these effects via bioactive peptides and amino acids generated during its gastrointestinal digestion. These amino acids and peptides stimulate the release of several gut hormones, such as cholecystokinin, peptide YY and the incretins gastric inhibitory peptide and glucagon-like peptide 1 that potentiate insulin secretion from β-cells and are associated with regulation of food intake. The bioactive peptides generated from whey protein may also serve as endogenous inhibitors of dipeptidyl peptidase-4 (DPP-4) in the proximal gut, preventing incretin degradation. Indeed, recently, DPP-4 inhibitors were identified in whey protein hydrolysates. This review will focus on the emerging properties of whey protein and its potential clinical application for obesity and Type 2 diabetes.

Topics: Appetite; Cholecystokinin; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Milk Proteins; Obesity; Peptide YY; Thermogenesis; Whey Proteins

The majority of patients with type 2 diabetes mellitus (T2DM) do not achieve the glycaemic goals recommended by leading diabetes organizations using monotherapy alone, and often require multiple antihyperglycaemic agents to achieve glycaemic control. Fixed-dose combination (FDC) therapies offer a means to simplify complex treatment regimens, and have several advantages that help patients reach their glycaemic goals. In this review, four key benefits are identified and discussed in support of FDCs for treatment of patients with T2DM: (i) Greater efficacy compared with higher dose monotherapy, (ii) Reduced risk of adverse reactions relative to higher dose monotherapy, (iii) Lower overall costs and (iv) Improved medication concordance. Given these advantages, the place of fixed combination therapy in the course of treatment is discussed. Establishing a therapeutic strategy that incorporates fixed combination therapy (including combinations with insulin) will simplify the treatment of diabetes, ideally resulting in improved medication concordance, clinical outcomes and quality of life for patients with T2DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Drug Combinations; Drug Costs; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Medication Adherence; Metformin; Quality of Life; Sulfonylurea Compounds; Treatment Outcome

Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Metformin; Treatment Outcome; Weight Loss

The introduction of dipeptidyl peptidase 4 (DPP4) inhibitors for the treatment of Type 2 diabetes acknowledges the fundamental importance of incretin hormones in the regulation of glycemia. Small molecule inhibitors of DPP4 exert their effects via inhibition of enzymatic degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The widespread expression of DPP4 in tissues such as the vasculature and immune cells suggests that this protein may play a role in cardiovascular function. DPP4 is known to exert its effects via both enzymatic and non-enzymatic mechanisms. A soluble form of DPP4 lacking the cytoplasmic and transmembrane domain has also been recently recognized. Besides enzymatic inactivation of incretins, DPP4 also mediates degradation of many chemokines and neuropeptides. The non-enzymatic function of DPP4 plays a critical role in providing co-stimulatory signals to T cells via adenosine deaminase (ADA). DPP4 may also regulate inflammatory responses in innate immune cells such as monocytes and dendritic cells. The multiplicity of functions and targets suggests that DPP4 may play a distinct role aside from its effects on the incretin axis. Indeed recent studies in experimental models of atherosclerosis provide evidence for a robust effect for these drugs in attenuating inflammation and plaque development. Several prospective randomized controlled clinical trials in humans with established atherosclerosis are testing the effects of DPP4 inhibition on hard cardiovascular events.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Inflammation; Mice

Incretin-based therapy was first made available for the treatment of type 2 diabetes mellitus (T2DM) in the US in 2006 and in Japan in 2009. Four DPP-4 inhibitors and two GLP-1 analog/receptor agonists are currently available. The effects of incretin-based therapy are assumed to be exerted mainly through the hormonal and neuronal actions of one of the incretins, GLP-1, which is secreted from L cells localized in the small intestine. The benefits of this therapy over conventional sulfonylureas or insulin injections, such as fewer hypoglycemic events and reduced body weight gain, derive from the glucose-dependent insulinotropic effect. The protective effects of this therapy on vulnerable pancreatic β-cells and against micro/macroangiopathy in T2DM are also most welcome. Indications and/or contraindications for incretin-based therapy should be clarified by prospectively studying the experiences of Japanese T2DM patients undergoing this therapy in the clinical setting.

Topics: Asian People; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Japan; Receptors, Glucagon; Treatment Outcome

Development of cardiovascular disease is one of the major complications of type 2 diabetes mellitus (T2DM). The chronic hyperglycaemic state is often accompanied by dyslipidaemia, hypertension, low-grade systemic inflammation and oxidative stress which collectively result in a high risk of micro- and macrovascular complications. Current glucose-lowering agents do not sufficiently address fore-mentioned macrovascular-risk factors. Recently, new therapeutic agents were introduced, based on the incretin hormone glucagon-like peptide-1 (GLP-1), that is, the GLP-1 receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 (DPP-4) inhibitors. Beside its effect on pancreatic insulin secretion, GLP-1 exerts several extra-pancreatic effects such as slowing down gastric emptying, promoting satiety and reducing food intake and weight loss. Also, GLP-1 and GLP-1RA were shown to improve cardiovascular-risk profiles, by reducing body fat content, blood pressure, circulating lipids and inflammatory markers in patients with T2DM. This review summarizes the presently known evidence with regard to extra-pancreatic effects of the incretin-based agents, focusing on the actions that improve the cardiovascular-risk profile. We present available data from clinical trials of at least 24 week duration, but also findings from small-sized clinical 'proof of principle' studies. We conclude that GLP-1 RA and to a lesser extent DPP-4 inhibitors are promising agents with regard to their effects on body weight, blood pressure and lipids, which collectively ameliorate the cardiovascular-risk profile and as such may have added value in the treatment of T2DM. However, large-sized long-term outcome studies are warranted to show the true added value of these agents in the treatment of patients with T2DM.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemic Agents; Incretins; Receptors, Glucagon; Risk Factors

The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from the salivary secretions of the Gila monster. Exenatide was developed as a first-in-class diabetes therapy, with immediate- and extended-release formulations. In preclinical diabetes models, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, reduced body weight, enhanced satiety, and preserved pancreatic β-cell function. In clinical trials, both exenatide formulations reduced hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and were associated with weight loss.. This article reviews the development of exenatide from its discovery and preclinical investigations, to the elucidation of its pharmacological mechanisms of action in mammalian systems. The article also presents the pharmacokinetic profiling and toxicology studies of exenatide, as well as its validation in clinical trials.. GLP-1 receptor agonists represent a new paradigm for the treatment of patients with T2DM. By leveraging incretin physiology, a natural regulatory system that coordinates oral nutrient intake with mechanisms of metabolic control, these agents address multiple core defects in the pathophysiology of T2DM. Studies have identified unique benefits including improvements in glycemic control and weight, and the potential for beneficial effects on the cardiometabolic system without the increased risk of hypoglycemia associated with insulin therapy. Peptide hormone therapeutics can offer significant advantages over small molecule drug targets when it comes to specificity, potency, and more predictable side effects. As exemplified by exenatide, injectable peptides can be important drugs for the treatment of chronic diseases, such as T2DM.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Models, Animal; Peptides; Venoms

Clinical trials comparing incretin-based therapies-glucagon-like peptide-1 receptor agonists (exenatide-twice daily and once weekly-and once-daily liraglutide) and dipeptidyl peptidase-4 inhibitors (vildagliptin, sitagliptin, saxagliptin and linagliptin)-with placebo and oral antidiabetic drugs show that these therapies effectively control glycaemia, with low risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists are associated with weight loss and reductions in systolic blood pressure, while dipeptidyl peptidase-4 inhibitors are weight-neutral. Based on this, the National Institute for Health and Clinical Excellence recommends using these agents in patients with type 2 diabetes for whom excess weight and/or hypoglycaemia are problematic.. This review aims to help decision making when selecting and using incretin-based therapies in type 2 diabetes.. A search or MEDLINE and Cochrane clinical trials databases, limited to clinical trials in humans, was performed using the search criteria 'exenatide or liraglutide or vildagliptin or sitagliptin, or saxagliptin or linagliptin'. Abstracts presented at recent American Diabetes Association and European Association for the Study of Diabetes meetings were also searched. Eighteen clinical trials directly comparing incretin-based therapies were identified.. Glucagon-like peptide-1 receptor agonists achieved significantly greater reductions in glycated hemoglobin and weight than dipeptidyl peptidase-4 inhibitors, which have a neutral effect on weight. Between-treatment differences were clinically important. Gastrointestinal side effects were more frequent with glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors. Comparisons between glucagon-like peptide-1 receptor agonists and between dipeptidyl peptidase-4 inhibitors showed that differences within the available agents in the two sub-classes are small. Greater treatment satisfaction was reported with glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors.. Glucagon-like peptide-1 receptor agonists achieve greater glycated hemoglobin reductions than dipeptidyl peptidase-4 inhibitors, with concomitant weight loss. Probably due to the greater efficacy of glucagon-like peptide-1 receptor agonists, patient satisfaction is greater with these agents compared with dipeptidyl peptidase-4 inhibitors despite injectable versus oral administration and more frequent gastrointestinal side effects with the agonists.

Topics: Blood Pressure; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Patient Satisfaction; Receptors, Glucagon; Weight Loss

As the pandemic of type 2 diabetes spreads globally, clinicians face many challenges in treating an increasingly diverse patient population varying in age, comorbidities, and socioeconomic status. Current therapies for type 2 diabetes are often unable to alter the natural course of the disease and provide durable glycemic control, and side effects in the context of individual patient characteristics often limit treatment choices. This often results in the progression to insulin use and complex regimens that are difficult to maintain. Therefore, a number of agents are being developed to better address the pathogenesis of type 2 diabetes and to overcome limitations of current therapies. The hope is to provide more options for glucose lowering and complication reduction with less risk for hypoglycemia and other adverse effects. These agents include newer incretin-based therapies and PPAR agonists, as well as new therapeutic classes such as sodium-coupled glucose cotransporter 2 inhibitors, free fatty acid receptor agonists, 11-β-hydroxysteroid dehydrogenase type 1 inhibitors, glucokinase activators, and several others that may enter clinical use over the next decade. Herein we review these agents that are advancing through clinical trials and describe the rationale behind their use, mechanisms of action, and potential for glucose lowering, as well as what is known of their limitations.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drugs, Investigational; Humans; Hypoglycemic Agents; Incretins; Peroxisome Proliferator-Activated Receptors; Receptors, G-Protein-Coupled; Receptors, Glucagon; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Type 2 diabetes is a major global health problem and there is ongoing research for new treatments to manage the disease. The GLP-1R (glucagon-like peptide-1 receptor) controls the physiological response to the incretin peptide, GLP-1, and is currently a major target for the development of therapeutics owing to the broad range of potential beneficial effects in Type 2 diabetes. These include promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin sensitivity and promotion of weight loss. Despite this, our understanding of GLP-1R function is still limited, with the desired spectrum of GLP-1R-mediated signalling yet to be determined. We review the current understanding of GLP-1R function, in particular, highlighting recent contributions in the field on allosteric modulation, probe-dependence and ligand-directed signal bias and how these behaviours may influence future drug development.

Topics: Allosteric Regulation; Amino Acid Sequence; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Molecular Mimicry; Molecular Sequence Data; Receptors, Glucagon; Sequence Homology, Amino Acid; Signal Transduction

Patients with diabetes are at greater risk of fractures mostly due to not only to extraskeletal factors, such as propensity to fall, but also to bone quality alteration, which reduces bone strength. In people with diabetes, insulin deficiency and hyperglycaemia seem to play a role in determining bone formation alteration by advanced glycation end product (AGE) accumulation or AGE/RAGE (receptors for AGE) axis imbalance, which directly influence osteoblast activity. Moreover, hyperglycaemia and oxidative stress are able to negatively influence osteocalcin production and the Wnt signalling pathways with an imbalance of osteoblast/osteoclast activity leading to bone quality reduction as global effect. In addition, other factors such as insulin growth factors and peroxisome proliferator-activated receptor-γ pathways seem to have an important role in the pathophysiology of osteoporosis in diabetes. Although there are conflicting data in literature, adequate glycaemic control with hypoglycaemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 diabetes. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycaemic control. Finally, preliminary data on animals and in humans suggest the hypothesis that incretins and dipeptidyl peptidase-4 inhibitors could have a positive effect on bone metabolism by a direct effect on bone cells; however, such issue needs further investigations.

Topics: Aging; Animals; Bone Density; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Fractures, Bone; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Incretins; Male; Metformin; Osteocalcin; Osteoporosis; PPAR gamma; Risk Factors; Signal Transduction; Thiazolidinediones; Wnt Proteins

A lot of contradictory data regarding the serious side effects of incretin-based therapies are currently available, with more being prepared or published every month. Considering the widespread use of these drugs it should be considered a priority to establish both short- and long-term risks connected with incretin treatment. We performed an extensive literature search of the PubMed database looking for articles dealing with connections between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Data obtained indicate that GLP-1 agonists and DPPIV inhibitors could increase the risk of pancreatitis and pancreatic cancer, possibly due to their capacity to increase ductal cell turnover, which has previously been found to be up-regulated in patients with obesity and T2DM. GLP-1 analogues exenatide and liraglutide seem to be connected with medullary thyroid carcinoma in rat models and, surprisingly, GLP-1 receptors have been found in papillary thyroid carcinoma, currently the most common neoplasm of the thyroid gland in humans. Changes in expression of DPPIV have been described in ovarian carcinoma, melanoma, endometrial adenocarcinoma, prostate cancer, non-small cell lung cancer and in certain haematological malignancies. In most cases loss of DPPIV activity is connected with a higher grading scale, more aggressive tumour behaviour and higher metastatic potential. In conclusion animal and human studies indicate that there could be a connection between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Therefore whenever such therapy is started it would be wise to proceed with caution, especially if personal history of neoplasms is present.

Topics: Animals; Cell Proliferation; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Models, Animal; Neoplasms; Outcome Assessment, Health Care; Pancreas; Pancreatic Diseases; Randomized Controlled Trials as Topic; Rats; Risk Factors

Discovery of physiological and pharmacological characteristics of incretins (glucagon-like peptide-1 and glucose-dependent insulinotrop polypeptide), and the introduction of various products of those into the clinical practice has fundamentally changed blood glucose lowering therapy in type 2 diabetes. In addition to the antidiabetic properties more attention is paid to their favourable pleiotropic effects independent from the blood glucose lowering such as cardio-, vaso- and renoprotectiv, blood pressure lowering effects, as well as beneficial changes on blood lipid values and hepatic steatosis. These preferential changes prevail in slightly different way when incretin mimetics applied and dipeptidyl peptidase-4 inhibitors, furthermore, prolonged action of peptides metabolised by this enzyme may serve additional benefits in this latter mentioned group. The article overviews the currently known most important pleiotropic effects of incretins from the point of view of cardiorenal risk accompanying type 2 diabetes.

Topics: Animals; Atherosclerosis; Blood Glucose; Blood Vessels; Cardiotonic Agents; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Kidney; Lipids; Liver; Vasodilation

Type 2 diabetes mellitus, also called non-insulin dependent diabetes mellitus, is a chronic endocrine disease characterized by insulin resistance in tissues such as fat, liver and skeletal muscle, and impaired insulin secretion in pancreatic β cells. The prevalence and incidence of type 2 diabetes exploded over last decades along with increased population obesity owing to western lifestyle factors such as lack of exercise and high calorie diets. As diabetes progresses without appropriate treatment, many micro- and macro-vascular complications occur, leading to increased risk of mortality. Although lifestyle modifications including a healthier diet and more frequent exercise are suggested as initial therapy for type 2 diabetes, pharmacotherapy is required in many cases. Currently, several anti-diabetic drugs with different mechanisms of action are available, but increased effectiveness and tolerability are a still unmet need for diabetes pharmacotherapy. Thus, the development of new anti-diabetic drugs is an active research area in both academia and the pharmaceutical industry. This review focuses on the targets in the latest developments of non-insulin anti-diabetics that attract the most interest in this disease area.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomedical Research; Diabetes Mellitus, Type 2; Drug Discovery; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Obesity

Type 2 diabetes mellitus is associated with a progressive decline in insulinproducing pancreatic β-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate glucose-induced insulin secretion; however, in patients with type 2 diabetes, the incretin system is impaired by loss of the insulinotropic effects of GIP as well as a possible reduction in secretion of GLP-1. Agents that modify GLP-1 secretion may have a role in the management of type 2 diabetes. The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2 diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes include G-protein-coupled receptor (GPCR) agonists, α-glucosidase inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, metformin, bile acid mimetics and bile acid sequestrants. Both the GPCR agonist AR231453 and the novel bile acid mimetic INT-777 have been shown to stimulate GLP-1 release, leading to increased insulin secretion and improved glucose tolerance in mice. Similarly, a study in insulin-resistant rats demonstrated that the bile acid sequestrant colesevelam increased GLP-1 secretion and improved glucose levels and insulin resistance. In addition, the bile acid sequestrant colestimide (colestilan) has been shown to increase GLP-1 secretion and decrease glucose levels in patients with type 2 diabetes; these results suggest that the glucose-lowering effects of bile acid sequestrants may be partly due to their ability to increase endogenous GLP-1 levels. Evidence suggests that GPCR agonists, α-glucosidase inhibitors, PPAR agonists, metformin, bile acid mimetics and bile acid sequestrants may represent a new approach to management of type 2 diabetes via modification of endogenous GLP-1 secretion.

Topics: Animals; Bile Acids and Salts; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Peroxisome Proliferator-Activated Receptors

Incretin-based therapies have established a foothold in the diabetes armamentarium through the introduction of oral dipeptidyl peptidase-4 inhibitors and the injectable class, the glucagon-like peptide-1 receptor agonists. In 2009, the American Diabetes Association and European Association for the Study of Diabetes authored a revised consensus algorithm for the initiation and adjustment of therapy in Type 2 diabetes (T2D). The revised algorithm accounts for the entry of incretin-based therapies into common clinical practice, especially where control of body weight and hypoglycemia are concerns. The gut-borne incretin hormones have powerful effects on glucose homeostasis, particularly in the postprandial period, when approximately two-thirds of the β-cell response to a given meal is due to the incretin effect. There is also evidence that the incretin effect is attenuated in patients with T2D, whereby the β-cell becomes less responsive to incretin signals. The foundation of incretin-based therapies is to target this previously unrecognized feature of diabetes pathophysiology, resulting in sustained improvements in glycemic control and improved body weight control. In addition, emerging evidence suggests that incretin-based therapies may have a positive impact on inflammation, cardiovascular and hepatic health, sleep, and the central nervous system. In the present article, we discuss the attributes of current and near-future incretin-based therapies.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

Achieving tight glycaemic control remains an unmet need for many patients with type 2 diabetes, despite improved treatments. To meet glycaemic targets, attempts have been made to improve existing drugs and to develop new classes of drugs. Recent advances include insulin analogues that more closely mimic physiologic insulin levels, and incretin-based therapies, which capitalize on the glucoregulatory properties of native glucagon-like peptide-1 (GLP-1). Although promising, these agents are associated with limitations, including hypoglycaemia with insulin, gastrointestinal adverse events with GLP-1 receptor agonists and frequent dosing with both classes. Albumin is an abundant natural drug carrier that has been used to improve the half-life, tolerability and efficacy of a number of bioactive agents. Here, we review the physiologic roles of albumin and how albumin technologies are being used to prolong duration of action of therapies for diabetes, including insulin and incretin-based therapies.

Topics: Adult; Aged; Albumins; Antioxidants; Blood Glucose; Diabetes Mellitus, Type 2; Drug Carriers; Female; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Lipid Metabolism; Male; Middle Aged; Young Adult

Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic β-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate glucose-induced insulin secretion; however, in patients with type 2 diabetes, the incretin system is impaired by loss of the insulinotropic effects of GIP as well as a possible reduction in secretion of GLP-1. Agents that modify GLP-1 secretion may have a role in the management of type 2 diabetes. The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2 diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes include G-protein-coupled receptor (GPCR) agonists, α-glucosidase inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, metformin, bile acid mimetics and bile acid sequestrants. Both the GPCR agonist AR231453 and the novel bile acid mimetic INT-777 have been shown to stimulate GLP-1 release, leading to increased insulin secretion and improved glucose tolerance in mice. Similarly, a study in insulin-resistant rats demonstrated that the bile acid sequestrant colesevelam increased GLP-1 secretion and improved glucose levels and insulin resistance. In addition, the bile acid sequestrant colestimide (colestilan) has been shown to increase GLP-1 secretion and decrease glucose levels in patients with type 2 diabetes; these results suggest that the glucose-lowering effects of bile acid sequestrants may be partly due to their ability to increase endogenous GLP-1 levels. Evidence suggests that GPCR agonists, α-glucosidase inhibitors, PPAR agonists, metformin, bile acid mimetics and bile acid sequestrants may represent a new approach to management of type 2 diabetes via modification of endogenous GLP-1 secretion.

Topics: Bile; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Intestinal Mucosa; Intestines

The prevalence of type 2 diabetes mellitus (T2DM) has increased markedly worldwide. A recent epidemiological study reported that approximately 63% of T2DM patients also have high blood pressure (>130/80 mmHg), which doubles their risk of cardiac events. Of the medications used to treat T2DM, the incretins are a group of peptides that not only regulate blood glucose effectively and moderately, but also protect patients against cardiovascular events and improve several cardiovascular parameters. Here were review data from preclinical and short- and long-term clinical studies investigating the antihypertensive effects of incretins. We also elucidate four possible mechanisms underlying the antihypertensive effects of incretins. We conclude that incretins can lower blood pressure of T2DM patients, independent of weight loss, and will surely improve the prognosis of these patients.

Topics: Animals; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hypertension; Incretins

It has been demonstrated that fatty acids (FAs) are physiological ligands of G-protein-coupled receptors (GPRs). Activation of the GPRs (40, 41, 43, 84, 119 and 120) by FAs or synthetic agonists modulates several responses. In this review, we discuss the current knowledge on the actions of FA-activated GPRs and their relevance in normal and pathological conditions.. Studies have shown that FA-activated GPRs modulate hormone secretion (incretin, insulin and glucagon), activation of leukocytes and several aspects of metabolism.. Understanding GPR actions and their involvement in the development of insulin-resistance, β-cell failure, dyslipidemia and inflammation associated with obesity, type 2 diabetes, metabolic syndrome and cardiovascular diseases is important for the comprehension of the mechanisms underlying these pathological conditions and for the establishment of new and effective interventions.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Acids; Feeding Behavior; Gastrointestinal Tract; Humans; Incretins; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leukocytes; Ligands; Obesity; Receptors, G-Protein-Coupled

Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists, are the latest addition to the range of available medications for the management of patients with type 2 diabetes. The GLP-1 analog liraglutide has been approved for use in Europe and the US for over a year and has undergone evaluation in several pharmacokinetic/pharmacodynamics studies and in an extensive phase 3 clinical program. The aim of this review is to assess the pharmacokinetics, efficacy and safety of the phase 3 data.. Data are presented from the pharmacokinetics/pharmacodynamics studies of liraglutide and from nine published phase 3 studies, including the six Liraglutide Effect and Action in Diabetes (LEAD) studies.. Liraglutide is effective at improving indices of glycemic control, and has a good tolerability and safety profile. Beneficial effects on weight (mean reduction of 1-3.4 kg) and blood pressure (systolic blood pressure decreased by 2.1-6.7 mmHg) are also observed.. Liraglutide is an effective and well tolerated option for the treatment of type 2 diabetes.

Topics: Blood Glucose; Blood Pressure; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin-Secreting Cells; Liraglutide; Male; Randomized Controlled Trials as Topic; Receptors, Glucagon; Treatment Outcome

Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretins physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide (GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic approach, since it is dually manifested by promoting weight reduction, in the case of GLP-1, or favoring lipid accumulation, in the case of GIP. The complete spectrum of incretin actions related to energy homeostasis is yet to be fully elucidated. Currently, new drugs based on incretin physiology are available for treatment of type 2 diabetes mellitus, whereas the implication of similar drugs in the treatment of obesity is under investigation. These agents exert several beneficial effects that minimize cardiovascular risk.

Topics: Animals; Anti-Obesity Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Design; Energy Metabolism; Feedback, Physiological; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Obesity; Risk Factors; Signal Transduction; Treatment Outcome

Studies of patients going into diabetes remission after gastric bypass surgery have demonstrated the important role of the gut in glucose control. The improvement of type 2 diabetes after gastric bypass surgery occurs via weight dependent and weight independent mechanisms. The rapid improvement of glucose levels within days after the surgery, in relation to change of meal pattern, rapid nutrient transit, enhanced incretin release and improved incretin effect on insulin secretion, suggest mechanisms independent of weight loss. Alternatively, insulin sensitivity improves over time as a function of weight loss. The role of bile acids and microbiome in the metabolic improvement after bariatric surgery remains to be determined. While most patients after bariatric surgery experienced sustained weight loss and improved metabolism, small scale studies have shown weight regain and diabetes relapse, the mechanisms of which remain unknown.

Topics: Bariatric Surgery; Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Follow-Up Studies; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance; Malnutrition; Metagenome; Obesity; Recurrence; Weight Loss

Glucagon-like peptide (GLP)-1 agonists and dipeptidyl peptidase-4 inhibitors are two classes of drugs that have been approved for treatment of Type 2 diabetes mellitus, based upon the glucose-lowering actions of the gastrointestinal hormone GLP-1. However, GLP-1 receptors are also present in cardiovascular tissues. Data from animal and in vitro studies suggest that GLP-1 may have cardioprotective effects and improve myocardial and endothelial dysfunction. Clinical data demonstrating cardiovascular effects are more limited, and there is some evidence that incretin-based therapies may be associated with improvements in cardiovascular risk factors. Large prospective cardiovascular outcome trials are underway to examine the cardiovascular safety of incretin-based therapies, and may reveal whether these agents are associated with any reduction in cardiovascular adverse events in patients with Type 2 diabetes mellitus.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Risk Factors

The two classes of incretin-related therapies, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have become important treatment options for patients with type 2 diabetes. Sitagliptin, saxagliptin, vildagliptin and linagliptin, the available DPP-4 inhibitors, are oral medications, whereas the GLP-1 RAs-twice-daily exenatide, once-weekly exenatide and once-daily liraglutide-are administered subcutaneously. By influencing levels of GLP-1 receptor stimulation, these medications lower plasma glucose levels in a glucose-dependent manner with low risk of hypoglycaemia, affecting postprandial plasma glucose more than most other anti-hyperglycaemic medications. Use of GLP-1 RAs has been shown to result in greater glycaemic improvements than DPP-4 inhibitors, probably because of higher levels of GLP-1 receptor activation. GLP-1 RAs can also produce significant weight loss and may reduce blood pressure and have beneficial effects on other cardiovascular risk factors. Although both classes are well tolerated, DPP-4 inhibitors may be associated with infections and headaches, whereas GLP-1 RAs are often associated with gastrointestinal disorders, primarily nausea. Pancreatitis has been reported with both DPP-4 inhibitors and GLP-1 RAs, but a causal relationship between use of incretin-based therapies and pancreatitis has not been established. In clinical trials, liraglutide has shown efficacy and tolerability and resulted in certain significant benefits when compared with exenatide and sitagliptin.

Topics: Administration, Oral; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Peptides; Randomized Controlled Trials as Topic; Risk Factors; Venoms; Weight Loss

The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide can improve glycaemic control by stimulating insulin release through pancreatic β-cells in a glucose-dependent manner. GLP-1 receptors are not restricted to the pancreas; therefore, GLP-1 RAs cause additional non-glycaemic effects. Preclinical and clinical trial data suggest a multitude of additional beneficial effects related to GLP-1 RA therapy, including improvements in β-cell function, systolic blood pressure and body weight. These effects are of a particular advantage to patients with type 2 diabetes, as most are affected by β-cell dysfunction, obesity and hypertension. Transient gastrointestinal adverse events, such as nausea and diarrhoea, are also common. To improve gastrointestinal tolerability, an incremental dosing approach is used with liraglutide and exenatide twice daily. A potential protective role for GLP-1 RAs in the cardiovascular and central nervous systems has been suggested from animal studies and short-term clinical trials. These effects and other safety aspects of GLP-1 therapy are currently being investigated in ongoing long-term clinical studies.

Topics: Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypertension; Incretins; Insulin-Secreting Cells; Liraglutide; Male; Neuroprotective Agents; Receptors, Glucagon; Weight Loss

Incretin-based therapies have a glucose-dependent mode of action that results in excellent glucose-lowering efficacy with very low risk of hypoglycaemia, and weight neutrality [dipeptidyl peptidase-4 (DPP-4) inhibitors] or weight loss [glucagon-like peptide-1 (GLP-1) receptor agonists], in people with type 2 diabetes mellitus (T2DM). Patient-reported outcomes (PROs) complement physician evaluations of efficacy and tolerability and offer insights into the subjective experience of using modern diabetes treatments. We conducted a systematic search of clinical trials of the GLP-1 receptor agonists liraglutide, exenatide and long-acting exenatide, one of which included the oral DPP-4 inhibitor sitagliptin as a comparator. No other PRO data for DPP-4 inhibitors were identified. This review summarizes PRO data from eight clinical trials, the majority of which used the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and/or Impact of Weight on Quality of Life-Lite (IWQOL-Lite) to evaluate patient experience. People with T2DM were highly satisfied with modern incretin-based therapies compared with traditional therapies. Treatment satisfaction (including perceptions of convenience and flexibility) was high and generally higher with GLP-1 agonists in association with their greater glucose-lowering efficacy and tendency to facilitate weight loss. Weight-related quality of life (QoL) also improved in people using incretin therapies. The glycaemic improvements achieved with GLP-1 receptor agonists, coupled with the low incidence of hypoglycaemia and ability to cause weight loss, seemed to offset potential concern about injections. It is plausible that superior patient-reported benefits found in clinical trials may translate into improved, clinically meaningful, long-term outcomes through increased treatment acceptability. Long-term, prospective data are needed to ascertain whether this is the case in practice.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Medication Adherence; Patient Satisfaction; Peptides; Pyrazines; Self Care; Sitagliptin Phosphate; Surveys and Questionnaires; Treatment Outcome; Triazoles; Venoms; Weight Loss

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel drugs for the treatment of type 2 diabetes mellitus. They exert their action through inhibition of the catabolism of locally secreted incretins such as glucagon-like peptide-4 (GLP-4) and glucose-dependent insulinotropic polypeptide (GIP) by inhibiting enzyme DPP-4. GLP-1 and GIP are secreted from the gastrointestinal tract in response to food intake. GLP-1 is secreted from L cells present in the mucosa of the small intestine and colon, whereas GIP is secreted from K cells of the jejunum. These 2 incretins lower blood glucose levels and postprandial hyperglycemia by stimulating insulin release from b cells of the pancreas, thus increasing insulin sensitivity, delaying gastrointestinal emptying, decreasing food intake through early satiety, and causing weight loss in the long term. However, their action is short-lived (2 to 3 minutes) because of catabolism by the DPP-4 enzyme. The importance of DPP-4 inhibitors lies in their blockade of the DPP-4 enzyme leading to the prevention of their catabolism and thus increasing their blood levels, extending the duration of their action, and improving their blood glucose-lowering effect. In addition to their antidiabetic action, recent experimental and clinical studies have demonstrated a pleiotropic cardiovascular protective effect of these agents independent of their antidiabetic action. They prevent atherosclerosis, improve endothelial dysfunction, lower blood pressure, and prevent myocardial injury. All these actions are discussed in this concise review. In conclusion, DPP-4 inhibitors are novel antidiabetic agents with pleiotropic cardiovascular protective effects in addition to their antidiabetic action.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Heart; Humans; Hypertension; Incretins; Receptors, Glucagon

Incretin-based glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitor therapies provide glycaemic control with reduced risks associated with weight gain or hypoglycaemia. Incretin therapies are compared with their mechanisms of action, effects on haemoglobin A(1C) (HbA(1C)), fasting plasma glucose (FPG), post-prandial glucose (PPG), body weight, β-cell function, cardiovascular biomarkers and in their safety profiles to aid clinicians in the selection of individualized pharmacotherapy for patients with type 2 diabetes.. Relevant articles for a systematic review were identified through PubMed. Randomized, head-to-head comparison studies among incretin therapies were identified and included in the review. Additionally, randomized, controlled monotherapy and combination therapy studies examining glycaemic and extraglycaemic effects of individual incretin therapies from 2007 to 2011 were reviewed.. Glucagon-like peptide-1 receptor agonists are generally preferred over DPP-4 inhibitors because of their greater effectiveness in reducing HbA(1C) , FPG and PPG excursions, and greater weight loss potentiation. As a monotherapy option, longer-acting GLP-1 RAs, including liraglutide and exenatide once-weekly, may be preferred at higher HbA(1C) because of their more pronounced effects on FPG. At lower/near normal HbA(1C) , a short-acting GLP-1 RA, such as exenatide twice-daily, may be a better choice as its effects are more pronounced with PPG. Ideal patients or patient situations for DPP-4 inhibitors include patients who need minimal reduction in HbA(1C,) elderly patients, patients who are unwilling or unable to take an injectable agent, when GLP-1 RAs are contraindicated or when the patient will not benefit from weight loss. Treatment benefits common to all incretin-based therapies include minimal hypoglycaemia risk, potential preservation of β-cell function and effective targeting of multiple organs underlying type 2 diabetes and of comorbidities commonly associated with type 2 diabetes, such as obesity and hypertension.. Key differences in mechanisms of action and in glycaemic and extra-glycaemic treatment outcomes exist among incretin therapies, both within the GLP-1 RA class, and between GLP-1 RAs and DPP-4 inhibitors. Clinical judgment acknowledging important differences among incretin therapies and treatment-related patient characteristics will aid in the selection of the appropriate incretin agent for individualized pharmacotherapy.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Receptors, Glucagon

Abstract Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, -0.8 to -1.1%; liraglutide, -0.8 to -1.6%), as has weight loss (exenatide, -1.6 to -3.1 kg; liraglutide, -1.6 to -3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Receptors, Glucagon; Venoms

Clarification of the molecular mechanisms of insulin secretion is crucial for understanding the pathogenesis and pathophysiology of diabetes and for development of novel therapeutic strategies for the disease. Insulin secretion is regulated by various intracellular signals generated by nutrients and hormonal and neural inputs. In addition, a variety of glucose-lowering drugs including sulfonylureas, glinide-derivatives, and incretin-related drugs such as dipeptidyl peptidase IV (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists are used for glycaemic control by targeting beta cell signalling for improved insulin secretion. There has been a remarkable increase in our understanding of the basis of beta cell signalling over the past two decades following the application of molecular biology, gene technology, electrophysiology and bioimaging to beta cell research. This review discusses cell signalling in insulin secretion, focusing on the molecular targets of ATP, cAMP and sulfonylurea, an essential metabolic signal in glucose-induced insulin secretion (GIIS), a critical signal in the potentiation of GIIS, and the commonly used glucose-lowering drug, respectively.

Topics: Adenosine Triphosphate; Blood Glucose; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exocytosis; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Receptors, Glucagon; Signal Transduction; Sulfonylurea Compounds

This article summarizes treatment regimens and issues involved in initiating insulin therapy in type 2 diabetes (T2D). Progressive deterioration of beta-cell mass and function characterizes the course of T2D. Following diet and exercise, oral antidiabetic drugs (OADs), and incretin therapies, many patients require insulin, but initiation is often delayed until complications develop.. Published guidelines for the management of T2D, primary and review articles, and Food and Drug Administration (FDA) prescribing information.. The diabetes nurse practitioner should encourage patients to initiate insulin when appropriate; patients need to know that this represents a natural step in treatment, not a personal failing. Initiation often occurs when OADs no longer confer adequate glycemic control. Treatment regimens available include once-daily basal insulin, sometimes with addition of prandial insulin, or premix/biphasic insulin. Insulin analogs confer less risk of hypoglycemia and weight gain, and greater dosing flexibility compared with conventional insulins. Insulin efficacy may be enhanced by continuing metformin and/or incretin therapies, while discontinuing other drugs as appropriate.. The well-versed diabetes nurse practitioner assists the patient in selecting the most appropriate option for his/her specific needs. It is essential to help patients overcome barriers, including fears of injection pain, public embarrassment, and hypoglycemia risk.

Topics: Algorithms; Decision Making; Diabetes Mellitus, Type 2; Disease Progression; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Nurse Practitioners; Patient Satisfaction; Power, Psychological; Time Factors

Glucagon-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors are two classes of treatments for type 2 diabetes, which enhance the well-known 'incretin effect' of increased insulin secretion in response to food intake. This concise review introduces both types of incretin-based therapies and focuses on the extra-pancreatic effect of GLP-1 on body weight. As well as improving glycaemic control in subjects with type 2 diabetes, these treatments have the additional benefits of improving weight management in these patients, with GLP-1 receptor agonists causing weight loss and DPP-4 inhibitors being weight neutral.

Topics: Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome

Renal impairment (RI) is common among patients with type 2 diabetes mellitus (T2DM), and these patients also experience an age-related decline in renal function. At the same time, treatment options are more limited and treatment is more complex, particularly in patients with moderate or severe RI due to contraindications, need for dose adjustment and/or regular monitoring, and side effects, such as fluid retention and hypoglycemia, which are a more serious concern in this patient population. Incretin therapies, consisting of the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are a promising new class of antihyperglycemic drugs. In the overall population, they improve glycemic control in a glucose-dependent manner and are not likely to cause hypoglycemia, representing a clear advantage in at-risk populations. Data regarding use of these agents in renally impaired patients have started to emerge, and the objective of this article is to provide an overview of the currently available data and the potential role of these novel agents in the management of patients with T2DM and RI. Data for the GLP-1 receptor agonists in patients with moderate or severe RI are still limited, with no trials dedicated to these populations currently published. In addition, their potential to cause gastrointestinal side effects may limit use in patients with RI due to the risk of dehydration and hypovolemia. The use of GLP-1 receptor agonists in patients with moderate or severe RI is therefore, at present, underlying caution and/or restrictions. On the other hand, data from specific trials in patients with moderate or severe RI are now becoming available for most of the DPP-4 inhibitors. These studies demonstrate good efficacy and tolerability of the DPP-4 inhibitors in patients with moderate or severe RI, thus opening a place for these therapies in the treatment of populations with T2DM and RI. Several of the DPP-4 inhibitors are already approved for use in patients with moderate or severe RI, including for those with end-stage renal disease. While discussing the advantages related to their common mechanism of action, this article also describes differences among the DPP-4 inhibitors (eg, related to their pharmacokinetic properties and the available clinical data). In conclusion, while initial data for these new therapies are promising, further experience is needed to fully assess the risk-benefit balance and cl

Topics: Administration, Oral; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Injections, Intravenous

The management of type 2 diabetes continues to evolve as new data emerge. Although glycaemic control is still important, other risk factors--such as hypertension, dyslipidaemia and obesity--must also be addressed in order to reduce the long-term risks of cardiovascular complications and mortality. In this context, targeting the incretin system, and glucagon-like peptide-1 (GLP-1) in particular, has generated much interest. GLP-1 is released from the gut in response to food ingestion and plays a crucial role in glucose homeostasis. GLP-1 receptors are expressed in the heart and vasculature, prompting evaluation of their physiological role and pharmacological stimulation, both in healthy and disease states. These studies indicate that GLP-1 and GLP-1-based therapies appear to have direct, beneficial effects on the cardiovascular system, in addition to their glucose-lowering properties, such as modulation of blood pressure, endothelial function, and myocardial contractility. Intriguingly, some of these effects appear to be independent of GLP-1 receptor signalling. Data from clinical studies of the GLP-1 receptor agonists, exenatide and liraglutide on cardiovascular risk factors, in patients with type 2 diabetes are also promising and the results from prospective studies to assess cardiovascular outcomes are eagerly awaited.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Endothelium, Vascular; Exenatide; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Mice; Peptides; Prospective Studies; Risk Factors; Treatment Outcome; Venoms

Type 2 diabetes mellitus is increasing over time as result of the obesity epidemics. In fact, the prevalence of Type 2 diabetes across Europe in 2010 was estimated to be 8.2% of the population and its projection for 2030 sees figures of 10.1%. This increase in the number of diabetic individuals has also dramatically raised the health expense, with spending on diabetes in Europe in 2010 accounting for 10% of the total healthcare cost. A meta-analysis of the literature evidenced that the clinical and laboratory manifestations of Type 2 diabetes are resolved in 78.1%, and are improved in 86.6% of obese patients (body mass index >35 kg/m²) after bariatric surgery. However, a gradation of effects of different surgical techniques in improving glucose control does exist, with the largest and durable effects observed in prevalently malabsorptive procedures. The outcome of bariatric surgery on insulin sensitivity and secretion is different in relation to the type of operation performed. In fact, while Roux-en-Y Gastric Bypass enhances insulin secretion after a meal thus improving glucose metabolism, Bilio-Pancreatic Diversion acts through the amelioration of insulin sensitivity allowing a subsequent reduction of insulin hypersecretion, which is a typical feature of the insulin resistance state. Gastric banding action is mediated uniquely through the weight loss, and the effect of sleeve gastrectomy is still to be elucidated. Incretin secretion is dramatically increased under nutrient stimulation after gastric bypass leading, probably, to an overstimulation of pancreatic β-cells resulting in the increase of insulin secretion.

Topics: Animals; Bariatric Surgery; Body Mass Index; Diabetes Mellitus, Type 2; Gastric Mucosa; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Intestinal Mucosa; Obesity, Morbid

The role of glucagon-like peptide (GLP)-1-based treatment approaches for type 2 diabetes mellitus (T2DM) is increasing. Although self-monitoring of blood glucose (SMBG) has been performed in numerous studies on GLP-1 analogs and dipeptidyl peptidase-4 inhibitors, the potential role of SMBG in GLP-1-based treatment strategies has not been elaborated. The expert recommendation suggests individualized SMBG strategies in GLP-1-based treatment approaches and suggests simple and clinically applicable SMBG schemes. Potential benefits of SMBG in GLP-1-based treatment approaches are early assessment of treatment success or failure, timely modification of treatment, detection of hypoglycemic episodes, assessment of glucose excursions, and support of diabetes management and diabetes education. Its length and frequency should depend on the clinical setting and the quality of metabolic control. It is considered to play an important role for the optimization of diabetes management in T2DM patients treated with GLP-1-based approaches.

Topics: Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Europe; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Practice Guidelines as Topic; Predictive Value of Tests; Time Factors; Treatment Outcome

The global burden of type 2 diabetes is growing. Traditional therapies are suboptimal and there is a clear unmet need for treatments that offer effective glucose control while addressing the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease, without the fear of hypoglycaemia. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors offer a novel way of reducing hyperglycaemia by targeting the incretin system. This review provides an overview of the development of incretin-based therapies and explains their differing modes of action compared with traditional interventions. A comparison of the clinical profiles of current glucagon-like peptide-1 receptor agonists [liraglutide and exenatide (twice-daily and once-weekly)] and dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, vildagliptin and linagliptin) is performed alongside a discussion of the placement of incretin-based therapies in treatment guidelines. Further improvements in this class are expected, and we will examine some of the novel glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors currently under development.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Receptors, Glucagon; Venoms

Dyslipidemia is a prominent feature of type 2 diabetes and insulin resistance that contributes to increased atherosclerosis and cardiovascular disease (CVD) risks under these conditions. Incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) have recently been developed and are approved for clinical use for treatment of type 2 diabetes. Besides improved glycemic control, other benefits are being increasingly appreciated, one of which is improved plasma lipid profile. This review aims to summarize the evidence and potential mechanism of such agents in humans in modulating fasting and postprandial lipoprotein metabolism.

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Lipids; Postprandial Period; Receptors, Glucagon

Cardiovascular disease continues to be a major cause of morbidity and mortality in patients with Type 2 Diabetes Mellitus. Whilst a focus on improved glucose control and HbA1c has led to a reduction in the progression and development of microvascular complications, the potential for this strategy to reduce cardiovascular event rates is less clearly defined. Identification of the incretin axis has facilitated the development of several novel therapeutic agents which target glucagon-like peptide-1 (GLP-1) pathways. The effects on glucose homeostasis are now established, but there is also now an increasing body of evidence to support a number of pleiotropic effects on the heart that may have the potential to influence cardiovascular outcomes. In this article, we review myocardial energy metabolism with particular emphasis on the potential benefits associated with a shift towards increased glucose utilisation and present the pre-clinical and clinical evidence regarding incretin effects on the heart. In addition we discuss the potential mechanism of action and benefit of drugs that modulate GLP-1 in patients with type 2 diabetes mellitus and coronary artery disease.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Humans; Incretins; Myocardium

Given the demonstrated importance of the incretin effect on the prandial insulin response, augmentation of the incretin effect in people with type 2 diabetes is an important pharmacological approach to glycemic management. In recent years, the use of incretin-based therapies, such as GLP-1 receptor agonists and DPP-4 inhibitors, has increased dramatically due to their demonstrated efficacy, low risk of hypoglycemia when used as monotherapy, and reasonable tolerability. Given their effects on glycemic parameters and the likelihood of aiding in weight loss, GLP-1 receptor agonists provide a unique treatment option for people with type 2 diabetes. Increased clinical experience and study of incretin-based therapies will help answer questions about safety issues that have arisen from post-marketing reports. The potential benefit of incretin-based therapies in the treatment of people with type 2 diabetes and cardiovascular disease is currently an active area of inquiry. While the potential benefits of incretin-based therapies in the arena of cardiovascular risk reduction are promising, results from ongoing outcomes-based studies will help determine the role of these agents in this setting.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Receptors, Glucagon

The endothelium is critical for multiple processes occurring on both sides of the vascular wall including regulation of blood flow, maintenance of blood fluidity and control of inflammation. Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and appears to be a critical determinant of cardiovascular events. It is frequently detected in the early stages of type 2 diabetes and even in pre-diabetes conditions. Risk factors for endothelial dysfunction are numerous and include among others fasting and postprandial hyperglycemia and hyperlipidemia, hypertension, obesity, insulin resistance and inflammation. Many of these conditions can be improved by synthetic glucagon like peptide 1 (GLP-1) mimetics or inhibitors of the main GLP-1 degrading enzyme dipeptidyl peptidase 4 (DPP-4). Acute increases in GLP-1 activity abolish endothelial dysfunction induced by high-fat meals or by hyperglycemia. In vitro and preliminary clinical studies also indicate that GLP-1 or GLP-1 agonists can improve endothelial function by direct action on endothelium. GLP-1 or GLP-1 mimetic effects appear to extend to both conduit arteries and the microvasculature, and may depend on activation of endothelial GLP-1 receptors and downstream nitric oxide production. Additional studies are necessary to confirm improvement of endothelial function after prolonged treatment with incretin based medications as well as the cardiovascular benefit of these agents.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Nitric Oxide Synthase Type III

Incretin-based therapies are currently being used in the treatment of type 2 diabetes mellitus (T2DM). Apart from glycemic control, these agents have been shown to have multiple extra-pancreatic effects, including their role in blood pressure (BP) regulation. This article will review the origins of incretins, the incretin axis, possible mechanisms of antihypertensive effect of these agents, as well as the recent evidence.. Preclinical and clinical studies demonstrate the antihypertensive effects of glucagon-like peptide-1 (GLP-1) and its analogs in patients with T2DM and hypertension. This effect seems to be mediated through vasodilatation as well as modulation of renal sodium handling causing natriuresis, although the exact mechanisms are not fully known.. Incretin-based therapies are emerging as a novel class of hypoglycemic agents that display antihypertensive properties. Given the small decreases in BP, it is unlikely that these agents will be used as stand-alone antihypertensive agents, but they may be an attractive option in patients with T2DM and hypertension.

Topics: Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypertension; Incretins

Recently, the crucial role of GLP-1 in cardiovascular disease has been suggested by both preclinical and clinical studies. In vivo and in vitro studies have demonstrated cardio-protective effects of GLP-1 by activating cell survival signal pathways, which have greatly reduced ischemia/reperfusion injury and also cardiac dysfunction in various congestive heart failure animal models. Clinically, beneficial effects of GLP-1 have been shown in patients with myocardial infarction, hypertension, and heart failure, and 2 classes of incretin enhancers, GLP-1 receptor agonists and DPP-4 inhibitors, are currently available for the treatment of type 2 diabetes mellitus. In this review, we will summarize the role of incretins in various cardiovascular events such as hypertension and heart failure and postprandial lipoprotein secretion, and discuss their molecular mechanisms and potentials as a new therapeutic as well as preventive drug type for reducing cardiovascular events in both diabetic and nondiabetic patients.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of oral antidiabetic agents that improve glycemic control in patients with type 2 diabetes mellitus. These agents differ in structure, but all act by inhibiting the DPP-4 enzyme. Dipeptidyl peptidase-4 inhibition increases levels of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which in turn stimulate insulin secretion in a glucose-dependent fashion. Clinical trials have shown that DPP-4 inhibitors provide significant reductions in glycated hemoglobin levels, with a low risk of hypoglycemia. Animal model experiments and proof-of-concept studies suggest that the incretins favorably affect the cardiovascular system; it is possible that these same effects may be conveyed by DPP-4 inhibitor therapy. Pooled and meta-analyses of DPP-4 inhibitor clinical trial data have shown no increase in major adverse cardiovascular events, and, in fact, suggest a potential cardiovascular benefit to such therapy. Long-term cardiovascular safety trials are currently underway to more fully define and understand the cardiovascular impact of DPP-4 therapy in patients with type 2 diabetes mellitus.

Topics: Blood Glucose; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Meta-Analysis as Topic

Type 2 diabetes is closely associated with fragility fracture risk. Metabolic control of diabetes may improve bone status, but several anti-diabetic medicines could directly affect bone metabolism. Thiazolidinediones (TZD) may have a negative effect by switching mesenchymal progenitor cells to adipose rather than bone tissue. Clinical trials and meta-analyses showed that elderly women taking TZD could be at increased risk of fractures. On the contrary, in vitro studies suggest that incretin mimetics and incretin enhancers could positively regulate bone metabolism. Dipeptidyl peptidase-4 (DPP-4) inhibitors, which enhance serum incretin concentration, have been reported to reduce clinical fractures. However, further studies would be required for their long term-efficacy and safety on bone metabolism.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Osteoporosis; Osteoporotic Fractures; Thiazolidinediones

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, abnormally elevated hepatic glucose production, and reduced glucose-stimulated insulin secretion. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary for many patients, in order to restore acceptable glycemic control and to reduce the risk of development and progression of disease complications. Notably, even patients who appear to have similar requirements of antidiabetic regimens show great variability in drug disposition, glycemic response, tolerability, and incidence of adverse effects during treatment. Pharmacogenomics is a promising area of investigation and involves the search for genetic polymorphisms that may explain the interindividual variability in antidiabetic therapy response. The initial positive results portend that genomic efforts will be able to shed important light on variability in pharmacologic traits. In this review, we summarize the current understanding of genetic polymorphisms that may affect the responses of subjects with T2DM to antidiabetic treatment. These genes belong to three major classes: genes involved in drug metabolism and transporters that influence pharmacokinetics (including the cytochrome P450 [CYP] superfamily, the organic anion transporting polypeptide [OATP] family, and the polyspecific organic cation transporter [OCT] family); genes encoding drug targets and receptors (including peroxisome proliferator-activated receptor gamma [PPARG], the adenosine triphosphate [ATP]-sensitive potassium channel [K(ATP)], and incretin receptors); and genes involved in the causal pathway of T2DM that are able to modify the effects of drugs (including adipokines, transcription factor 7-like 2 (T cell specific, HMG-box) [TCF7L2], insulin receptor substrate 1 [IRS1], nitric oxide synthase 1 (neuronal) adaptor protein [NOS1AP], and solute carrier family 30 (zinc transporter), member 8 [SLC30A8]). In addition to these three major classes, we also review the available evidence on novel genes (CDK5 regulatory subunit associated protein 1-like 1 [CDKAL1], insulin-like growth factor 2 mRNA binding protein 2 [IGF2BP2], potassium voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1], paired box 4 [PAX4] and neuronal differentiation 1 [NEUROD1] transcription factors, ataxia telangiectasia mutated [ATM], and serine racema

Topics: Adipokines; Cyclin-Dependent Kinase 5; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin Secretion; Insulin-Like Growth Factor II; Ion Channels; Mitochondrial Proteins; Nicotinamide Phosphoribosyltransferase; Nitric Oxide Synthase Type I; Pharmacogenetics; Polymorphism, Genetic; PPAR gamma; Racemases and Epimerases; Transcription Factor 7-Like 2 Protein; tRNA Methyltransferases; Uncoupling Protein 2

Recent research has led to an interest in the role of the gut and liver in type 2 diabetes mellitus (T2DM).. To review the role of the gastrointestinal system in glucose homoeostasis, with particular focus on the effects of incretin hormones, hepatic steatosis and bile acids.. PubMed and Google Scholar were searched using terms such as incretin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4), hepatic steatosis, bile acid and gastric bypass. Additional relevant references were identified by reviewing the reference lists of articles.. Perturbations of incretin hormones and bile acid secretion contribute to the pathogenesis of T2DM, leading to their potential as therapeutic targets. The incretin hormones (GIP and GLP-1) are deactivated by DPP-4. GLP-1 agonists and DPP-4 inhibitors improve glycaemic control in patients with T2DM. Hepatic steatosis, along with insulin resistance, may precede the development of T2DM, and may benefit from anti-diabetes medications. Bile acids play an important role in glucose homoeostasis, with effects mediated via the farnesoid X receptor (FXR) and the cell surface receptor TGR5. The bile acid sequestrant colesevelam has been shown to be effective in improving glycaemic control in patients with T2DM. Altered gastrointestinal anatomy after gastric bypass surgery may also affect enterohepatic recirculation of bile acids and contribute to improved glycaemic control.. Research in recent years has led to new pathways and processes with a role in glucose homoeostasis, and new therapeutic targets and options for type 2 diabetes mellitus.

Topics: Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Liver; Gastric Bypass; Gastrointestinal Tract; Homeostasis; Humans; Incretins; Non-alcoholic Fatty Liver Disease

Macrovascular complications of type 2 diabetes mellitus (DM) are primarily driven by the combination of underlying atherosclerosis and propensity for thrombosis. Prevention of macrovascular complications in DM relies on therapies directed at multiple coexisting intermediary pathophysiologies that contribute to cardiovascular events, including hyperglycemia, lipoprotein abnormalities, hypertension, inflammation, and propensity for thrombosis. Multiple noninsulin, glucose-lowering agents have been developed that effectively lower blood glucose levels. This review explores the literature on the cardiovascular benefits and harms associated with these therapies, with an emphasis on cardiovascular outcomes when available. The lack of long-term data on cardiovascular outcomes regarding safety and efficacy of available traditional glucose-lowering agents has led to recommendations for more thorough evaluations of new therapies before approval. Furthermore, recent data suggest harm from intensive hemoglobin A(1c) reductions. Accordingly, there are multiple, large, cardiovascular-event driven phase 3-4 trials of therapies from the incretin axis currently enrolling. Recommendations for a therapeutic approach with noninsulin, glucose-lowering agents for the prevention of cardiovascular events in patients with type 2 DM are provided based on current data. Ultimately, multifactorial risk interventions, including lifestyle modifications, antihyperglycemic agents, antihypertensives, statins, and aspirin remain the primary focus to prevent macrovascular complications in patients with type 2 DM.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Practice Guidelines as Topic; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is one of the most troubling chronic disease regarding the huge number of new cases diagnosed annually worldwide. Currently available oral antidiabetic drugs (OADs) attempt to correct the underlying pathophysiological dysfunctions leading to T2DM: insulin resistance for the insulin sensitizers (metformin and thiazolidinediones), and impaired insulin secretion for the insulin secretagogues (sulfonylureas, glinides and more recently incretin mimetics). Incretin-based therapies include GLP-1 receptor agonists that provide pharmacologic levels of GLP-1 receptor stimulation beyond those that would occur from the action of the native hormone alone, and dipeptidyl-peptidase-4 (DPP-4) inhibitors that preserve endogenous GLP-1 by decreasing its degradation by the DPP-4 enzyme. In 2012, the development of new OADs aims to target untapped pathophysiological aspects of the disease (kidney homeostasis, glucagon signalling, chronic low-grade inflammation) for tailoring glycaemic control in T2DM. SGLT-2 inhibitors are the most advanced new OADs that lower HbA1C by increasing glycosuria and lead to a moderate weight loss. Although there is genuine hope that the range of OADs can be extended, a long-term evaluation of side effects and true clinical benefits is necessary.

Topics: Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Glycosuria; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Receptors, G-Protein-Coupled; Receptors, Glucagon; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones

New drugs for type 2 diabetes that act on incretin metabolism have been shown to improve glycemic control, reduce body weight and have a low risk for hypoglycemia. Among these, liraglutide is the first glucagon-like peptide 1 (GLP-1) analogue approved for subcutaneous, once-daily administration. According to results from clinical trials, liraglutide is an attractive alternative for the early treatment of type 2 diabetes. The results of the LEAD (Liraglutide Effect and Action in Diabetes) study program demonstrated the efficacy and safety of liraglutide in terms of reduction of glycated hemoglobin (HbA1c) levels, significant loss of body weight that was maintained over the long term, better control of the lipid profile and systolic arterial pressure, reduction of the risk for hypoglycemia and reduction of cardiovascular risk. Moreover, the drug was demonstrated to be safe and can be co-administered with oral antidiabetic agents. The product's tolerability has been demonstrated, with nausea as the most common adverse event, which waned from the fourth week of treatment.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Triazoles

Insulin, the first treatment for diabetes, was discovered >90 years ago. Since then, many new types of insulin have become available, including analogs that more closely mimic the characteristics of endogenous insulin. In addition, oral antidiabetes drugs and other types of injectable therapies have been approved for the treatment of patients with type 2 diabetes. As newer treatments are approved for type 2 diabetes, the choice and-paradoxically-the complexity of treatment increases. The potential benefits of all treatment options must be carefully balanced against potential adverse events to truly analyze the overall efficacy, safety, tolerability, and potential long-term effects. The manner in which outcomes are assessed and the methods employed to make such assessments have changed over time. This review will address these issues as they are related to therapies for type 2 diabetes, including insulin, oral antidiabetes drugs, and incretin-based agents.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 2; Drug Design; Humans; Hypoglycemic Agents; Incretins; Insulin

Type 2 diabetes mellitus is a chronic dysmetabolic condition characterized by hyperglycemia and accompanied by dyslipidemia (low HDL, high triglycerides), and hypertension associated with insulin resistance in obesity. In addition to the glucose-reducing effects, incretin-based therapies have been found to have cardiovascular protective properties. This review summarizes the best available evidence favoring these positive pleiotropic effects of incretin mimetics as well as incretin enhancers.. Studies in animals and humans are accumulating showing the direct as well as indirect actions of the glucagon-like peptide 1 analogues and dipeptidyl peptidase 4 inhibitors on the cardiovascular system. This class of agents appear to have effects on the cardiomyocytes, blood vessels, adipose tissue, regulation of blood pressure, and postprandial intestinal lipoprotein metabolism.. Long-term hard outcome trials are under way that investigate the effects of incretin-based treatments on elevated cardiovascular risks in patients with type 2 diabetes.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

Type 2 diabetes mellitus is widely prevalent and is often coexistent with obesity. Many of the available treatment options have side effects such as weight gain which often affect patient's willingness to continue the treatment. Effective weight loss, lack of significant hypoglycaemia, and favourable cardiometabolic profile make Incretin based therapies an attractive treatment option for type 2 diabetes. Incretin based therapies are available as either incretin mimetics (also called GLP-1 agonists) or incretin enhancers (DPP-4 inhibitors). Although agents in both these classes of incretin based therapy are effective through a common GLP-1 pathway, there are many differences amongst them including the route of administration, frequency of administration, effects on body weight, extent of glycaemic improvement. There are several trials evaluating these individual incretin based agents either as monotherapy or in combination with other anti-diabetic agents, however very few have looked into direct comparison amongst the agents in these two classes. This review is aimed to look at important mechanistic differences between incretin mimetics and enhancers through direct comparison trials and impact of these differences on biochemical, metabolic and patient satisfaction parameters.

Topics: Diabetes Mellitus, Type 2; Humans; Incretins

The primary treatment goal for patients with diabetes is to prevent the onset and progression of diabetic complications. To prevent cardiovascular events, patients must maintain optimal long-term glycemic control and avoid hypoglycemia. DPP-4 inhibition enhances endogenous incretin action, and promotes glucose dependent insulin secretion and optimal glucagon secretion. Thus, DPP-4 inhibitor can improve postprandial hyperglycemia, without causing hypoglycemia in patients with diabetes. In this section, a continuous glucose monitoring(CGM), a device able to measure a patient's blood glucose fluctuation levels continuously, was used to evaluate efficacy of DPP-4 inhibitors.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hyperglycemia; Incretins; Insulin

The incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency is the rationale for replacing endogenous incretins with GLP-1 receptor agonists or re-normalising active GLP-1 concentrations with dipeptidyl peptidase-4 inhibitors. This review summarises the literature on this topic, including a meta-analysis of published studies on GLP-1 secretion in individuals with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual incretin secretory responses and explain some of the variations in published findings of group differences in GLP-1 responses to nutrient intake.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Meta-Analysis as Topic; Models, Biological

New classes of treatments for type 2 diabetes have been developed recently and are now available in the UK. This review aims to summarise key clinical efficacy, tolerability and safety data for these agents, including liraglutide, which has received preliminary review by the National Institute for Clinical Excellence (NICE) and was launched in the UK in 2009.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Evidence-Based Medicine; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome; United Kingdom

As of 2010, approximately 285 million people worldwide have diabetes; that number is estimated to increase to 439 million by 2030. The majority of these individuals (> 90%) have type 2 diabetes, a chronic and progressive disease.. Metformin monotherapy is a safe and effective option. However, its effects on glycemia are typically of limited durability. Progressive loss of β-cell function and failure of metformin monotherapy to control glucose adequately prompt the addition of other oral antidiabetic drugs, such as sulfonylureas and thiazolidinediones, which have their own limitations. Evidence suggests that incretin-based agents can successfully achieve glycemic control while potentially providing cardiovascular and β-cell-function benefits.. Knowledge of the available clinical evidence on the incretin-based therapies and other pharmacotherapeutic options for patients with type 2 diabetes who fail first-line therapy with metformin, through an analysis of improved glycemic parameters and overall risk:benefit profiles.. Traditional oral antidiabetic agents, recommended as first- and second-line therapies in patients with type 2 diabetes inadequately controlled with diet/exercise or monotherapy, have limited durability of effect and are associated with an increased risk of adverse events. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors provide glycemic control and are promising additions to the pharmacotherapeutic armamentarium.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Life Style; Metformin; Treatment Failure

The health burden of type 2 diabetes mellitus continues to increase worldwide. A substantial portion of this burden is due to the development of cardiovascular disease in patients with diabetes. Recent failures of clinical trials of intensive glucose control to reduce macrovascular events, coupled with reports of potential harm of certain diabetic therapy, have led to increased scrutiny as new diabetic therapies are developed. Incretin peptides are a group of gastrointestinal proteins that regulate glucose metabolism through multiple mechanisms, and incretin-based therapies have been developed to treat type 2 diabetes. These agents include glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-IV (DPP-IV) inhibitors. In addition to effects on glucose homeostasis, growing evidence suggest that these peptides may also affect the cardiovascular system. In this review, we discuss recent findings concerning the potential, yet untested, benefits of incretin-based pharmacotherapy in the treatment of cardiovascular disease.

Topics: Administration, Oral; Age Distribution; Aged; Cardiovascular Diseases; Causality; Comorbidity; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Incretins; Male; Middle Aged; Prevalence; Primary Prevention; Prognosis; Randomized Controlled Trials as Topic; Risk Factors; Severity of Illness Index; Sex Distribution; Survival Rate

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1), which are secreted by cells of the gastrointestinal tract in response to meal ingestion, exercise important glucoregulatory effects, including the glucose-dependent potentiation of insulin secretion by pancreatic β-cells. Research on the defective incretin action in type 2 diabetes mellitus suggests that the observed loss of insulinotropic activity may be due primarily to a decreased responsiveness of β-cells to GIP. GLP-1 does retain efficacy, albeit not at physiologic levels. Accordingly, augmentation of GLP-1 is a logical therapeutic strategy to ameliorate this deficiency, although the short metabolic half-life of the native hormone renders direct infusion impractical. GLP-1 receptor agonists that resist degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) and have protracted-action kinetics have been developed, and DPP-4 inhibitors that slow the enzymatic cleavage of native GLP-1 provide alternative approaches to enhancing incretin-mediated glucose control. However, GLP-1 receptor agonists and DPP-4 inhibitors are premised on highly divergent mechanisms of action. DPP-4 is ubiquitously expressed in many tissues and is involved in a wide range of physiologic processes in addition to its physiologic influence on incretin hormone biological activity. GLP-1 receptor agonists provide a pharmacologic level of GLP-1 receptor stimulation, whereas DPP-4 inhibitors appear to increase levels of circulating GLP-1 to within the physiologic range. This article examines the physiology of the incretin system, mechanistic differences between GLP-1 receptor agonists and DPP-4 inhibitors used as glucose-lowering agents in the treatment of type 2 diabetes, and the implications of these differences for treatment. The results of recent head-to-head trials are reviewed, comparing the effects of incretin-based therapies on a range of clinical parameters, including glycemia, β-cell function, weight, and cardiovascular function.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin-Secreting Cells; Treatment Outcome

The global epidemic of diabetes mellitus (~95% type 2 diabetes) has been fueled by a parallel increase in obesity and overweight. Together, these metabolic disease epidemics have contributed to the increasing incidence and prevalence of cardiovascular disease. The accumulation of metabolic and cardiovascular risk factors in patients with type 2 diabetes--risk factors that may exacerbate one another--complicates treatment. Inadequate treatment, treatment that fails to achieve goals, increases the risk for cardiovascular morbidity and mortality. From a clinical perspective, type 2 diabetes is a cardiovascular disease, an observation that is supported by a range of epidemiologic, postmortem, and cardiovascular imaging studies. Vascular wall dysfunction, and particularly endothelial dysfunction, has been posited as a "common soil" linking dysglycemic and cardiovascular diseases. Vascular wall dysfunction promoted by environmental triggers (e.g., sedentary lifestyle) and metabolic triggers (chronic hyperglycemia, obesity) has been associated with the upregulation of reactive oxygen species and chronic inflammatory and hypercoagulable states, and as such with the pathogenesis of type 2 diabetes, atherosclerosis, and cardiovascular disease. Glucagon-like peptide-1 (GLP)-1, an incretin hormone, and synthetic GLP-1 receptor agonists represent promising new areas of research and therapeutics in the struggle not only against type 2 diabetes but also against the cardiovascular morbidity and mortality associated with type 2 diabetes. In a number of small trials in humans, as well as in preclinical and in vitro studies, both native GLP-1 and GLP-1 receptor agonists have demonstrated positive effects on a range of cardiovascular disease pathologies and clinical targets, including such markers of vascular inflammation as high-sensitivity C-reactive protein, plasminogen activator inhibitor-1, and brain natriuretic peptide. Reductions in markers of dyslipidemia such as elevated levels of triglycerides and free fatty acids have also been observed, as have cardioprotective functions. Larger trials of longer duration will be required to confirm preliminary findings. In large human trials, GLP-1 receptor agonists have been associated with significant reductions in both blood pressure and weight.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Treatment Outcome

Elderly patients and patients with renal impairment present unique challenges in the management of diabetes mellitus. Impaired renal function is a common comorbidity (or complication) associated with type 2 diabetes, as well as a complicating factor in the treatment of the disease. Renal insufficiency, which can result in elevated plasma concentrations of pharmaceutical agents, may preclude the use of some antihyperglycemic medications and require that the dosages of others be reduced. Failure to select and dose medications carefully in these patients may increase the risk of hypoglycemia and other adverse effects. For example, elevated plasma concentrations of some sulfonylureas may increase the risk of hypoglycemia. Because patients with chronic renal insufficiency tend to retain fluids, treatment with a thiazolidinedione--a class of agents associated with fluid retention--may exacerbate the risk of edema. Older patients with type 2 diabetes--like patients with renal insufficiency an important and populous subgroup--also have issues with therapy selection and dosing regimens. As a result of the effects of aging on kidney function, older patients may also be subject to elevated plasma levels with consequent additional risk of hypoglycemia and other adverse events. Because older patients tend to be treated with multiple medications for multiple comorbidities, it becomes challenging to design regimens that avoid or reduce the risk of drug-drug interactions. For both older patients and patients with chronic renal insufficiency, the most important drug-related adverse effect to avoid is hypoglycemia. Accordingly, incretin-based agents have an advantage because they are unlikely to cause hypoglycemia.

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Renal Insufficiency; Treatment Outcome

Management guidelines recommend metformin as the first-line therapy for most patients with type 2 diabetes uncontrolled by diet and exercise. Efficacy with metformin therapy is usually of limited duration, which necessitates the early introduction of one or two additional oral agents or the initiation of injections, glucagon-like peptide-1 (GLP-1) agonists or insulin. Although safe and effective, metformin monotherapy has been associated with gastrointestinal side effects (≈20% of treated patients in randomized studies) and is contraindicated in patients with renal insufficiency or severe liver disease. Patients treated with a sulphonylurea are at increased risk for hypoglycaemia and moderate weight gain, whereas those receiving a thiazolidinedione are subject to an increased risk of weight gain, oedema, heart failure or fracture. Weight gain and hypoglycaemia are associated with insulin use. Thus, there is an unmet need for a safe and efficacious add-on agent after initial-therapy failure. Evidence suggests that incretin-based agents, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, can successfully achieve glycaemic targets and potentially provide cardiovascular and β-cell-function benefits. This review will examine current approaches for treating type 2 diabetes and discuss the place of incretin therapies, mainly GLP-1 agonists, in the type 2 diabetes treatment spectrum.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Metformin

Regulatory role of the brain in energy expenditure, appetite, glucose metabolism, and central effects of insulin has been prominently studied. Certain neurons in the hypothalamus increase or decrease appetite via orexigenes and anorexigenes, regulating energy balance and food intake. Hypothalamus is the site of afferent and efferent stimuli between special nuclei and beta- and alpha cells, and it regulates induction/inhibition of glucose output from the liver. Incretines, produced in intestine and in certain brain cells (brain-gut hormones), link to special receptors in the hypothalamus. Central role of insulin has been proved both in animals and in humans. Insulin gets across the blood-brain barrier, links to special hypothalamic receptors, regulating peripheral glucose metabolism. Central glucose sensing, via "glucose-excited" and "glucose-inhibited" cells have outstanding role. Former are active in hyperglycaemia, latter in hypoglycaemia, via influencing beta- and alpha cells, independently of traditional metabolic pathways. Evidence of brain insulin resistance needs centrally acting drugs, paradigm changes in therapy and prevention of metabolic syndrome, diabetes, cardiovascular and oncological diseases.

Topics: Animals; Appetite Depressants; Appetite Regulation; Blood Glucose; Brain; Ceramides; Cognition; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypothalamus; Incretins; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Metabolic Syndrome; Neuropeptides; Non-alcoholic Fatty Liver Disease; Oligopeptides; Orexins; Pyrrolidonecarboxylic Acid

Type 2 diabetes mellitus is increasing in prevalence at alarming rates. Concurrent with its expanding prevalence is the increase in the related risk of morbidity and mortality. Because diabetic patients are prone to cardiovascular disease, treatment strategies should address the cardiovascular risk factors, including blood pressure, lipids, and body weight, in addition to the glycemic aspects of the disease. Newer agents, such as glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors, have varying degrees of evidence to support their effects on body weight, blood pressure, and lipid levels, beyond glycated hemoglobin reduction. While GLP-1 agonists produce a weight loss, the DPP-4 inhibitors, conversely, appear to have a weight-neutral effect. Substantial evidence demonstrates that both medications produce modest reductions in systolic blood pressure and, in some cases, diastolic blood pressure, and reduce several markers of cardiovascular risk, including C-reactive protein. Moreover, GLP-1 influences endothelial function. The effect of the incretin hormones on serum lipids are either neutral or beneficial, with small, non-significant decreases in LDL cholesterol, increases in HDL cholesterol, and occasionally significant decreases in fasting triglyceride levels. Also, they have positive effects on hepatic steatosis. Although GLP-1 agonists and DPP-4 inhibitors are at present not appropriate for primary treatment of cardiovascular risks factors, the reduction of these parameters is evidently beneficial.

Topics: Animals; Combined Modality Therapy; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Health Services Needs and Demand; Humans; Incretins; Models, Biological; Patient Care Planning

Topics: C-Peptide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins

The historical background of the discovery of incretins became of particular interest when insulin response was found to be much more pronounced when glucose was given orally, rather than intravenously. The robust insulin secretion seen in response to oral glucose, as opposed to intravenous glucose, is due to incretin hormones. Since the discovery of incretins, the significance of sitagliptin and metformin combination therapy has become an essential strategy in combating diabetes. The use of combination therapy such as sitagliptin and metformin in achieving the desired level of glycemia in patients with diabetes is very important and is an additional armamentarium in the fight against diabetes.. This article reviews the history of incretins, the pathophysiology of diabetes and the use of sitagliptin and metformin combination therapy.. Achieving optimum blood glucose control is crucial in avoiding or at least delaying the progression of complications related to diabetes. Recently, it has become very clear that treatment with a single antidiabetic agent is often not successful in achieving glycemic control. Thus, many patients with type 2 diabetes require multiple combinations. Using sitagliptin and metformin combination therapy is an ideal strategy in the treatment of diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Metformin; Pyrazines; Sitagliptin Phosphate; Triazoles

Glucose homeostasis is regulated by a complex interaction of hormones, principally including insulin, glucagon, amylin, and the incretins. Glucagon, cortisol, catecholamines, and growth hormone serve as the classic glucose counterregulatory hormones. The incretins are hormones released by enteroendocrine cells in the intestine in response to a meal. Classically, type 2 diabetes mellitus (T2DM) has been considered to be a triad of insulin resistance, increased hepatic gluconeogenesis, and progressive β-cell exhaustion/failure. However, disordered enteroendocrine physiology, specifically the reduced activity of glucagon-like peptide-1 (GLP-1), is also a principal pathophysiologic abnormality of the disease. Glucagon-like peptide-1 receptor agonists that have been studied include exenatide and liraglutide, which have been approved by the US Food and Drug Administration for use in patients with T2DM. Sitagliptin and saxagliptin, both approved for use in the United States, modulate incretin physiology by inhibiting degradation of GLP-1 by the enzyme dipeptidyl peptidase-4 (DPP-4). Modulators of incretin physiology have been shown to improve glycemic control with a low risk for hypoglycemia and beneficially affect β-cell function. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produces weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The GLP-1 receptor agonists have also demonstrated beneficial effects on cardiovascular risk factors other than hyperglycemia and excess body weight, such as lipid concentrations and blood pressure. This article describes incretin physiology and studies of pharmacologic therapy designed to address the blunted incretin response in patients with T2DM. Information was obtained by a search of the PubMed and MEDLINE databases for articles published from January 1, 1995 to June 1, 2009.

Topics: Adamantane; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms

Diabetes therapies based on manipulation of the incretin system are now widely available, with millions of people receiving treatment. The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, but those most relevant to metabolic dysfunction include stimulation of insulin and suppression of glucagon secretion, with resultant reduction in fasting and postprandial glucose. Incretin secretion and/or action is impaired in type 2 diabetes, leading to development of strategies aimed at redressing this abnormality. These strategies include pharmacological inhibition of dipeptidyl peptidase-4, the enzyme responsible for the short half-life of endogenous incretins, and administration of long-acting dipeptidyl peptidase-4-resistant peptides that bind to and activate the glucagon-like peptide-1 receptor. In this review, we address aspects of incretin biology and pharmacotherapy with a view to highlighting potentially clinically relevant issues and areas of basic research that may impinge on these.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Eating; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin-Secreting Cells; Receptors, Glucagon

The pathophysiology of type 2 diabetes mellitus is complex, consisting of far more physiologic defects than simple insulin resistance and β-cell dysfunction. Our understanding of this progressive disease has moved from a "dual defect" to an "ominous octet" description. This multifactoral concept may explain the difficulty in achieving and maintaining glycemic goals with traditional therapies. Glucagon-like peptide-1 (GLP-1) agonists, which improve insulin secretion, decrease glucagon secretion, increase satiety (and therefore decrease food intake), and may have beneficial effects on β-cell function, represent an important addition to treatment options. Their glucose-dependent mechanism limits the risk for hypoglycemia, and they are associated with weight loss. Glucagon-like peptide-1 agonists may be used alone in patients intolerant of metformin or in combination with metformin, thiazolidinediones, and sulfonylureas (or in any combination therereof). Concomitant use of dipeptidyl-peptidase-4 inhibitors is not recommended because they have a similar basis of action. Current US Food and Drug Administration indications do not include the concomitant use of GLP-1 agonists with insulin.

Topics: Algorithms; Chronic Disease; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

The management of type 2 diabetes mellitus and, in particular, blood glucose levels can be complex and challenging for physicians and patients. Many patients are frustrated with the agents currently available because they have associated limitations of weight gain, hypoglycemia, and tolerability issues. Advantages of glucagon-like peptide-1 (GLP-1) agonists include their efficacy in lowering blood glucose levels, their lack of association with weight gain, and their indirect association with weight loss. Patients likely to benefit from GLP-1 agonist therapy are those in the early stages of the disease and those in need of sufficient benefit from an agent with good efficacy. Setting appropriate expectations for patients is important, as well as explaining the significance of glucose control and reminding patients that this is the main goal of therapy. Patients (and physicians) who have concerns about hypoglycemia can be reassured that GLP-1 agonists work only in the presence of hyperglycemia. Longer-acting GLP-1 agonists are dosed less frequently, appear to be associated with less nausea, and may be associated with better rates of adherence than shorter-acting agents. When initiating therapy with GLP-1 agonists, doses should be gradually escalated to minimize gastrointestinal adverse effects. The dose of a sulfonylurea may need to be lowered if a GLP-1 agonist is added. A review of possible adverse effects, contraindications, dosing and administration techniques, and expected benefits of therapy is provided in the present article to optimize success rates with this new class of agents.

Topics: Algorithms; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Metformin; Middle Aged; Peptides; Sulfonylurea Compounds; Treatment Outcome; Venoms

Aging is characterized by a progressive increase in the prevalence of type 2 diabetes mellitus (T2DM), which approaches 20% by age 70 years. Older patients with T2DM are a very heterogeneous group with multiple comorbidities, an increased risk of hypoglycemia, and a greater susceptibility to adverse effects of antihyperglycemic drugs, making treatment of T2DM in this population challenging. The risk of severe hypoglycemia likely represents the greatest barrier to T2DM care in the elderly. Although recent guidelines recommend more flexibility in treating this population with individualized targets, inadequate glycemic control is still closely linked to poor outcome in elderly patients. Incretins (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) are hormones released post-meal from intestinal endocrine cells that stimulate insulin secretion and suppress postprandial glucagon secretion in a glucose-dependent manner. "Incretin therapies," comprising the injectable GLP-1 analogs and oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are promising new therapies for use in older patients because of their consistent efficacy and low risk of hypoglycemia. However, data with these new agents are still scarce in this population, which has not been particularly well represented in clinical trials, highlighting the need for additional specific studies. The objective of this article is to provide an overview of the available data and potential role of these novel incretin therapies in managing T2DM in the elderly. With the exception of the DPP-4 inhibitor vildagliptin, there is no published trial to date dedicated to this population, although a few studies are currently ongoing. Therefore, available data from elderly subgroups of individual studies were also reviewed when available, as well as pooled analyses by age subgroups across clinical programs conducted with incretin therapies.

Topics: Adamantane; Age Factors; Aged; Aging; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Male; Middle Aged; Nitriles; Peptides; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Vildagliptin

Novel therapeutic options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were introduced in 2005. Incretin-based therapies consist of two classes: (1) the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor and (2) dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) as oral medications raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In type 2 diabetes therapy, incretin-based therapies are attractive and more commonly used due to their action and safety profile. Stimulation of insulin secretion and inhibition of glucagon secretion by the above-mentioned agents occur in a glucose-dependent manner. Therefore, incretin-based therapies have no intrinsic risk for hypoglycemias. GLP-1 receptor agonists allow weight loss; DPP-4 inhibitors are weight neutral. This review gives an overview on the mechanism of action and the substances and clinical data available.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Guidelines as Topic; Humans; Hypoglycemic Agents; Incretins

Although several classes of pharmacotherapy are available for type 2 diabetes, glycaemic control is often hampered by medication-related adverse effects and contraindications such as renal impairment. Glucagon-like peptide-1 (GLP-1) receptor agonists provide a new pharmacotherapeutic option based on the multiple glucose-lowering effects of the human hormone GLP-1. This mechanism of action not only provides therapeutic efficacy but also suggests that GLP-1 receptor agonists have distinct safety and tolerability concerns compared with other diabetes therapies. Stimulation of pancreatic insulin secretion by GLP-1 receptor agonists is glucose dependent, conferring a lesser risk of hypoglycaemia than that seen with sulfonylureas. Individual GLP-1 receptor agonists differ in their metabolism and excretion profiles, affecting the choice of agent for patients with renal impairment. As with other protein-based therapies, GLP-1 receptor agonists may induce the formation of antibodies that may attenuate therapeutic efficacy and affect safety. Conclusions on cardiovascular safety must await outcomes studies, but at present no signal of harm has been reported, and preclinical data and effects on risk markers suggest a potential for benefit. Current data on thyroid medullary cancer in humans and pancreatic malignancy in rodents do not suggest that there is any reason to restrict the clinical use of GLP-1 analogues in most people with diabetes. It is currently difficult to ascertain the possible contributory role of GLP-1 receptor agonists in increasing the risk of pancreatitis, and vigilance for signs and symptoms is prudent. Primary tolerability issues include transient gastrointestinal symptoms, common with GLP-1 receptor agonists, which can be reduced through dose titration.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Incretins; Liraglutide; Nausea; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Thyroid Gland; Venoms; Vomiting

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Humans; Incretins; Islets of Langerhans

The complex pathological mechanisms responsible for development of type 2 diabetes are not fully addressed by conventional drugs, which are also associated with inconvenient side effects such as weight gain or hypoglycemia. Two types of incretin-based therapies are now in use: incretin mimetics (glucagon-like peptide-1 [GLP-1] receptor agonists that bind specific receptors and mimic the action of natural GLP-1) and incretin enhancers (inhibitors of the enzyme that degrade the incretin hormones and thus prolong their activity). Both offer important advantages over previous agents. In addition to the proven glucose-lowering efficacy, they promote weight loss (or are weight neutral) by slowing gastric emptying and inducing satiety, inhibit glucagon secretion with maintenance of counterregulatory mechanisms, and exhibit cardiovascular benefits, while having a low risk profile. Importantly, short-term studies have shown that incretins/incretin-based therapies protect β-cells (by enhancing cell proliferation and differentiation and inhibiting apoptosis) and stimulate their function (by recruiting β-cells to the secretory process and increasing insulin biosynthesis/secretion). These therapies have the opportunity to interfere with the disease progression if used as an early intervention, when enough β-cell mass/function can still be preserved or restored.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins

In type 2 diabetes mellitus, oral hypoglycemic agents and analogues of glucagon-like peptide-1 provide adequate glycemic control early in the disease. Insulin therapy becomes necessary for those with advanced disease. Further, some experts recommend electively starting insulin therapy in early diabetes. This review addresses practical approaches to insulin therapy, particularly when it is indicated and which regimen to use.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Metformin; Risk Factors

The prevalence of diabetes is increasing worldwide. Over the recent years, new discoveries have led to the development of new pharmacological agents targeting the incretin hormones gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1). These agents, called incretin-mimetics, are the newest agents added to the diabetes treatment options. The purpose of this article is to review the relevant literature on the chemistry, pharmacology, pharmacokinetics, metabolism, clinical trials, safety, drug interactions and place in therapy of liraglutide in the treatment of type 2 diabetes.. An extensive search of the literature was performed with liraglutide and NN2211 as key terms. This article presents a review of the literature related to the chemistry, pharmacology, pharmacokinetics, drug interactions and safety and efficacy of liraglutide.. Liraglutide, a subcutaneously administered GLP-1 agonist, displays phamacodynamic and pharmacokinetic properties that allow for once-daily administration. The agent has been shown to be efficacious as monotherapy, as well as in combination with glimperide, metformin and/or rosiglitazone, reducing glycoslyated haemoglobin (A1C) between 0·84% and 1·5%. The primary adverse event reported with liraglutide is transient nausea.. Liraglutide has been well studied in dual and triple combination therapies with sulfonylureas, metformin and rosiglitazone and appears safe and effective. For patients who cannot tolerate first-line agents, metformin, insulin and sulfonylureas, liraglutide is a reasonable treatment option.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Nausea

Increased morbidity and mortality risk due to diabetes-associated cardiovascular diseases is partly associated with hyperglycaemia as well as dyslipidaemia. Pharmacological treatment of diabetic hyperglycaemia involves the use of the older oral antidiabetic drugs [OADs: biguanides, sulphonylureas (SUs), α-glucosidase inhibitors and thiazolidinediones], insulin (human and analogues) and/or incretin-based therapies (glucagon-like peptide-1 analogues and dipeptidyl peptidase 4 inhibitors). Many of these agents have also been suggested to improve lipid profiles in patients with diabetes. These effects may have benefits on cardiovascular risk beyond glucose-lowering actions. This review discusses the effects of OADs, insulins and incretin-based therapies on lipid variables along with the possible mechanisms and clinical implications of these findings. The effects of intensive versus conventional antihyperglycaemic therapy on cardiovascular outcomes and lipid profiles are also discussed. A major conclusion of this review is that agents within the same class of OADs can have different effects on lipid variables and that contrary to the findings in experimental models, insulin has been shown to have beneficial effects on lipid variables in clinical trials. Further studies are needed to understand the precise effect and the mechanisms of these effects of insulin on lipids.

Topics: Biguanides; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Thiazolidinediones

TCF7L2 is a Wnt signaling-associated transcription factor and is ubiquitously expressed. Polymorphisms in the TCF7L2 gene exhibit the strongest association with type 2 diabetes among approximately twenty susceptibility gene variants identified to date. Although the mechanisms by which TCF7L2 affects susceptibility to type 2 diabetes remain to be elucidated, several studies have shown that decreased TCF7L2 protein inhibits the insulin secretory response to oral glucose through impaired incretin action(GLP-1, GIP). In this review, we discuss studies that investigate the association between polymorphisms of TCF7L2 and the diabetic phenotype, especially in vitro beta cell function with special reference to incretin action and the response to lifestyle intervention.

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Phenotype; Polymorphism, Genetic

Increased prevalence of type 2 diabetes mellitus and its close clustering with obesity, arterial hypertension, dyslipidemia and other pathologies commonly referred to as metabolic or insulin resistance syndrome, represents one of the major health problem worldwide. The side effects of most of oral antidiabetics and insulin include increase in body weight and/or hypoglycemia that may limit its use in some patients. GLP-1 agonists are medicaments stimulating GLP-1 receptor similarly as endogenous GLP-1. These substances are in contrast to endogenous GLP-1 resistant to inactivation by ubiquitous enzyme dipeptidyl-peptidase 4 which enables its administration once or twice daily. GLP-1 agonists not only significantly improve diabetes compensation with minimal risk of hypoglycemia but also decrease body weight, blood pressure and improve numerous parameters of cardiovascular risk. The aim of this review is to summarize current knowledge with respect to use of GLP-1 agonists in the treatment of type 2 diabetes and its future perspectives. We will focus mostly on the two drugs that are currently available in Czech Republic--exenatide and liraglutide.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Peptides; Venoms

Incretin therapy includes treatment with incretin analogues (exenatid and liraglutid) and so called incretin enhancers (gliptins and DPP-4 inhibitors respectively--sitagliptin, vildagliptin, saxagliptin, linagliptin). In patients with type 2 diabetes, this novel antidiabetic treatment usually leads to successful reduction in fasting as well as postprandial glycaemia and glycosylated haemoglobin. At the same time, it importantly improves all components of metabolic syndrome (dyslipidemia, hypertension, systemic inflammation). Incretin analogues also reduce body weight while DPP-4 inhibitors are weight-neutral. Both groups of drugs are expected to have positive cardiovascular effects, although it is not clear whether these are likely to be direct or indirect, i.e. facilitated by improved compensation of metabolic syndrome components.

Topics: Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Metabolic Syndrome

Glucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes.. The aim of this article was to review incretin physiology and studies of incretin therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors that were developed to specifically address the blunted incretin response in patients with T2DM.. Relevant English-language publications between 1995 and 2010 were identified through a search of the MEDLINE and EMBASE databases using the search terms incretin, type 2 diabetes mellitus, GLP-1, glucose-dependent insulinotropic polypeptide, and DPP-4. Review articles and preclinical and clinical trials that described relevant details of the epidemiology of diabetes and incretin physiology in health and in T2DM were selected for review and inclusion. Clinical trials were used to describe the clinical efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. An occasional systematic review article and/or meta-analysis summarizing numerous clinical trials of a particular agent was selected for summarizing key data.. Pharmacologic modulation of incretin pathophysiology by GLP-1 receptor agonists and DPP-4 inhibitors significantly improved glycemic control, benefited β-cell function, improved dyslipidemia, and lowered the risk of hypoglycemia compared with insulin and sulfonylureas. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produced weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The most common adverse events with GLP-1 receptor agonist therapy included nausea (28%-44%), vomiting (13%-17%), and diarrhea (11%-17%), which generally reduced in incidence and severity with continued therapy. The tolerability profile of the DPP-4 inhibitors was very good, with the incidence of adverse events similar to that of placebo. There was a suggestion of an increased incidence of nasopharyngitis versus placebo (5%-6% vs 3%-4%) with sitagliptin and urinary tract infection (6.8% vs 6.1% with placebo) and headache with saxagliptin (6.5% vs 5.9% with placebo).. The 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term β-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins

Increased understanding of the role of incretin hormones in maintaining glucose homeostasis has enabled the development of pharmacotherapies that target deficient incretin activity in type 2 diabetes mellitus (T2DM). Incretin therapies are premised on 1 of 2 approaches: (1) augmenting the activity of the hormone glucagon-like peptide (GLP)-1 (GLP-1 receptor agonists) and (2) inhibiting the degradation of GLP-1 by dipeptidyl peptidase (DPP)-4 (DPP-4 inhibitors).. This review discusses the pharmacokinetic properties and clinical profiles of the GLP-1 receptor agonists (exenatide twice daily, liraglutide once daily, exenatide once weekly, taspoglutide, and albiglutide) and the DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, and alogliptin) available for use or in late-stage development.. A search of PubMed for literature published between 2000 and mid-2010 was conducted using the names of each agent as key words. Phase III and IV studies were included in the review of efficacy and tolerability. Supplemental searches of abstracts from major diabetes conferences provided additional information on pharmacokinetic properties. Searches of all reference lists were performed to identify additional references of interest.. The PubMed search identified multiple randomized, controlled clinical studies of the GLP-1 receptor agonists and the DPP-4 inhibitors administered as monotherapy or in combination regimens. Reductions from baseline in glycosylated hemoglobin ranged from 0.4% to 1.5% with exenatide 5 to 10 μg/d (7 studies), 0.6% to 1.5% with liraglutide 0.6 to 1.8 mg/d (6 studies), 0.3% to 1.0% with sitagliptin 25 to 200 mg/d (9 studies), 0.5% to 0.9% with saxagliptin 2.5 to 10 mg/d (3 studies), 0.4% to 1.0% with vildagliptin 50 to 100 mg/d (6 studies), and 0.4% to 0.8% with alogliptin 12.5 to 25 mg/d (4 studies). Dosage adjustments and caution in prescribing incretin therapies are recommended in patients with renal disease, with those recommendations varying based on the agent and the degree of dysfunction. Incretin therapies have been associated with few interactions with commonly used antihyperglycemic and cardiovascular therapies.. Based on the pharmacokinetic and therapeutic characteristics described in previously published Phase III and IV studies of incretin therapies, these agents may provide an option for the management of T2DM.

Topics: Diabetes Mellitus, Type 2; Half-Life; Humans; Hypoglycemic Agents; Incretins

The incidence and prevalence of type 2 diabetes mellitus (T2DM) have reached epidemic proportions in the United States. In addition to growing numbers of individuals in whom T2DM has been diagnosed, in numerous others T2DM or prediabetes remains undiagnosed or is likely to develop in the near future. Identification of individuals at risk for T2DM, as well as those who may already have the disease but in whom it has not yet been diagnosed, is a key element in reducing the overall burden of this disease. Early initiation of treatment can prevent or delay disease progression and reduce the risk for diabetes-related complications. Achieving evidence-based clinical goals by implementing effective management strategies substantially reduces the risk of morbidity and mortality and ultimately improves patient outcomes. A review of the latest and most effective approaches to T2DM management and practical suggestions for implementing treatment strategies in order to provide optimal T2DM care will be presented.

Topics: Diabetes Mellitus, Type 2; Disease Progression; Health Knowledge, Attitudes, Practice; Humans; Hypoglycemic Agents; Incretins; Life Style; Mass Screening; Metformin; Physicians, Primary Care; Risk Assessment; Risk Factors

Pancreatic beta cell dysfunction is pivotal to the development of diabetes, and restoration of insulin action is of primary importance. Here, we present a review of the mechanism of insulin secretion by pancreatic beta cells and discuss the mutual interaction of signaling pathways in stimulus-secretion coupling to better understand the scientific basis of pharmacological treatment for insulin secretion deficiency. Glucose stimulates insulin secretion via membrane depolarization by closure of ATP-sensitive K(+) channels (K(ATP) channels) and opening of L-type voltage-dependent Ca(2+) channels. The resultant elevation of cytosolic free Ca(2+) triggers insulin exocytosis. This is termed the "K(ATP)-dependent pathway" and is shared by sulfonylurea, which closes K(ATP) channels. Glucose also stimulates insulin release independent of its action on K(ATP) channels. This is referred to as the "K(ATP)-independent pathway," the molecular basis of which remains elusive. In the pancreatic beta cell, incretin hormones increase cAMP level, which enhances glucose-stimulated insulin release by protein kinase A-dependent and -independent mechanisms. Importantly, cAMP does not directly augment Ca(2+)-stimulated insulin release per se. The stimulatory level of ambient glucose is an absolute requirement for incretin to enhance insulin release. Therefore, incretin/cAMP enhances K(ATP)-independent insulinotropic action of glucose. The robust glucose-lowering effect of DPP4 inhibitor add-on in diabetic patients with sulfonylurea secondary failure is intriguing. With the clinical availability of DPP4 inhibitor and GLP-1 mimetics, the importance of the interactions between cAMP signaling and K(ATP) channel-independent actions of glucose is reappraised.

Topics: Calcium Channels, L-Type; Diabetes Mellitus, Type 2; Glucose; Humans; Incretins; Insulin; Insulin-Secreting Cells; KATP Channels; Signal Transduction

Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diabetic Retinopathy; Epigenesis, Genetic; Female; Fetal Development; Genetic Predisposition to Disease; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Life Style; Liver; Muscle, Skeletal; Myocardium; Obesity; Prediabetic State; Pregnancy

Long-acting glucagon-like peptide-1 receptor agonists (LA-GLP-1RAs) may deliver additional therapeutic benefits over other available incretin-based therapies.. To pool results of randomized controlled trials comparing the efficacy and safety of maximum dose LA-GLP-1RAs (liraglutide, exenatide once weekly) with exenatide twice daily and dipeptidyl-peptidase-IV inhibitors in patients with type 2 diabetes.. We searched PubMed, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE (all from inception-December 2010), and abstracts presented at the American Diabetes Association Scientific Sessions in 2009 and 2010 to identify English-language reports of studies of at least 24 weeks' duration. The primary endpoint was mean change in hemoglobin A(1c) (A1C) from baseline to study endpoint. Weighted mean differences or odds ratios and their 95% confidence intervals for each outcome relative to control were calculated as appropriate.. A1C was reduced favoring LA-GLP-1RAs compared with exenatide twice daily and sitagliptin (weighted mean difference [WMD] -0.47% [95% CI -0.69 to -0.25] and WMD -0.60% [95% CI -0.75 to -0.45], respectively). Odds ratios greater than 1 favored LA-GLP-1RAs for reaching the A1C target goal of less than 7%. Fasting plasma glucose (FPG) was reduced and favored the LA-GLP-1RA-based regimens. Exenatide demonstrated significantly greater reductions in postprandial glucose (PPG) after the morning and evening meals, compared with LA-GLP-1RAs. Body weight was reduced similarly between LA-GLP-1RAs and exenatide, but favored LA-GLP-1RAs in the sitagliptin comparator trials. LA-GLP-1RA therapy was not associated with severe hypoglycemia or acute pancreatitis. Compared with exenatide twice daily, vomiting was reduced significantly with LA-GLP-1RAs (OR 0.55; 95% CI 0.34 to 0.89); there was a trend toward decreased nausea (OR 0.58; 95% CI 0.32 to 1.06) and no difference in the incidence of diarrhea (OR 1.03; 95% CI 0.67 to 1.58).. Compared with other incretin-based therapies, LA-GLP-1RAs produce greater improvement in A1C and FPG. They provide lesser effect on PPG, similar reduction in body weight, and result in a potentially favorable adverse event profile compared with exenatide twice daily.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Male; Middle Aged; Peptides; Pyrazines; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms

Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperlipidemias; Incretins; Lipid Metabolism; Postprandial Period; Randomized Controlled Trials as Topic; Risk Factors

Glucagon-like peptide 1 (GLP-1) is a hormone secreted predominantly by the distal small intestine and colon and released in response to enteral nutrient exposure. GLP-1-based therapies are now used widely in the management of type 2 diabetes and have the potential to be effective antiobesity agents. Although widely known as an incretin hormone, there is a growing body of evidence that GLP-1 also acts as an enterogastrone, with profound effects on the gastrointestinal motor system. Moreover, the effects of GLP-1 on gastrointestinal motility appear to be pivotal to its effect of reducing postprandial glycaemic excursions and may, potentially, represent the dominant mechanism. This review summarizes current knowledge of the enterogastrone properties of GLP-1, focusing on its effects on gut motility at physiological and pharmacological concentrations, and the motor actions of incretin-based therapies. While of potential importance, the inhibitory action of GLP-1 on gastric acid secretion is beyond the scope of this paper.

Topics: Animals; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Gastrointestinal Motility; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Movement; Peptides

Diabetes mellitus (DM) is one of the most common chronic disorders, with increasing prevalence worldwide. Type 2 diabetes (T2DM), a multifaceted disease involving multiple pathophysiological defects, accounts for nearly 85-95% of total reported cases of DM. Chances of developing T2DM are increased by obesity and physical inactivity and are augmented further with age. Two most important unmet needs associated with the management of T2DM are the lack of lasting efficacy in reducing hyperglycemia and failure to target primary causes. Different classes of Oral Hypoglycemic Agents (OHA's) with nearly equipotent efficacy are now available targeting the different pathophysiologic factors contributing to T2DM; however, almost all of them are associated with one or the other kind of adverse effect. Several studies have found that certain diabetes drugs may carry increased cardiovascular (CV) risks compared to others. The new approach in management of T2DM based upon the effects of incretin hormones; Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Vildagliptin is a drug from a new class of medications called dipeptidyl peptidase IV (DPP4) inhibitors. By inhibiting DPP-4, vildagliptin causes an increase in GLP-1, an intestinal hormone that aids in glucose homeostasis and insulin secretion. Vildagliptin has a half-life of about 90 minutes; however, > or = 50% of DPP4 inhibition continues for more than 10 hours, allowing for once- or twice-daily dosing. Clinical trials have shown that vildagliptin is effective in significantly lowering glycosylated hemoglobin (HbA1c), fasting plasma glucose, and prandial glucose levels. beta-cell function may also be improved. The drug has placebo like tolerability and rate of hypoglycemia events. Vildagliptin expands non-injectable treatment options available for management of T2DM patients, who are poorly controlled with monotherapy.

Topics: Adamantane; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Half-Life; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Nitriles; Pyrrolidines; Vildagliptin

Topics: Administration, Oral; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Thiazolidinediones

Insulin secretion from pancreatic β cells is stimulated by glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal. GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the β cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM). An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase-IV (DPP-IV) inhibitors (e.g., Januvia, Galvus). These compounds slow metabolic degradation of intestinally released GLP-1, thereby raising post-prandial levels of circulating GLP-1 substantially. Investigational compounds that stimulate GLP-1 secretion also exist, and in this regard a noteworthy advance is the demonstration that small molecule GPR119 agonists (e.g., AR231453) stimulate L cell GLP-1 secretion while also directly stimulating β cell insulin release. In this review, we summarize what is currently known concerning the signal transduction properties of the β cell GLP-1R as they relate to insulin secretion. Emphasized are the cyclic AMP, protein kinase A, and Epac2-mediated actions of GLP-1 to regulate ATP-sensitive K⁺ channels, voltage-dependent K⁺ channels, TRPM2 cation channels, intracellular Ca⁺ release channels, and Ca⁺-dependent exocytosis. We also discuss new evidence that provides a conceptual framework with which to understand why GLP-1R agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells

As knowledge of pathophysiologic mechanisms of diabetes mellitus has increased, clinical attention has shifted to the incretin system. Incretin hormones, including glucagon-like peptide-1, or GLP-1, and glucose-dependent insulinotropic polypeptide, are vital to the control of glucose homeostasis and pancreatic β-cell preservation. Novel strategies for the treatment of patients with type 2 diabetes mellitus (T2DM) engage the incretin system. Glucagon-like peptide-1 receptor agonists provide robust glycemic control as well as beneficial reductions in body weight. Dipeptidyl peptidase-4, or DPP-4, inhibitors exhibit beneficial glycemic effects and are weight-neutral. Incretin-based medications are becoming increasingly recognized in guidelines as early treatment options because of their efficacy and well-tolerated profiles. The author reviews the safety and efficacy of currently approved incretin-based agents, as well as the role of these medications in treatment paradigms for patients with T2DM. He also discusses investigational incretin-based agents.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Incretins; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine upon ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which belong to the G-protein coupled receptor family. Receptor binding activates and increases the level of intracellular cAMP in pancreatic β cells, thereby stimulating insulin secretion glucose-dependently. In addition to their insulinotropic effects, GIP and GLP-1 have been shown to preserve pancreatic β cell mass by inhibiting apoptosis of β cells and enhancing their proliferation. Due to such characteristics, incretin hormones have been gaining mush attention as attractive targets for treatment of type 2 diabetes, and indeed incretin-based therapeutics have been rapidly disseminated worldwide. However, despites of plethora of rigorous studies, molecular mechanisms underlying how GIPR and GLP-1R activation leads to enhancement of glucose-dependent insulin secretion are still largely unknown. Here, we summarize the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic actions and their effects on pancreatic β cell preservation. We then try to discuss potential of GLP-1 and GIP in treatment of type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells

Glucagon secretion plays an essential role in the regulation of hepatic glucose production, and elevated fasting and postprandial plasma glucagon concentrations in patients with type 2 diabetes (T2DM) contribute to their hyperglycaemia. The reason for the hyperglucagonaemia is unclear, but recent studies have shown lack of suppression after oral but preserved suppression after isoglycaemic intravenous glucose, pointing to factors from the gut. Gastrointestinal hormones that are secreted in response to oral glucose include glucagon-like peptide-1 (GLP-1) that strongly inhibits glucagon secretion, and GLP-2 and GIP, both of which stimulate secretion. When the three hormones are given together on top of isoglycaemic intravenous glucose, glucagon suppression is delayed in a manner similar to that observed after oral glucose. Studies with the GLP-1 receptor antagonist, exendin 9-39, suggest that endogenous GLP-1 plays an important role in regulation of glucagon secretion during fasting as well as postprandially. The mechanisms whereby GLP-1 regulates glucagon secretion are debated, but studies in isolated perfused rat pancreas point to an important role for a paracrine regulation by somatostatin from neighbouring D cells. Clinical studies of the antidiabetic effect of GLP-1 in T2DM suggest that the inhibition of glucagon secretion is as important as the stimulation of insulin secretion.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Rats; Receptors, Glucagon

Incretin-based therapy for type 2 diabetes is based on the antidiabetic effects of glucagon-like peptide-1 (GLP-1) and instituted by GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors targeting the key islet defects of the disease. The treatment is clinically efficient and safe, and associated with a low risk of adverse events. It can be used both in early and late stages of the disease and both as monotherapy and add-on to other therapies. Current research on the future of incretin-based therapy focuses on optimizing its place in diabetes treatment and examines its potential in type 1 diabetes, in subjects with obesity without type 2 diabetes and in cardiovascular and neurodegenerative disorders. Other studies aim at prolonging the duration of action of the GLP-1 receptor agonists to allow weekly administration, and to develop orally GLP-1 receptor agonists. Furthermore, other investigators focus on stimulation of GLP-1 secretion by activating GLP-1-producing L-cells or using gene therapy. Finally, also other gastro-entero-pancreatic bioactive peptides are potential targets for drug development as are synthetic peptides engineered as co-agonists stimulating more than one receptor. We can therefore expect a dynamic development within this field in the coming years.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Receptors, Glucagon

Roux-en-Y gastric bypass surgery (GBP) results in 30-40% sustained weight loss and improved type 2 diabetes in up to 80% of patients. The relative contribution of the gut neuroendocrine changes after GBP versus the weight loss has not been fully elucidated. There are clear differences between weight loss by GBP and by dietary intervention or gastric banding. One of them is the enhanced post-prandial release of incretin hormones and the recovery of the incretin effect on insulin secretion after GBP, not seen after diet-induced weight loss. The favorable changes in incretin hormones after GBP result in recovery of the early phase insulin secretion and lower post-prandial glucose levels during oral glucose administration. The enhanced incretin response may be related to the neuroglycopenia post-GBP. In parallel with changes of glucose metabolism, a larger decrease of circulating branched-chain amino acids in relation to improved insulin sensitivity and insulin secretion is observed after GBP compared to diet. The mechanisms of the rapid and longterm endocrine and metabolic changes after GBP are not fully elucidated. Changes in rate of eating, gastric emptying, nutrient absorption and sensing, bile acid metabolism, and microbiota may all be important. Understanding the mechanisms by which incretin release is exaggerated post-prandially after GBP may help develop new less invasive treatment options for obesity and diabetes. Equally important would be to identify biological predictors of success or failure and to understand the mechanisms of weight regain and/or diabetes relapse.

Topics: Amino Acids; Animals; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Incretins; Obesity; Obesity, Morbid; Recurrence; Severity of Illness Index; Weight Loss

The term incretin effect was used to describe the fact that oral glucose load produces a greater insulin response than that of an isoglycemic intravenous glucose infusion. This difference has been attributed to gastrointestinal peptides GLP-1 and GIP. Since incretin effect is reduced in subjects with type 2 diabetes, despite GLP-1 activity preservation, two forms of incretin-based treatment have emerged: GLP-1R agonists, administered subcutaneously and DPP-4 inhibitors, administered orally. There is a great interest whether incretin-based treatment will be associated with sustained long-term control and improvement in β-cell function. The observation that GLP-1R agonists improve myocardial function and survival of cardiomyocytes highlights the need for further studies. Incretin-based therapies offer a new option and show great promise for the treatment of type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Peptides; Receptors, Glucagon; Venoms

The release of incretin based therapeutic entities has brought the possibility to offer control of the disease by augmenting a natural process in the body that has become deficient with type 2 diabetes. Liraglutide, an incretin mimetic, and saxagliptin, a dipeptidyl peptidase-4 inhibitor, have been approved and introduced to the market.. To (a) review the efficacy and safety data of for the treatment of type 2 diabetes, and (b) recommend their place in therapy.. A MEDLINE search was performed using key words "liraglutide" and "saxagliptin" for articles published and available through July 2010.. The Liraglutide Effect and Action in Diabetes (LEAD) trials encompassed six published phase 3 trials that evaluated the efficacy and safety of liraglutide either as monotherapy or in addition to oral hypoglycemic medications. Saxagliptin has been studied as monotherapy and in combination to oral hypoglycemic medications.. Liraglutide has been shown to improve glucose control and weight loss compared to other pharmacologic treatments with diabetes and may offer improved control with a decrease in daily dosing compared to exenatide. Saxagliptin improved glucose control as monotherapy or in combination with medications other than sulfonylurea. Saxagliptin has not been evaluated head to head with sitagliptin other than in combination with metformin where saxagliptin was deemed noninferior. Given the lack of long-term safety and clinical data compared to current treatment modalities, and more importantly the overall cost of the therapies to the health care system, a global recommendation for their use cannot be issued.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide

Diabetes accounts for millions of office visits each year to primary care offices in the United States. Successful care of the patient with type 2 diabetes requires not only focus on glucose management but also on comorbidities such as hypertension, dyslipidemia and obesity which are closely linked to microvascular and macrovascular complications. Primary care clinicians must stay abreast of frequently published diabetes literature and new treatments to care for these increasingly complex patients. Metformin and its effect on B12 absorption continues to be an issue encountered by clinicians in daily clinical practice. There has also been recent discussion regarding the increased risk of diabetes with statins; data to date on this issue have been conflicting. Rosiglitazone continues to face public scrutiny and there are now Food and Drug Administration regulations regarding its increased risk of cardiovascular disease. Liraglutide and saxagliptin represent new treatment options for type 2 diabetes, increasing the available options for treating this complex disease. A review of the primary literature involving these topics is provided.

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Incretins; Liraglutide; Metformin; Primary Health Care; Rosiglitazone; Thiazolidinediones; Vitamin B 12 Deficiency

Nearly 90% of the diabetic patients are suffering of type 2 diabetes while approximately 60-65% of patients with type 2 diabetes are treated with oral antidiabetic drugs. In the last couple of years a new treatment option, namely incretin-based therapy, became available. The dipeptidyl-peptidase-4-inhibitors (gliptins) are designated as incretin enhancers. Using gliptins, sustained glycemic control can be achieved without gaining weight and increasing the risk of hypoglycemia. All gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin) can be used as tablets without a need for dose titration. For treating patients with type 2 diabetes, gliptins can primarily be used in combination with metformin.

Topics: Adamantane; Animals; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Metformin; Nitriles; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Tablets; Treatment Outcome; Triazoles; Vildagliptin

Novel therapeutic options for type 2 diabetes mellitus based on the action of the incretin hormone glucagon-like peptide (GLP)-1 were introduced in 2005. As injectable GLP-1 receptor agonists acting on the GLP-1 receptor, exenatide and liraglutide are available in many countries. In type 2 diabetes treatment, incretin-based therapies are attractive and more commonly used because of their mechanism of action and safety profile. Stimulation of insulin secretion and inhibition of glucagon secretion by these agents occur in a glucose-dependent manner. Therefore, incretin-based therapies have no intrinsic risk for hypoglycaemia. Furthermore, GLP-1 receptor agonists allow weight loss and lower systolic blood pressure. This review gives a brief overview of the mechanism of action and summarizes the clinical data available on exenatide and liraglutide as established substances. It further highlights the clinical study data of exenatide once weekly as the first long-acting GLP-1 receptor agonist and covers other new long acting GLP-1 receptor agonists currently in clinical development. The placement of GLP-1 receptor agonists in the treatment algorithm of type 2 diabetes is discussed.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Receptors, Glucagon; Venoms

Gastric bypass surgery (GBP) results in important and sustained weight loss and remarkable improvement of Type 2 diabetes. The favorable change in the incretin gut hormones is thought to be responsible, in part, for diabetes remission after GBP, independent of weight loss. However, the relative role of the change in incretins and of weight loss is difficult to differentiate. After GBP, the plasma concentrations of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide increase postprandially by three- to fivefold. The postprandial incretin effect on insulin secretion, blunted in diabetes, improves rapidly after the surgery. In addition to the change in incretins, the pattern of insulin secretion in response to oral glucose changes after GBP, with recovery of the early phase and significant decrease in postprandial glucose levels. These changes were not seen after an equivalent weight loss by diet. The improved insulin release and glucose tolerance after GBP were shown by others to be blocked by the administration of a GLP-1 antagonist, demonstrating that the favorable metabolic changes after GBP are, in part, GLP-1 dependent. The improved incretin levels and effect persist years after GBP, but their long-term effect on glucose metabolism, and on hypoglycemia post GBP are yet unknown. Understanding the mechanisms by which incretin release is exaggerated postprandially after GBP may help develop new less invasive treatment options for obesity and diabetes. Changes in rate of eating, gastric emptying, intestinal transit time, nutrient absorption and sensing, as well as bile acid metabolism, may all be implicated.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Intestine, Small; Obesity, Morbid; Remission Induction; Weight Loss

Type 2 diabetes is making up to 90% of the all diabetic cases. In addition to insulin resistance, insufficient B-cell function also plays an important role in the pathogenesis of the disease. The insufficient production and secretion of insulin can be increased by secretagogue drugs, like sulfonylureas and incretin mimetics/enhancers. In recent years growing number of genetic failures of the B-cells has been detected. These genetic variants can influence the efficacy of secretagogue drugs. Some of these gene polymorphisms were identified in the genes encoding the KATP channel (KCNJ11 and ABCC8). These mutations are able either to reduce or increase the insulin secretion and can modify the insulin response to sulfonylurea treatment. Other polymorphisms were found on genes encoding enzymes or transcription factors. In recent years, the genetic variants of TCF7L2 and its clinical importance have been intensely studied. Authors give a summary of the above gene polymorphisms and their role in insulin secretion.

Topics: ATP-Binding Cassette Transporters; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; KATP Channels; Mutation; Polymorphism, Genetic; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Compounds; Sulfonylurea Receptors

In the last couple of years, a new class of antidiabetic drugs became available for the clinical practice. Due to the intensive research, several new drugs reached the market. Among the incretinmimetics both the GLP-1 (glucagon like peptide-1)-receptor agonist exenatide and the GLP-1-analogue liraglutide can be used for treatment. As for incretin enhancers (dipeptidyl-peptidase-4 [DPP-4]-inhibitors), sitagliptin, vildagliptin and saxagliptin are available in Hungary, linagliptin will be introduced to the market in the near future. In clinical practice, any incretin-based new drugs can be used for treating patients with type 2 diabetes, preferably in combination with metformin. The clinical experiences with these new drugs are reviewed focusing on both the benefits and the potential side-effects of the particular compounds.

Topics: Adamantane; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Approval; Drug Therapy, Combination; Exenatide; Gliclazide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hungary; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Metformin; Nitriles; Peptides; Pioglitazone; Purines; Pyrazines; Pyrrolidines; Quinazolines; Receptors, Glucagon; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Triazoles; Venoms; Vildagliptin

Exenatide, a synthetic glucagon GLP-1 receptor agonist, belongs to a new class of agents approved as a treatment option in patients with poorly controlled type 2 diabetes not adequately controlled on oral antidiabetic agents. The principal mode of drug action includes enhanced glucose-dependent insulin secretion --the so called "incretin effect"-- suppression of glucagon and inhibition of endogenous glucose production. The potential to address these dysregulated pathways allows exenatide to be a valuable adjunct to existing treatment options for patients with poorly controlled type 2 diabetes. Clinical trials with twice-daily exenatide have shown significant improvements in glycemic control (HbA(1c) reductions of 0.8-1% across studies), progressive weight loss and low incidence of hypoglycemia. Common side effects include nausea and vomiting which usually subside after a few days of therapy and do not usually necessitate withdrawal of the drug. In recent months, a longer-acting, once-weekly preparation of exenatide, which is currently approved for use in Europe, has shown promise and phase III studies indicate that it may be more potent and efficacious than existing twice-daily preparations. Meanwhile, the results from long-term studies to assess cardiovascular benefits with exenatide therapy are eagerly awaited.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Interactions; Exenatide; Humans; Hypoglycemic Agents; Incretins; Peptides; Quality of Life; Venoms

Incretin-based therapy functions through the increase of endogenous glucagon-like peptide-1 (GLP-1) levels due to inhibition of dipeptidyl peptidase-4--an enzyme degrading GLP-1 (gliptins) or through the administration of drugs activating GLP-1 receptor (GLP-1 agonists). Both approaches increase insulin and decrease glucagon secretion leading to improved diabetes compensation. The advantages of gliptins include little side effects, body weight neutrality and potential protective effects on pancreatic beta cells. GLP-1 agonists on the top of that consistently decrease body weight and blood pressure and their effects on diabetes compensation and likelihood of protective effects on beta cells is somewhat higher than those of gliptins. Another advantage of both approaches includes their safety with respect to induction of hypoglycemia. In addition to well-known metabolic effects, other potentially benefitial consequences of incretin based therapy in both type 2 diabetic and non-diabetic patients are anticipated. Direct positive effects of incretin-based therapy on myocardial metabolism and function as well as its positive influence on endothelial dysfunction and neuroprotective effects are intensively studied. The possible indications for GLP-1 agonists could be in future further widened to obese patients with type 1 diabetes and obese patients without diabetes. The aim of this review is to summarize both metabolic and extrapancreatic effects of incretin-based therapies and to outline perspectives of potential wider use of this treatment approach.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

Incretins are a novel class of drugs indicated for therapeutic intervention in patients with type 2 diabetes. They provide effective and safe therapy. Their advantages include low risk of hypoglycaemia and positive effect on body weight. Literature published so far consistently evidences reduced cardiovascular risk. If long-term prospective studies confirm such an effect, incretin therapy will, together with metformin, become the first line treatment for type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins

The increased burden of type 2 diabetes (T2D) necessitates the need for effective and safe novel drugs to treat this epidemic disease and its complications. By compiling this RDS Special Issue, our aim was to provide a comprehensive and critical overview on recent, ongoing, and future developments in this field. In collaboration with distinguished and renowned experts, we analyzed and discussed the most important advances in the field of incretin-based therapies, their extraglycemic effects, cardiovascular actions, and specific properties of the central nervous system. Another important drug class currently in development, the SGLT-2 inhibitors, and the role of the kidney in T2D are topics also covered by this issue. In addition to drug developments, new physiological insights into the understanding of the organ pathophysiology in T2D are presented that may eventually lead to additional therapeutic targets for obesity, T2D, and chronic inflammation acting on the brain, cardiovascular system, and pancreatic islets. The outcome of this Special Issue is a comprehensive reference work including bundled knowledge and expert opinions on the various aspects of the disease and its possible therapy strategies available now and in the near future. However, despite the advances delivered by modern incretin-based therapies today, there are still many limitations associated with efficacy data, application routes, and safety issues, which prevent the decline in diabetes complication rates. We conclude that further drug development and clinical trials are required to overcome these limitations, and to counteract the movement towards higher incidence rates of T2D and its complications.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Design; Health Services Needs and Demand; Humans; Hypoglycemic Agents; Incretins

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gut peptides which are secreted by endocrine cells in the intestinal mucosa. Their plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Incretins; Obesity

Although newer treatments for type 2 diabetes (T2D) patients have produced continual improvements in outcome, a large and growing population with prediabetes remains under-treated. In the last few years, incretin-based therapies have become an important treatment option for patients with T2D. There are two classes of incretin agents: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon like peptide 1 (GLP-1) receptor agonists. The ultimate goal of agents within both of these classes is to increase GLP-1 signaling, which results in augmented glucose-induced insulin secretion, inhibition of glucagon secretion, and decreased appetite. This should result in improved regulation of glucose homeostasis. GLP-1 receptor agonists enable patients to achieve significant weight loss. In contrast, DPP-4 inhibitors result in a less dramatic increase in GLP-1 levels; therefore, they are weight neutral. Incretin therapies are currently recommended for use early in the treatment algorithm for T2D patients whose disease is not manageable by diet and exercise alone, but the potential for these agents may be farther reaching. Current studies are evaluating the potential benefits of combining incretin therapies with basal insulin to provide continuous glucose control before and after meals. In addition, these agents may be promising for patients with prediabetes since they effectively reduce glycosylated hemoglobin levels and fasting plasma glucose levels, enable weight control, and have the potential to preserve β-cell function. Clearly, all of these properties are desirable for patients with prediabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Hypoglycemic Agents; Incretins

The pathogenetic mechanisms causing type 2 diabetes are complex, and include a significant reduction of the incretin effect. In patients with type 2 diabetes, GLP-1 secretion may be impaired, while GIP secretion seems unaffected. In contrast, the insulinotropic activity of GIP is severely altered, whereas that of GLP-1 is maintained to a great extent. Better understanding of the role of incretin hormones in glucose homeostasis has led to the development of incretin-based therapies that complement and offer important advantages over previously used agents. Incretin-based agents have significant glucose-lowering effects, promote weight loss (or are weight-neutral), inhibit glucagon secretion while maintaining counter-regulatory mechanisms, exhibit cardiovascular benefits, and protect β-cells while possessing a low risk profile. At present, incretin-based therapies are most widely used as add on to metformin to provide sufficient glycemic control after metformin failure. However, they are also recommended as monotherapy early in the disease course, and later in triple combination. These agents may also be a promising therapeutic tool in prediabetic subjects. Therefore, a therapeutic algorithm is needed for their optimal application at different stages of diabetes, as suggested in this article.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Progression; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Prediabetic State

It has long been known that peptide hormones from the gastrointestinal tract have significant impact on the regulation of nutrient metabolism. Among these hormones, incretins have been found to increase insulin secretion, and thus incretin-based therapies have emerged as new modalities for the treatment of type 2 diabetes. In contrast to other antidiabetic treatments, these agents have a positive outcome profile on body weight. Worldwide there are 500 million obese people, and 3 million are dying every year from obesity-related diseases. Recently, incretin-based therapy was proposed for the treatment of obesity. Currently two different incretin therapies are widely used in the treatment of type 2 diabetes: 1) the GLP-1 receptor agonists which cause significant and sustained weight loss in overweight patients, and 2) dipeptidyl peptidase 4 (DPP-4) inhibitors being weight neutral. These findings have led to a greater interest in the physiology of intestinal peptides with potential weight-reducing properties. This review discusses the effects of the incretin-based therapies in obesity, and provides an overview of intestinal peptides with promising effects as potential new treatments for obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Humans; Incretins; Obesity

GLP-1-modulating therapies are a class of anti-diabetic drugs that improve glycemic control by stimulating glucose-dependent insulin secretion from pancreatic beta-cells. In addition, GLP-1-based therapies have a variety of extrapancreatic effects, including satiety induction and gastric mobility reduction, which extend to distinct cardiovascular actions. GLP-1 was found to reduce infarct size in the context of acute myocardial ischemia which depends on the activation of prosurvival pathways including PI3-kinase, Akt, and ERK1/2. Also, GLP-1 augments the left ventricular function in dilative and metabolic cardiomyopathy, possibly by increasing insulin independent cardiomyocyte glucose uptake. Furthermore, experimental and preliminary clinical evidence suggest vasoprotective efficacy of GLP-1 mediated by improved endothelial function and anti-inflammatory capacities leading to atheroprotection. Mechanistically, the GLP-1 receptor is relevant for glucose lowering efficacy of GLP-1. However, many of its vasoprotective actions have also been described for the GLP-1 metabolite (9-37), which does not activate the GLP-1 receptor, suggesting the presence of an additional, yet unknown, signaling pathway. Ongoing research investigates the relevance of these observations in human disease and underlying mechanisms, which are reviewed in the present article.

Topics: Animals; Cardiovascular Agents; Cardiovascular System; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins

The incretin hormones glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the intestine following oral ingestion of nutrients. Incretins promote insulin secretion, while GLP-1 also inhibits glucagon release and gastric emptying, minimizing postprandial glucose excursions. The incretins share similar effects on the pancreatic β cell; however, there are a number of differences in extrapancreatic actions. Type 2 diabetes (T2DM) is associated with abnormal incretin physiology, and although treatment with GIP is ineffective, GLP-1 effects are preserved. The current incretin-based approaches to T2DM include the GLP-1 agonists that are resistant to the serine protease dipeptidylpeptidase-4 (DPP4), which normally rapidly degrades the incretins, and DPP4 inhibitors (DPP4i). Incretin-based treatments have provoked much interest due to use-associated weight loss (GLP-1 agonists), minimal hypoglycemia, and potential for positive effects on pancreatic β cell biology and the cardiovascular system. However, the long-term safety of these agents has yet to be established. This review outlines the current understanding of incretin biology, available data pertaining to incretin-based treatment in T2DM, and differences between GLP-1 and DPP4i therapy.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Receptors, Gastrointestinal Hormone

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a clinically validated target for treatment of insulin resistance. PPARgamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARgamma provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARgamma is a nuclear receptor that forms a complex with coreceptor RXR and a cell type- and cell state-specific array of coregulators to control gene transcription. PPARgamma affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARgamma modulator profile would include high-affinity interaction with the PPARgamma-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARgamma modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gluconeogenesis; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Resistance; Pioglitazone; PPAR gamma; Quinolines; Retinoid X Receptors; Rosiglitazone; Sulfonamides; Thiazolidinediones

Type 2 diabetes mellitus (T2DM) is a worldwide public health challenge. Despite the availability of many antidiabetes agents and pharmacotherapies targeting cardiovascular risk factors, the morbidity, mortality and economic consequences of T2DM are still a great burden to patients, society, health care systems and the economy. The need for new therapies for glycaemic control is compounded by the fact that existing treatments have limitations either because of their side effects (particularly weight gain and hypoglycaemia) or contraindications that limit their use. Furthermore, none of the current therapies have a significant impact on disease progression. Incretin-based therapies offer a new therapeutic approach to the management of T2DM, and there are also several even newer therapies in development. There are two groups of incretin-based therapies currently available; dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 analogues/mimetics. The former are given orally while the latter subcutaneously. These drugs result in glucose-dependent insulin secretion and glucose-dependent glucagon suppression, with consequent low risk of hypoglycaemia when used as mono- or combination therapy (except when used with sulphonylureas). In addition, they are either weight neutral in the case of DPP-4 inhibitors or cause weight loss in the case of incretin mimetics/analogues. Furthermore, animal studies have shown that these agents prolong beta cell survival which offers the theoretical possibility of slowing the progression to T2DM. In this article we will review the currently available antidiabetes agents with particular emphasis on incretin-based and future therapies. In addition, we will review and discuss the evidence relating to glycaemic control and cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Routes; Drug Interactions; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

Type 2 diabetes mellitus and comorbidities related to overweight/obesity are risk factors for the development of cardiovascular disease (CVD). In addition to insulin resistance and progressive beta-cell failure as key factors in the pathogenesis of type 2 diabetes mellitus, defects in the incretin system are now known to contribute as well. Lifestyle modifications including diet and exercise are often insufficient for reducing glucose and weight, and most patients with type 2 diabetes will require pharmacotherapy to treat their hyperglycemia. Goals of therapy should be to reduce blood glucose to as low as possible, for as long as possible, without weight gain and hypoglycemia, and correcting cardiovascular risk factors. Numerous antidiabetes medications lower blood glucose; however, many are associated with weight gain and do not address risk factors present for CVD. Newer pharmacotherapies include the glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and amylinomimetics. The GLP-1 receptor agonists and amylinomimetics reduce glucose while promoting weight loss and improving other cardiovascular risk factors with a low incidence of hypoglycemia. The DPP-4 inhibitors effectively lower glucose and are weight neutral.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Life Style; Liraglutide; Obesity; Overweight; Peptides; Receptors, Glucagon; Venoms; Weight Loss

Rates of type 2 diabetes, obesity and their associated detrimental cardiovascular effects are rapidly increasing. Despite the availability of several treatment options for type 2 diabetes and the use of intensive regimens combining several antidiabetic drugs, less than one-half of all patients reach a target glycosylated hemoglobin level of less than 7%. Disease progression due to ongoing deterioration of pancreatic islet cell health and beta-cell function is likely responsible. Therefore, there is a need to identify new pharmacological compounds that may not only treat hyperglycemia, but may also correct impaired glucose homeostasis and preserve endogenous beta-cell function. Identification and characterization of the incretin system and its effect on glucose homeostasis have resulted in the development of new antidiabetic agents that target these concerns. The current review examines the incretin effect and the pharmacological agents that have been developed based on the understanding of this physiological system. The influence of incretins on the cardiovascular system beyond the proatherogenic effect of type 2 diabetes will also be discussed.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Incretins; Metabolic Syndrome

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

Type 2 diabetes mellitus is a chronic debilitating disease characterized by insulin resistance and progressive pancreatic dysfunction. Concomitant with declining pancreatic function and decreasing insulin production, there is a progressive increase in blood glucose levels. Hyperglycemia plays a major role in the development of the microvascular and macrovascular complications of diabetes. Traditional agents used for the treatment of type 2 diabetes are able to improve glycemia, but their use is often limited by treatment-associated side effects, including hypoglycemia, weight gain, and edema. Moreover, these agents do not have any sustained effect on beta-cell mass or function. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both exenatide (the first dipeptidyl peptidase-4-resistant glucagonlike peptide-1 receptor agonist approved by the US Food and Drug Administration [FDA]), and liraglutide (a long-acting incretin mimetic), improve beta-cell function and glycemia with minimal hypoglycemia. Both agents have trophic effects on beta-cell mass in animal studies. The use of these agents is also associated with reduced body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic function, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

Topics: Animals; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Endothelium, Vascular; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Liraglutide; Liver; Peptides; Receptors, Glucagon; Venoms

Incretin hormones are secreted in response to food ingestion and help manage glycemic control by regulating insulin and glucagon release, slowing gastric emptying, and reducing caloric intake. Glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, secreted from the L-cells of the lower gut and K-cells of the intestines, respectively, are responsible for these incretin effects, which are reduced in patients with type 2 diabetes mellitus. Initially, the rapid degradation of either incretin by dipeptidyl peptidase-4 (DPP-4) complicated the development of viable therapeutics based on either hormone. However, the US Food and Drug Administration (FDA) has approved 2 incretin-based therapies in which their mechanisms of action augment or amplify the effects of naturally occurring GLP-1. Exenatide, a first-in-class GLP-1 receptor agonist, exhibits the same mechanisms of action as native GLP-1. Sitagliptin inhibits the DPP-4 enzyme, thus increasing the half-life of endogenous GLP-1. This review examines data from recent GLP-1 receptor agonist and DPP-4 inhibitor studies in patients with type 2 diabetes, as well as data on other incretin-based therapies in clinical development.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms

Impaired insulin secretion (beta-cell), increased hepatic glucose production (liver), and decreased peripheral (muscle) glucose utilization constitute the traditional primary defects responsible for the development and progression of type 2 diabetes mellitus. beta-Cell failure, ultimately leading to decreased insulin secretion, is now known to occur much earlier in the natural history of type 2 diabetes than originally believed. Additionally, a better understanding of the pathophysiology of type 2 diabetes reveals other etiologic mechanisms beyond the classic triad, now referred to as the ominous octet. In addition to the beta-cell, liver, and muscle, other pathogenic mechanisms include adipocyte insulin resistance (increased lipolysis), reduced incretin secretion/sensitivity (gastrointestinal), increased glucagon secretion (alpha-cell), enhanced glucose reabsorption (kidney), and central nervous system insulin resistance resulting from neurotransmitter dysfunction (brain). Currently, the management of type 2 diabetes focuses on glucose control via lowering of blood glucose (fasting and postprandial) and hemoglobin A(1c). However, the goal of therapy should be to delay disease progression and eventual treatment failure. Treatment should target the known pathogenic disturbances of the disease (i.e., reducing the deterioration of beta-cell function and improving insulin sensitivity). In recent years, treatment strategies have focused on the development of novel therapeutic options that affect many of the defects contributing to type 2 diabetes and that provide durable glucose control through a blunting of disease progression. Optimal management of type 2 diabetes should include early initiation of therapy using multiple drugs, with different mechanisms of action, in combination.

Topics: Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin Resistance; Insulin-Secreting Cells; Prediabetic State

The incretin hormone, glucagon-like peptide-1 (GLP-1), is now being used in the clinic to enhance insulin secretion and reduce body weight in patients with type 2 diabetes. Although much is already known about the biology of GLP-1, much remains to be understood. Hence, this review will consider recent findings related to the potential for enhancing endogenous levels of GLP-1 through selective use of secretagogues and the beneficial cardiovascular, neuroprotective, and immunomodulatory effects of GLP-1, as well as the possible effects of GLP-1 to enhance beta-cell growth and/or to induce pancreatitis or thyroid cancer. Finally, the potential for molecular medicine to enhance the success of GLP-1 therapy in the clinic is considered. A better understanding of the fundamental biology of GLP-1 may lead to new therapeutic modalities for the clinical use of this intestinal hormone.

Topics: Animals; Apoptosis; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Receptors, Glucagon

Type 2 diabetes mellitus (T2DM), which is characterized by insulin and glucose dysregulation, is a major contributor to the development of cardiovascular disease, renal failure and premature death. Incretin hormones are released from the intestines upon nutrient ingestion and contribute to glucose homeostasis in part by promoting insulin secretion from the pancreas. Drugs that enhance the incretin response have emerged as effective treatments for T2DM. Several recent studies have revealed that incretin secretion from enteroendocrine cells in the intestines can be modulated by T1R and T2R receptors, proteins that have been demonstrated to function as taste receptors. This review focuses on the intriguing finding that taste receptors may be involved in modulating the incretin response, and considers T1Rs and T2Rs as potential targets for new hypoglycemic drugs.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Receptors, G-Protein-Coupled

Analogues of the incretins Glucagon-like peptide 1 (GLP-1) and Glucose-dependent insulinotropic peptide (GIP) have been developed to treat type 2 diabetes mellitus. They are protease resistant and have a longer biological half life than the native peptides. Some of these novel analogues can cross the blood-brain barrier, have neuroprotective effects, activate neuronal stem cells in the brain, and can improve cognition. The receptors for GIP and GLP-1 are expressed in neurons, and both GIP and GLP-1 are expressed and released as transmitters by neurons. GIP analogues such as DAla(2)GIP and GLP-1 analogues such as liraglutide enhance synaptic plasticity in the brain and also reverse the betaamyloid induced impairment of synaptic plasticity. In mouse models of Alzheimer's disease, GLP-1 analogues Val(8)GLP-1 and liraglutide prevent memory impairment and the block of synaptic plasticity in the brain. Since two GLP- 1 analogues exendin-4 (Exenatide, Byetta) and liraglutide (Victoza) are already on the market as treatments for Type 2 diabetes, and others are in late stage clinical trials, these drugs show promise as treatments for neurodegenerative diseases such as Alzheimer's disease. Currently, there are three patents covering native GLP-1 and different GLP-1 analogues and one patent for the use of GIP and different GIP analogues for the treatment of neurodegenerative diseases.

Topics: Alzheimer Disease; Amino Acid Sequence; Animals; Blood-Brain Barrier; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Models, Neurological; Molecular Sequence Data; Neuroprotective Agents; Patents as Topic

Topics: Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Approval; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Metformin; Middle Aged; Pyrazines; Risk Factors; Satiety Response; Sitagliptin Phosphate; Triazoles; Weight Loss

Despite the wide array of treatments available, a significant number of patients with type 2 diabetes continue to remain uncontrolled. The discovery of the incretin hormones and their role in glucose homeostasis has brought about a new class of medications called the glucagon-like peptide-1 (GLP-1) analogs. This new class of medications provides the benefits of weight loss as well as a lack of hypoglycemia. However, the currently available agents require once or twice daily injections.. Relevant literature will be discussed on albiglutide, a new GLP-1 analog in Phase III clinical trials. Several clinical trials examining the use of albiglutide as combination therapy are currently ongoing.. To date, results of clinical trials suggest that albiglutide may provide a more attractive dosing profile compared with the currently available GLP-1 analogs.. The results of ongoing trials will help define the role of albiglutide in treating patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Evidence-Based Medicine; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Treatment Outcome

Obesity has reached epidemic proportions and is continuing to grow into one of the leading healthcare issues worldwide. With this development, bariatric surgery has emerged as an acceptable treatment for morbid obesity, generally achieving meaningful and sustained weight loss. In a surprising turn of events, bariatric surgery was also found to be the most effective therapy for type 2 diabetes mellitus (T2DM). This observation has sparked a great deal of research that has improved our understanding of T2DM pathophysiology; it has facilitated the development of medical treatment and is expanding the indications for bariatric surgery. It was traditionally accepted that bariatric surgery causes weight loss by restriction of gastric volume, intestinal malabsorption, or a combination of the two. Laparoscopic adjustable gastric banding (LAGB) is considered a purely restrictive procedure that involves the placement of an adjustable band around the cardia of the stomach, creating a 15 ml pouch. Laparoscopic sleeve gastrectomy (LSG) is the resection of the fundus all along the greater curvature of the stomach. LSG was once considered a restrictive procedure, but this presumption has recently come under scrutiny. Bilio-pancreatic diversion (BPD) is an example of a procedure that was considered predominantly malabsorptive. In this operation, the ingested nutrients are diverted from the stomach to the ileum, bypassing a large segment of proximal bowel. Roux-en-Y gastric bypass (RYGB) traditionally combines both mechanisms, partitioning a small pouch from the proximal stomach and diverting the ingested nutrients to the jejunum with a roux-en-Y gastro-jejunostomy. However, recent investigation suggests additional mechanisms of action including hormonal. Today, RYGB is the procedure of choice for morbidly obese patients. The effect of bariatric surgery on T2DM was initially described in 1995 by Pories et al., who reported that there was an overall T2DM resolution after RYGB of 82.9% (1). A resolution rate of approximately 80% has been demonstrated repeatedly (2,3). The initial assumption was that the mechanism causing this effect was through weight loss. It is becoming evident that the anti-diabetic effect is not entirely weight loss as there is a consistent observation that the improvement of glucose and insulin levels occurs within days after RYGB, clearly too soon to be due to the weight loss (1,4). The ensuing body of literature has generated two leading theories att

Topics: Animals; Bariatric Surgery; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Obesity

Type 2 diabetes (T2D) is associated with increased cardiovascular disease and mortality. Most diabetes treatments have not proven to reduce this risk and may be associated with worsening of specific cardiovascular risk factors. GLP-1 receptor agonists (GLP-1R agonists) are new incretin-based therapies for the treatment of T2D. They improve glucose control by stimulating insulin secretion and suppressing glucagon release, both in a glucose-dependent manner. There are two GLP-1R agonists approved for the treatment of T2D: once daily liraglutide and twice daily exenatide, both administered by sc injection. Based on recent clinical trials, GLP-1R agonists suggest having a protective role in cardiovascular risk factors besides improving glycemic control, compared to placebo and to standard diabetes therapies. Both liraglutide and exenatide have demonstrated to induce clinically significant weight loss and to reduce systolic blood pressure. Liraglutide also has a positive effect on the lipid profile and cardiovascular risk biomakers. Furthermore, recent data shows a direct effect of GLP-1 and its metabolites in the vascular endothelium and the myocardium, leading to vasodilator effects and improved cardiac function in humans with acute myocardial infarction or congestive heart failure. GLP-1R agonists have a positive impact on cardiovascular risk factors otherwise not addressed by most standard diabetes therapies. Whether these new compounds actually decrease cardiovascular disease and mortality remains to be demonstrated in outcome studies.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Models, Biological; Molecular Sequence Data; Receptors, Glucagon; Risk Factors

Treatment of patients with type 2 diabetes mellitus (T2DM) traditionally has involved a progression of phases, from conventional lifestyle interventions and monotherapy, to combination therapy involving oral agents, to insulin initiation and its use either alone or with oral pharmacotherapy. Currently, the need for antidiabetic therapies with fewer adverse effects (eg, weight gain, reduced rates of hypoglycemia) is unmet. In addition, most treatments fail to adequately control postprandial hyperglycemia. Traditional options have generally been directed at the "insulin demand" aspect and have targeted insulin secretion or insulin resistance in peripheral tissues. Only recently have agents been available to address the "glucose supply" aspect that leads to fasting hyperglycemia in patients with T2DM. Incretin-based therapies, however, address both aspects. Two classes of incretin-directed therapies are available and work by either increasing endogenous levels of glucagon-like peptide-1 (GLP-1) (ie, dipeptidyl peptidase-4 inhibitors) or by mimicking the activity of endogenous GLP-1 (ie, GLP-1 agonists). These therapies treat the key metabolic abnormalities associated with T2DM but do so with reduced rates of hypoglycemia and do not promote weight gain as compared with conventional therapies.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Incretins; Piperidines; Pyrazines; Sitagliptin Phosphate; Triazoles; Uracil

Saxagliptin (BMS-477118) has been recently FDA approved drug for the management of T2DM developed by Bristol-Myers Squibb and AstraZeneca under the trade name Onglyza. Saxagliptin is a nitrile-containing selective, potent, reversible and durable DPP IV inhibitor developed as an alternative second-line adds on to Metformin in place of a sulphonylurea. Saxagliptin increases and prolongs the action of incretin hormones by inhibiting the DPP IV enzyme that inactivates incretins usually within minutes. Saxagliptin is well absorbed and has low plasma protein binding and displays slow-binding properties to DPP IV. Saxagliptin is metabolized in vivo to form an active metabolite (BMS-510849), which is twofold less potent than the parent molecule. The X-ray crystallography revealed that Saxagliptin is covalently bound to the DPP IV active site. In drug-native patients with T2DM and inadequate glycemic control, once-daily Saxagliptin monotherapy for 24 wks demonstrated clinically meaningful with no weight gain and generally well tolerated.

Topics: Adamantane; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Humans; Hypoglycemic Agents; Incretins; Protease Inhibitors

Type 2 diabetes mellitus traditionally has been characterized by insulin resistance and beta-cell dysfunction, leading to hyperglycemia and eventual micro- and macrovascular complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of drugs available for the management of type 2 diabetes. In order to provide a comprehensive evaluation and comparison of the pharmacology, pharmacokinetics, efficacy, and safety of the DPP-4 inhibitors-sitagliptin, vildagliptin, saxagliptin, and alogliptin-in the treatment of type 2 diabetes, we conducted a MEDLINE search (1966-July 2009) for pertinent English-language articles. Abstracts of the annual meetings of the American Diabetes Association and European Association for the Study of Diabetes from 2005-2009 were also searched. As a drug class, the DPP-4 inhibitors have become widely accepted in clinical practice because of their low risk of hypoglycemia, favorable adverse-effect profile, and once-daily dosing. They are weight neutral (do not cause weight gain or loss) and appear to decrease beta-cell apoptosis and increase beta-cell survival. Because clinical studies directly comparing agents from this class have not, to our knowledge, been conducted, making comparisons in terms of efficacy and safety will become difficult for clinicians as more agents become available. Based on information from preclinical, clinical, and postmarketing data, there does not appear to be a compelling advantage of one DPP-4 inhibitor over another in terms of efficacy, safety, or ease of clinical use. Although theoretical advantages exist for agents with a higher specificity for DPP-4 inhibition versus inhibition of other isoenzymes associated with toxicity, comparative studies and/or increased clinical experience with this class of drug will determine the clinical advantages, if any, of one agent over another.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Enzyme Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells

The gastrointestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), termed incretins, are essential regulators of normal glucose homeostasis. Research indicates that the incretin effect is impaired in type 2 diabetes, and this seems to be a consequence rather than a cause of type 2 diabetes. This review describes the defects in the incretin system seen in diabetic patients and discusses the potential roles of GIP and GLP-1 in the pathogenesis of type 2 diabetes. In addition, new information on clinical applications that exploit the enteroinsular axis to control blood glucose is discussed.

Topics: Animals; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Humans; Hypoglycemic Agents; Incretins; Insulin

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin-Secreting Cells; Models, Biological

GIP and GLP-1 are major incretins and secreted from K-cell and L-cell in response to meal ingestion, respectively. GIP and GLP-1 potentiate glucose-induced insulin secretion by binding GIP receptor and GLP-1 receptor, respectively, on pancreatic beta-cell and increasing intracellular cAMP concentration (incretin effect). GIP receptor and GLP-1 receptor are expressed in some different organs. GIP receptor is expressed in intestine, adipose tissue, brain, adrenal gland, and bone, while GLP-1 receptor is expressed in intestine, CNS, lung, kidney and heart. GIP and GLP-1 have not only pancreatic effect, such as potentiation of insulin secretion, but also many extrapancreatic effects. Incretin effect is known to be decreased in type 2 diabetes patients compared to that in healthy subjects. GLP-1 was target peptide as anti-diabetic drug, because insulin secretion in response to GLP-1 infusion was intact in type 2 diabetic patients. GLP-1 mimetics and DPP-4 inhibitor were produced as incretin-based therapy. Type 2 diabetic patients already use them in USA and Europe and get improved glycemic control. Both drugs are reported to improve in Japanese type 2 diabetic patients more glycemic controls compared to those in Caucasian type 2 diabetic patients. Thus, incretin-based therapies may have benefits for Asian patients who have less insulin secretory ability than Caucasian.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Receptors, Glucagon

Most patients with type 2 diabetes present with comorbid overweight or obesity. Reaching and maintaining acceptable glycemic control is more difficult in overweight and obese patients, and these conditions are associated with increased risk for cardiovascular and other diseases. Glycemic management for these patients is complicated by the fact that insulin and many of the oral medications available to treat type 2 diabetes produce additional weight gain. However, an increasing number of therapeutic options are available that are weight neutral or lead to weight loss in addition to their glycemic benefits. This article evaluates the evidence from clinical trials regarding the relative glycemic benefits, measured in terms of glycated hemoglobin change, versus the impact on body weight of each medication currently approved for type 2 diabetes. In general, the sulfonylureas, thiazolidinediones, and D-phenylalanine derivatives have been shown to promote weight gain. The dipeptidyl peptidase-4 inhibitors are weight neutral, while the biguanides, incretin mimetics, and amylin mimetics promote weight loss. Trials examining the glycemic benefits of the weight loss agents orlistat and sibutramine are also examined. Awareness of this evidence base can be used to inform medication selection in support of weight management goals for patients with type 2 diabetes.

Topics: Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Obesity

Type 2 diabetes mellitus is a complicated metabolic disease affecting millions of individuals worldwide. The medications used to manage the disease are based on different pharmacologic approaches, including decreasing hepatic gluconeogenesis, stimulating pancreatic insulin production, slowing polysaccharide digestion, and increasing insulin sensitivity in muscle, liver, and fat to lower blood glucose. Incretin-based therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists, mimic the effects of native GLP-1, while dipeptidyl peptidase-4 inhibitors increase circulating concentrations of endogenous GLP-1. This review focuses on means by which primary care physicians might evaluate the utility of pharmacologic agents based on their relation to the pathogenesis of type 2 diabetes. In general, patients with type 2 diabetes should be treated to their lowest targeted glycemic goals as soon as they are diagnosed, for as long as possible, as safely as possible, and as rationally as possible.

Topics: Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Receptors, Glucagon; Thiazolidinediones

Incretin-based therapies encompass two new classes of antidiabetic drugs: glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide, exenatide, and exenatide long-acting release), which are structurally related to GLP-1, and the dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin and saxagliptin), which limit the breakdown of endogenous GLP-1. To evaluate the safety and effectiveness of incretin-based therapies for the treatment of type 2 diabetes mellitus and the role of these therapies in clinical practice, a MEDLINE search (January 1985-November 2009) was conducted. Relevant references from the publications identified were also reviewed. Of 28 studies identified, 22 were randomized controlled trials. Data show that these therapies affect insulin secretion in a glucose-dependent manner, achieving clinically meaningful reductions in hemoglobin A(1c) levels, with very low rates of hypoglycemia. In addition, reductions in body weight have been observed with GLP-1 receptor agonists, which also exert a pronounced effect on systolic blood pressure. Various human and animal studies show that GLP-1 improves beta-cell function and increases beta-cell proliferation in vitro, which may slow disease progression. Thus, incretin-based therapies represent a promising addition to the available treatments for type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Models, Molecular; Randomized Controlled Trials as Topic; Receptors, Glucagon

Type 2 diabetes patients are usually overweight or obese. Further weight gain induced by antidiabetic treatment should be avoided if possible. Much attention has been focussed recently on the potential for GLP-1 mimetics, in particular, to reduce weight.. Effects on weight are but one of several important criteria in selecting antidiabetic therapy, however. This review explores the effects on weight of older classes of antidiabetic agents (metformin, sulfonylureas, thiazolidinediones) and the newer drugs acting via the GLP-1 system. Other aspects of their therapeutic profiles and current therapeutic use are reviewed briefly to place effects on weight within a broader context.. Comparative trials demonstrated weight neutrality or weight reduction with metformin, and weight increases with a sulfonylurea or thiazolidinedione. There was no clinically significant change in weight with DPP-4 inhibitors and a small and variable decrease in weight (about 3 kg or less) with GLP-1 mimetics. Improved clinical outcomes have been demonstrated for metformin and a sulfonylurea (cardiovascular and microvascular benefits, respectively, in the UK Prospective Diabetes Study), and secondary endpoints improved modestly with pioglitazone in the PROactive trial. No outcome benefits have been demonstrated to date with GLP-1-based therapies, and these agents exert little effect on cardiovascular risk factors. Concerns remain over long-term safety of these agents and this must be weighed against any potential benefit on weight management.. Considering effects on weight within the overall risk-benefit profile of antidiabetic therapies, metformin continues to justify its place at the head of current management algorithms for type 2 diabetes, due to its decades-long clinical evidence base, cardiovascular outcome benefits and low cost.

Topics: Blood Glucose; Body Weight; Decision Making; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Obesity; Randomized Controlled Trials as Topic; Treatment Outcome

Type 2 diabetes and acute coronary syndromes (ACS) are widely interconnected. Individuals with type 2 diabetes are more likely than non-diabetic subjects to experience silent or manifest episodes of myocardial ischaemia as the first presentation of coronary artery disease. Insulin resistance, inflammation, microvascular disease, and a tendency to thrombosis are common in these patients. Intensive blood glucose control with intravenous insulin infusion has been demonstrated to significantly reduce morbidity and mortality in critically ill hyperglycaemic patients admitted to an intensive care unit (ICU). Direct glucose toxicity likely plays a crucial role in explaining the clinical benefits of intensive insulin therapy in such critical patients. However, the difficult implementation of nurse-driven protocols for insulin infusion able to lead to rapid and effective blood glucose control without significant episodes of hypoglycaemia has led to poor implementations of insulin infusion protocols in coronary care units, and cardiologists now to consider alternative drugs for this purpose. New intravenous or oral agents include the incretin glucagon-like peptide 1 (GLP1), its analogues, and dipeptidyl peptidase-4 inhibitors, which potentiate the activity of GLP1 and thus enhance glucose-dependent insulin secretion. Improved glycaemic control with protective effects on myocardial and vascular tissues, with lesser side effects and a better therapeutic compliance, may represent an important therapeutic potential for this class of drugs in acutely ill patients in general and patients with ACS in particular. Such drugs should be known by practicing cardiologists for their possible use in ICUs in the years to come.

Topics: Acute Coronary Syndrome; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Prognosis

Type 2 diabetes poses a major health challenge among African Americans. Older therapies are associated with shortcomings such as hypoglycemia and/or weight gain. In recent years the "incretin system" has become understood as offering great promise for drug development. Two drug classes-namely, the injectable glucagon-like peptide 1 (GLP-1) receptor agonists, which produce pharmacological GLP receptor activity, and the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, which raise levels of endogenously produced GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) by preventing enzymatic degradation--have been available for several years. These drugs can be given as monotherapy or added to other antidiabetic drugs to lower blood glucose with very low risk of hypoglycemia without weight gain. In fact, GLP-1 receptor agonists may induce clinically significant reductions in weight and systolic blood pressure, as well as improve indices of beta-cell function. Although transient nausea occurs in some patients with GLP-1 receptor agonists, these agents are generally well tolerated, and the available clinical data are encouraging. Clinical experience shows that these treatments are acceptable to patients.

Topics: Black or African American; Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Routes; Humans; Hypoglycemic Agents; Incretins; Prevalence; Treatment Outcome; United States

Type 2 diabetes mellitus (T2DM) has been shown to be characterised by an almost abolished incretin effect. The incretin effect refers to the phenomenon of oral glucose eliciting a higher insulin response than intravenous glucose at identical plasma glucose profiles. It is conveyed by the two insulinotropic incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are secreted from the small intestines in response to ingestion of nutrients. The incretin defect of T2DM has been characterised by a virtually lost insulinotropic effect of GIP. It is unknown whether the incretin defect is a primary event leading to T2DM or arises as a consequence of the diabetic state. To investigate this we studied patients with chronic pancreatitis (CP). Over time, CP leads to secondary diabetes mellitus (DM). If patients with CP and secondary DM exhibit the characteristic type 2 diabetic incretin deficiencies and patients with CP and normal glucose tolerance are normal in that regard, it is more likely that these deficiencies are consequences of the diabetic state rather than primary events leading to T2DM. On the other hand, if incretin physiology is preserved independently of the endocrine status of patients with CP, the incretin defect could represent a primary pathogenetic defect. Three protocols have been employed to investigate this. In a study investigating postprandial incretin responses in 8 patients with CP and exocrine pancreatic insufficiency, with and without pancreatic enzyme supplementation (PES), we observed preserved incretin responses as compared to matched healthy subjects; and, further, that PES increased postprandial incretin responses in these patients. This suggests not only that the secretion of incretin hormones is regulated by the mere presence of nutrients in the small intestine, but also that the assimilation of such nutrients is involved, as well. Furthermore, we gauged the incretin effect in 8 patients with CP and normal glucose tolerance and in 8 patients with CP and secondary DM. Eight healthy subjects and 8 patients with T2DM were studied for comparison. The incretin effect was shown to be preserved in normal glucose tolerant patients with CP, whereas it was strongly reduced in patients with CP and secondary DM, suggesting the incretin defect to be a consequence of the diabetic state. Lastly, we investigated the insulinotropic effect of the incretin hormones in 8 patients with CP

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Insulin-Secreting Cells; Pancreatitis, Chronic

To evaluate the emerging classes of antihyperglycemic agents that target the incretin pathway, including their therapeutic efficacy and side effect profiles, in order to help identify their place among the treatment options for patients with type 2 diabetes.. MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched. Most evidence is level I and II.. Two classes of incretin agents are currently available: glucagonlike peptide 1 (GLP1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, both of which lower hyperglycemia considerably without increasing the risk of hypoglycemia. The GLP1 receptor agonists have a greater effect on patients' glycated hemoglobin A(1c) levels and cause sustained weight loss, whereas the DPP4 inhibitors are weight-neutral.. The GLP1 and DPP4 incretin agents, promising and versatile antihyperglycemic agents, are finding their way into the therapeutic algorithm for treating type 2 diabetes. They can be used in patients not adequately controlled by metformin monotherapy or as initial therapy in those for whom metformin is contraindicated.

Topics: Adult; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Evidence-Based Medicine; Exenatide; Glucagon-Like Peptide 1; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Venoms

Incretins are hormones that are released after ingestion of a meal and augment the secretion of insulin. Current research suggests that GLP-1 (glucagon-like peptide 1) is the most important. Their action is terminated by enzymes known as dipeptidyl peptidase-4 (DPP-4). The observation that the incretin response may be diminished in individuals with type 2 diabetes mellitus has led to advances in the management of this disease. Agents that act as incretin mimetics, such as exenatide and liraglutide, and DPP-4 inhibitors, such as sitagliptin phosphate and saxagliptin, improve glycated hemoglobin levels either as monotherapy or in combination with other agents. Importantly, these agents either lead to weight loss or are weight neutral and are associated with a low risk of hypoglycemia--properties that further contribute to their clinical utility.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Attenuation of the prandial incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), contributes to hyperglycemia in type 2 diabetes mellitus (T2DM). Since the launch of sitagliptin in 2006, a compelling body of evidence has accumulated showing that dipeptidyl peptidase-4 (DPP-4) inhibitors, which augment endogenous GLP-1 and GIP levels, represent an important advance in the management of T2DM. Currently, three DPP-4 inhibitors - sitagliptin, vildagliptin and saxagliptin - have been approved in various countries worldwide. Several other DPP-4 inhibitors, including linagliptin and alogliptin, are currently in clinical development. As understanding of, and experience with, the growing number of DPP-4 inhibitors broadens, increasing evidence suggests that the class may offer advantages over other antidiabetic drugs in particular patient populations. The expanding evidence base also suggests that certain differences between DPP-4 inhibitors may prove to be clinically significant. This therapeutic diversity should help clinicians tailor treatment to the individual patient, thereby increasing the proportion that safely attain target HbA(1c) levels, and reducing morbidity and mortality. This review offers an overview of DPP-4 inhibitors in T2DM and suggests some characteristics that may provide clinically relevant differentiators within this class.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Energy Intake; Gastric Emptying; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Intestinal Mucosa; Linagliptin; Neurons; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

Recent genome-wide association studies identified several novel risk genes for type 2 diabetes. The majority of these type 2 diabetes risk variants confer impaired pancreatic beta cell function. Though the molecular mechanisms by which common genetic variation within these loci affects beta cell function are not completely understood, risk variants may alter glucose-stimulated insulin secretion, proinsulin conversion, and incretin signals. In humans, the incretin effect is mediated by the secretion and insulinotropic action of two peptide hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. This review article aims to give an overview of the type 2 diabetes risk loci that were found to associate with incretin secretion or incretin action, paying special attention to the potential underlying mechanisms.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Genome-Wide Association Study; Glucagon-Like Peptide 1; Humans; Incretins; Insulin-Secreting Cells

Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP-1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies.

Topics: Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Drug Interactions; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Diseases; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Kidney Diseases; Pancreatitis; Receptors, Glucagon; Sulfonylurea Compounds; Thiazolidinediones; Thyroid Diseases

Type 2 diabetes mellitus (T2DM) with concomitant CKD is an emerging clinical and public health problem reaching epidemic proportions in the United States. Achieving and maintaining glycemic targets in clinical practice are significant challenges in majority of the patients with T2DM and CKD, and this has created significant barriers for clinicians managing these patients. Commonly used antihyperglycemic agents are either contraindicated or lack efficacy and safety information in this population. Recently, 2 distinct classes of agents that augment incretin hormone action have been added to the therapeutic armamentarium targeting hyperglycemia. This review will discuss the literature examining the efficacy and safety of incretin-based therapies in T2DM and the available evidence for their use in CKD.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hypoglycemic Agents; Incretins; Renal Insufficiency, Chronic; Treatment Outcome

In addition to the hypoglycemia and weight gain associated with many treatments for type 2 diabetes, alpha-glucosidase inhibitors, thiazolidinediones, metformin, sulfonylureas, and the glinides do not address all of the multiple defects existing in the pathophysiology of the disease. Cumulatively, these oral agents address the influx of glucose from the gastrointestinal tract, impaired insulin activity, and acute beta-cell dysfunction in type 2 diabetes; however, until recently, there were no means to deal with the inappropriate hyperglucagonemia or chronic beta-cell-decline characteristic of the disease. The recently introduced incretin-based therapies serve to address some of the challenges associated with traditionally available oral antidiabetic agents. In addition to improving beta-cell function, stimulating insulin secretion, and inhibiting glucagon secretion, these agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. Of the incretin-based therapies, both the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and inhibit glucagon secretion. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 receptor agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and saxagliptin. Earlier and more frequent use of these incretin-based therapies is recommended in the treatment of type 2 diabetes, based on their overall safety and ability to achieve the glycosylated hemoglobin level goal. As such, both the American Diabetes Association and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) treatment algorithms recommend the use of incretin-based therapy in both treatment-naive and previously treated patients. The AACE/ACE guidelines clearly state that these agents should not be limited to third- or fourth-line therapy.

Topics: Adamantane; Algorithms; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Evidence-Based Medicine; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Liraglutide; Managed Care Programs; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms

The pharmacology, pharmacokinetics, efficacy, safety, and dosage and administration of saxagliptin are reviewed.. Saxagliptin is a selective, reversible inhibitor of dipeptidyl peptidase-4 (DPP-4) approved for the treatment of type 2 diabetes mellitus in adults. By inhibiting DPP-4, saxagliptin reduces the degradation of endogenous incretin hormones, resulting in increased glucose-dependent insulin release and decreased glucagon secretion from the pancreas. Saxagliptin is rapidly absorbed after oral administration, and its pharmacokinetic profile allows for once-daily oral administration. Clinical trials of saxagliptin as monotherapy and as combination therapy with other oral antidiabetic medications including metformin, glyburide, pioglitazone, and rosiglitazone have demonstrated clinical benefits in various glycemic endpoints, including glycosylated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), and postprandial glucose (PPG) levels over 24 to 102 weeks of therapy. Due to its glucose-dependent mechanism of action, saxagliptin as monotherapy or in combination with metformin results in a low risk for hypoglycemia in patients with type 2 diabetes. Saxagliptin was generally well tolerated in clinical trials, with headache, upper-respiratory-tract infection, and urinary tract infection being the most common adverse events. Saxagliptin has demonstrated a low risk for drug-drug interactions. For patients with moderate or severe renal impairment or end-stage renal disease or patients taking a strong inhibitor of cytochrome P-450 isoenzyme 3A4 or 3A5, the recommended dosage is 2.5 mg once daily.. Saxagliptin, a DPP-4 inhibitor approved for the treatment of type 2 diabetes, demonstrated safety and efficacy in lowering HbA(1c), FPG, and PPG levels as both monotherapy and in combination with other oral antidiabetic medications.

Topics: Adamantane; Adult; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins

Type 2 diabetes mellitus (T2DM) is rapidly increasing in prevalence and is a major public health problem. It is a progressive disease which commonly requires multiple pharmacotherapy. Current options for treatment may have undesirable side effects (particularly weight gain and hypoglycaemia) and contraindications, and little effect on disease progression. Incretin based therapy is one of several newer therapies to improve glycaemia and is available in two different forms, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Use of these agents results in a 'glucose-dependant' increase in insulin secretion and glucagon suppression resulting in improved glycaemia with low incidence of hypoglycaemia. DPP-4 inhibitors are oral drugs which are weight neutral, while GLP-1 agonists are injected subcutaneously and help promote weight loss while improving glycaemia. GLP-1 agonists have also been shown to increase beta cell mass in rat models. Bariatric surgery is another option for the obese patient with T2DM, with blood glucose normalizing in over half of the patients following surgery. Other therapies in development for the treatment of T2DM include sodium-glucose transporter 2 (SGLT-2) inhibitors, glucagon receptor antagonists, glucokinase activators and sirtuins. In this article, we will review the various existing and emerging treatment options for T2DM.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Obesity; Sodium-Glucose Transporter 2 Inhibitors

Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in type 2 diabetes mellitus (T2DM). Pioglitazone is a potent insulin sensitizer, improves pancreatic beta cell function and has been shown in several outcome trials to lower the risk of atherosclerotic and cardiovascular events. Glucagon-like peptide-1 deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Alogliptin is a new DPP-4 inhibitor that reduces glycosylated hemoglobin (HbA(1c)), is weight neutral, has an excellent safety profile, and can be used in combination with oral agents and insulin. Alogliptin has a low risk of hypoglycemia, and serious adverse events are uncommon. An alogliptin-pioglitazone combination is advantageous because it addresses both insulin resistance and islet dysfunction in T2DM. HbA(1c) reductions are significantly greater than with either monotherapy. This once-daily oral combination medication does not increase the risk of hypoglycemia, and tolerability and discontinuation rates do not differ significantly from either monotherapy. Importantly, measures of beta cell function and health are improved beyond that observed with either monotherapy, potentially improving durability of HbA(1c) reduction. The alogliptin-pioglitazone combination represents a pathophysiologically sound treatment of T2DM.

Topics: Animals; Cardiovascular System; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucose; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Liver; Mice; Pioglitazone; Piperidines; Rats; Thiazolidinediones; Uracil

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. It is characterized by high circulating levels of glucose resulting from insulin resistance and impaired insulin secretion. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Alogliptin is a potent, highly selective dipeptidyl peptidase-4 inhibitor now undergoing clinical testing to support a new drug application for the treatment of type 2 diabetes. The results of Phase II and Phase III human studies, upon evaluation for clinical efficacy, safety and tolerability in patients with type 2 diabetes, have demonstrated that Alogliptin is effective and well tolerated as a treatment for type 2 diabetes, either as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas and insulin, with an excellent safety profile.

Topics: Animals; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Incretins; Insulin-Secreting Cells; Piperidines; Structure-Activity Relationship; Uracil

Type 2 diabetes (T2DM) is a multifaceted disease, characterized by hyperglycaemia, resulting from a combination of insulin resistance, impaired incretin action and β-cell dysfunction leading to relative insulin deficiency. Although traditional anti-diabetes agents improve hyperglycaemia, they do so at a cost, which may entail hypoglycemia and increased body weight; exacerbating dyslipidemia, hypertension and components of insulin resistance and metabolic syndrome associated with T2DM-potentially increasing cardiovascular risk. At diagnosis, many patients with T2DM are treated with medical nutritional therapy (MNT) and exercise, then single or multiple oral anti-diabetes agents until treatment failure, when insulin is used. This strategy has been challenged by recommendations for polypharmacy approaches to the treatment of T2DM, as current strategies are unable to improve multiple aspects of the disease, nor are they likely to address underlying pathophysiology. Although the 2009 American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) treatment algorithm recommends a stepwise approach with MNT and metformin, later adding oral agents, incretin-based therapies or insulin, some experts have recommended a more aggressive approach. In his 2008 ADA Banting Lecture, Dr. Ralph DeFronzo recommended early treatment with metformin, TZD and exenatide at initiation of therapy. The authors' of this article recommend an aggressive early polypharmacy approach addressing underlying pathophysiology, including the incretin defect-with MNT and exercise, metformin and an incretin-based therapy and/or basal insulin if glycemic goal is not achieved within 3 months. This approach attempts to modify the disease, aiming for tight glycemic control, weight loss, reduced hypoglycemia, improvements to hypertension, dyslipidemia and insulin resistance-and improved cardiovascular outcomes.

Topics: Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Insulin; Male; Treatment Outcome

Incretin, GIP and GLP-1, are blood glucose lowering hormones secreted from K cells and L cells, and are rapidly degenerated by DPP-4 within a few minutes. Recently incretin related drugs, GLP-1 analogs and DPP-4 inhibitors are developed. GLP-1 analogs have amino acid substitutions, which make the GLP-1 peptide resistant to degeneration by DPP-4, while DPP-4 inhibitors prevent endogenous GLP-1 to be degenerated by DPP-4. Since they exert blood glucose lowering effect only when blood glucose levels are high, hypoglycemia rarely occurs when administrated without other anti-diabetic drugs. Incretin related drugs are expected to be a new strategy for treating type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Molecular Targeted Therapy

In addition to progressive pancreatic β-cell failure resulting in impaired insulin secretion, and increased insulin resistance in muscle and liver, incretin hormone-related abnormalities have been identified as key underlying defects in patients with type 2 diabetes mellitus. Treatment goals for patients with type 2 diabetes should be aligned with the basic defects of the disease. Many of the available antidiabetes agents correct hyperglycemia but do not impact other cardiovascular risk factors, and may actually aggravate some. This paper reviews the role of defects in the incretin system in the pathophysiology of type 2 diabetes, and discusses recent advances in the use of incretinbased agents that target the fundamental disease mechanisms of type 2 diabetes. The incretinbased agents reduce hyperglycemia and provide beneficial effects on surrogate markers of cardiovascular risk, including weight gain, elevated blood pressure, and dyslipidemia.

Topics: Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins

The recent introduction of new drugs in the therapeutic arsenal for the management of hyperglycemia in type 2 diabetes has opened up new perspectives and raised hope for improved metabolic control in these patients. DPP-4 inhibitors are a family of drugs whose action is mediated by the incretin hormones, in particular GLP-1. This hormone is involved in the control of glucose homeostasis, as it stimulates insulin secretion in response to food intake and halts glucagon production. This effect, which is altered in patients with type 2 diabetes, can be improved by administering this group of drugs. The available evidence suggests that the efficacy, tolerability, safety, low drop-out rate and limited effects on weight, together with the low risk of hypoglycemic episodes, could place this group of drugs high on the treatment list in patients with type 2 diabetes. Incretin therapy provides an alternative to currently available glucose-lowering drugs for type 2 diabetes with good efficacy and a favorable profile on weight. In the studies performed to date, DPP-4 inhibitors seem safe. However, these agents must continue to be evaluated in long-term studies performed in clinical practice to ensure their effectiveness and safety profile, as well as to determine their precise role among all the currently available options in the treatment of type 2 diabetes.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Humans; Incretins

Traditionally, successful treatment of patients with type 2 diabetes mellitus (DM) has been defined strictly by achievement of targeted glycemic control, primarily using a stepped-care approach that begins with changes in lifestyle combined with oral therapy that is slowly intensified as disease progression advances and β-cell function declines. However, stepped care is often adjusted without regard to the mechanism of hyperglycemia or without long-term objectives. A more comprehensive definition of treatment success in patients with type 2 DM should include slowing or stopping disease progression and optimizing the reduction of all risk factors associated with microvascular and macrovascular disease complications. To achieve these broader goals, it is important to diagnose diabetes earlier in the disease course and to consider use of more aggressive combination therapy much earlier with agents that have the potential to slow or halt the progressive β-cell dysfunction and loss characteristic of type 2 DM. A new paradigm for managing patients with type 2 DM should address the concomitant risk factors and morbidities of obesity, hypertension, and dyslipidemia with equal or occasionally even greater aggressiveness than for hyperglycemia. The use of antidiabetes agents that may favorably address cardiovascular risk factors should be considered more strongly in treatment algorithms, although no pharmacological therapy is likely to be ultimately successful without concomitant synergistic lifestyle changes. Newer incretin-based therapies, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, which appear to have a favorable cardiovascular safety profile as well as the mechanistic possibility for a favorable cardiovascular risk impact, are suitable for earlier inclusion as part of combination regimens aimed at achieving comprehensive treatment success in patients with type 2 DM.

Topics: Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Risk Assessment; Safety Management; Severity of Illness Index; Total Quality Management; Treatment Outcome; United States

Type 2 diabetes mellitus (DM) is a prevalent disorder that affects children, adolescents, and adults worldwide. In addition to risks of microvascular disease, patients with type 2 DM often have multiple risk factors of macrovascular disease; for example, approximately 90% of patients with type 2 DM are overweight/obese. Type 2 DM is a complex disease that involves a variety of pathophysiologic abnormalities, including insulin resistance, increased hepatic glucose production, and abnormalities in the secretion of hormones, such as insulin, glucagon, amylin, and incretins. Incretins are gut-derived peptides with a variety of glucoregulatory functions. Incretin dysfunction can be treated with glucagon-like peptide 1 (GLP-1) receptor agonists (eg, exenatide and liraglutide) or inhibitors of dipeptidyl peptidase 4 (DPP-4) (eg, sitagliptin and saxagliptin), the enzyme that degrades GLP-1. The GLP-1 receptor agonists and DPP-4 inhibitors both elevate GLP-1 activity and substantially improve glycemic control. The GLP-1 receptor agonists are more effective in lowering blood glucose and result in substantial weight loss, whereas therapy with DPP-4 inhibitors lowers blood glucose levels to a lesser degree, and they are weight neutral. Treatment with GLP-1 receptor agonists has demonstrated durable glycemic control and improvement in multiple cardiovascular disease risk factors. In addition, unlike insulin or sulfonylureas, treatment with a GLP-1 receptor agonist or a DPP-4 inhibitor has not been associated with substantial hypoglycemia. These factors should be considered when selecting monotherapy or elements of combination therapy for patients with type 2 DM who are overweight/obese, for patients who have experienced hypoglycemia with other agents, and when achieving glycemic targets is difficult.

Topics: Adolescent; Adult; Blood Glucose; Child; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Treatment Outcome; Young Adult

The prevalence of type 2 diabetes mellitus (DM) is increasing substantially in the United States. Almost 24 million people have the disease, with most of these patients treated by primary care physicians. Optimal treatment of type 2 DM requires physicians to understand the pathophysiology of this disorder. Once the physiologic defects are determined, lifestyle interventions and glucose lowering medications can be prescribed to minimize the state of chronic hyperglycemia and to address the pathophysiologic defects associated with type 2 DM. Other metabolic abnormalities, including hyperlipidemia, hypertension, and oxidative stress, must also be addressed to reduce the patient's risk of cardiovascular disease. The incretin system plays a role in the pathogenesis of type 2 DM. Incretin-based therapies, including glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, have shown efficacy and safety in treating type 2 DM and have been reviewed in consensus treatment algorithms. This article provides an overview of the role of incretin-based therapies in the management of patients with type 2 DM and how primary care physicians can incorporate these agents into their practice.

Topics: Attitude of Health Personnel; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Incretins; Male; Patient Care; Physician's Role; Practice Patterns, Physicians'; Primary Health Care; Treatment Outcome; United States

Progressive deterioration of β-cell function is a hallmark of type 2 diabetes mellitus (DM). Together with increasing insulin resistance in peripheral tissues (in both the liver and the skeletal muscle), the inability of pancreatic insulin secretion to manage fasting and postprandial glucose levels results in hyperglycemia. Currently available oral antidiabetes agents improve glycemic parameters, but no single drug addresses the numerous pathophysiologic defects known to contribute to hyperglycemia in patients with type 2 DM. Dysregulation in the incretin system is another component of the pathophysiologic processes that lead to DM. Agents used to correct defects in the incretin system, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, offer the potential to restore glucose-dependent insulin secretion and improve β-cell function. Glucagon-like peptide 1 receptor agonists also promote weight loss and provide beneficial effects on cardiovascular risk factors. A new approach that promotes the selection of pharmacotherapy for the treatment of patients with DM, with the goal of slowing or reversing the natural history of the disease, may be in order. Clinicians can select agents to address specific pathophysiologic defects to improve glycemia, with the hope of preventing the development of complications.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Insulin Resistance; Islets of Langerhans; Male; Risk Assessment; Treatment Outcome

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Nurse Practitioners; Physician Assistants

The demonstration that the incretin hormone glucagon-like peptide 1 can improve glycaemic control in patients with type 2 diabetes has led to the rapid development during the last decade of promising new classes of agent for the management of type 2 diabetes. These agents possess a range of physiological effects that are associated with improved glycaemic control in diabetes including stimulation of glucose-dependent insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, and reduction of food intake. In addition, preclinical studies suggest that incretin-based therapies may improve beta-cell function via enhancement of beta-cell mass and induction of genes important for differentiated beta-cell function. Exenatide, and the dipeptidyl peptidase-4 inhibitors, sitagliptin and vildagliptin are already approved, and liraglutide is currently completing Phase 3 trials. As these agents and standard oral therapies for type 2 diabetes lower glucose levels through different, but potentially complementary mechanisms, their use in combination should provide effective, potentially additive, glycaemic control. The incretin-based therapies also offer other advantages such as weight loss with exenatide and liraglutide, a reduced risk of hypoglycaemia, and as suggested by preclinical studies, a potential beta-cell preserving effect. Long-term outcome and safety data are not available for these agents, but they appear generally well-tolerated in comparison with existing therapies for type 2 diabetes. The multiple underlying glucose-lowering actions of the incretin-based therapies, as well as a lack of weight gain or even weight loss, make these important new additions to available antidiabetic agents expanding the treatment options available for patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Incretins; Insulin; Risk Factors; Weight Loss

The incretin hormones are released during meals from gut endocrine cells. They potentiate glucose-induced insulin secretion and may be responsible for up to 70% of postprandial insulin secretion. The incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. However, in supraphysiological doses, GLP-1 administration may completely normalize beta as well as alpha cell sensitivity to glucose. The impaired action of GLP-1 and GIP in T2DM may be at least partly restored by improved glycaemic control, as shown in studies involving 4 weeks of intensive insulin therapy. The reduced incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM, and, in support of this, exogenous GLP-1 administration may restore blood glucose regulation to near normal levels. Thus, the pathogenesis of T2DM seems to involve a dysfunction of both incretins. Enhancement of incretin action may therefore represent a therapeutic solution. Clinical strategies therefore include the development of metabolically stable activators of the GLP-1 receptor; and inhibition of DPP-4, the enzyme that destroys native GLP-1 almost immediately. Orally active DPP-4 inhibitors and the metabolically stable activators, exenatide (Byetta), are now on the market, and numerous clinical studies have shown that both principles are associated with durable antidiabetic

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

Gastric bypass surgery (GBP), in addition to weight loss, results in dramatic remission of type 2 diabetes (T2DM). The mechanisms by which this remission occurs are unclear. Besides weight loss and caloric restriction, the changes in gut hormones that occur after GBP are increasingly gaining recognition as key players in glucose control. Incretins are gut peptides that stimulate insulin secretion postprandially; the levels of these hormones, particularly glucagon-like peptide-1, increase after GBP in response to nutrient stimulation. Whether these changes are causal to changes in glucose homeostasis remain to be determined. The purpose of this review is to assess the evidence on incretin changes and T2DM remission after GBP, and the possible mechanisms by which these changes occur. Our goals are to provide a thorough update on this field of research so that recommendations for future research and criteria for bariatric surgery can be evaluated.

Topics: Animals; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Gastric Bypass; Gastric Emptying; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose; Homeostasis; Humans; Incretins; Intestine, Small; Leptin; Liver; Obesity, Morbid; Peptide YY; Randomized Controlled Trials as Topic; Remission Induction; Weight Loss

The stomach is commonly the source of chronic digestive symptoms in patients with diabetes mellitus; erratic stomach emptying may result in poor glycemic control. On the other hand, medications that mimic or enhance the function of the endogenous incretins retard gastric emptying to enhance glycemic control. In patients with obesity and type 2 diabetes, bariatric procedures alter food intake and weight; however, effects on glycemic control precede and are out of proportion with the degree of weight loss. The mechanisms responsible for the improved glycemic control after bariatric surgery are the subject of ongoing research, and include increased circulating incretins stimulated by the delivery of nutrients to the intestine, contributing to weight loss and independently to glycemic control. The stomach is not always a villain, but is an ally in patients with type 2 diabetes.

Topics: Bariatric Surgery; Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Stomach

Type 2 diabetes constitutes the main bulk (85-90%) of diabetic population. It is a chronic metabolic disorder with progressive ?beta-cell dysfunction, impaired insulin actions and various other abnormalities. Insulin response of beta-cell is more after oral glucose or following meal than intravenous infusion of glucose. Gut related peptides, the incretin hormones released after meal following activation of the enteroinsular axis plays an important role in glucose homeostasis by pancreatic and extrapancreatic glucoregulatory effects and helps in preservation of beta-cell function. In type 2 diabetes, there is progressive decline of these incretins level, glucagons like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) with loss of beta-cell mass, beta-cell function and glycemic deterioration. These peptides are rapidly degraded by endogenous proteases, dipeptidyl peptides-4 (DPP-4) giving a very short half life of 2-3 minutes. Currently available anti-diabetic drugs do not address these arms of glucoregulatory dysfunction of type 2 diabetes. Modern therapeutic strategy should be targeted at preservation of beta-cell mass and function by exploiting the incretin hormones and enteroinsular axis. DPP-4 resistant incretin analogues/mimetics (e.g. exenatide, liraglutide) that have been developed by modifications/ substitutions in the polypeptide chain may be an effective alternative of the existing therapy of type-2 DM. DPP-4 inhibitors (e.g. sitagliptin, vindagliptin) prevent the degradation of endogenous GLP-1 and GIP, thereby potentiate their actions and help in glycemic control. Distinctive features of incretin mimetics are: their action is glucose dependent, do not produce hypoglycemia, help in preservation of beta-cell mass and function, help in weight reduction. DPP-4 inhibitors are weight neutral. Ongoing studies will reveal newer avenues and long term outcome of these molecules.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Exenatide is the first-in-class incretin mimetic for the treatment of type 2 diabetes.. To assess exenatide's mechanism of action, therapeutic and adverse effects.. Pharmacokinetics and pharmacodynamics of exenatide were reviewed, as well Phase I, II and III clinical trials, and postmarket reports.. Exenatide improves fasting plasma glucose and HbA1c in type 2 diabetic patients not controlled on other antidiabetic drugs, due to its effects on glucose-dependent stimulation on insulin secretion, suppression elevated glucagon secretion, slowing the accelerated rate of gastric emptying, reduction of food intake and possible beta-cell preservation. Nausea and vomiting were the most common and dose-related side effects. Rare reports of acute pancreatitis do not appear greater than the rate in the general population of patients with type 2 diabetes.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Peptides; Treatment Outcome; Venoms

In the adult, the pancreatic beta-cell mass adapts insulin secretion to meet long-term changes in insulin demand and, in particular, in the presence of insulin resistance that is either physiological, such as pregnancy, or pathophysiological, such as obesity. The failure of beta cells to compensate for insulin resistance is a major component of impaired glucose homeostasis and overt diabetes. This defect is clearly the consequence of a decline of insulin response to glucose due to functional beta-cell deficiency. It is also the consequence of an inability of the endocrine pancreas to adapt the beta-cell mass to insulin demand (pancreas plasticity), which eventually leads to a decrease in functional beta-cell mass. This idea has resulted in considerable attention being paid to the development of new therapeutic strategies aiming to preserve and/or regenerate functional beta-cell mass. The latter is governed by a constant balance between beta-cell growth (replication from pre-existing beta cells and neogenesis from precursor cells) and beta-cell death (mainly apoptosis). Disruption of this balance may lead to rapid and marked changes in beta-cell mass. Glucagon-like peptide-1 (GLP-1), an incretin, enhances beta-cell survival (by activating beta-cell proliferation and differentiation, and inhibiting beta-cell apoptosis), thus contributing to the long-term regulation of insulin secretion by maintaining a functional beta-cell mass. The development of drugs regulating this parameter will be the major challenge of the next few years in the management of type 2 diabetes.

Topics: Adaptation, Physiological; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells

Diabetes mellitus (DM) is currently considered to be an epidemic disease. A safe and effective treatment has long been sought by scientists. Incretin mimetics and dipeptidyl peptidase-4 (DPP4) inhibitors represent a new class of agents that have recently been included as antidiabetic drugs. Although only a limited number of studies exist regarding the treatment of DM based on the incretin effect, DPP4 inhibitors have so far proved to be safe and effective, both when administered alone or in combination with other antidiabetic medication. This review focuses on incretin-effect physiology, as well as the DPP4 inhibitors, from sitagliptin to the new alogliptin-pioglitazone combination agent, given as monotherapy and in combination with other antidiabetic agents.

Topics: Adamantane; Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Pioglitazone; Piperidines; Pyrazines; Sitagliptin Phosphate; Thiazolidinediones; Triazoles; Uracil

The enteroinsular axis (EIA) constitutes a physiological signalling system whereby intestinal endocrine cells secrete incretin hormones following feeding that potentiate insulin secretion and contribute to the regulation of blood glucose homeostasis. The two key hormones responsible are named glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent years have witnessed sustained development of antidiabetic therapies that exploit the EIA. Current clinical compounds divide neatly into two classes. One concerns analogues or mimetics of GLP-1, such as exenatide (Byetta) or liraglutide (NN2211). The other group comprises the gliptins (e.g. sitagliptin and vildagliptin) which boost endogenous incretin activity by inhibiting the enzyme dipeptidyl peptidase 4 (DPP 4) that degrades both GLP-1 and GIP. Ongoing research indicates that further incretin and gliptin compounds will become available for clinical use in the near future, offering comparable or improved efficacy. For incretin analogues there is the prospect of prolonged duration of action and alternative routes of administration. This review focuses on recent advances in pre-clinical research and their translation into clinical studies to provide future therapies for type 2 diabetes targeting the EIA.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Delivery Systems; Drug Evaluation, Preclinical; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Signal Transduction

This review article focuses on the therapeutic potential of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in treating type 2 diabetes mellitus (T2DM). T2DM is characterized by insulin resistance, impaired glucose-induced insulin secretion and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular diabetic complications. Traditional treatment modalities--even multidrug approaches--for T2DM are often unsatisfactory at getting patients to glycemic goals as the disease progresses due to a steady, relentless decline in pancreatic beta-cell function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens, safety and tolerability issues, the latter including hypoglycemia, body weight gain, edema and gastrointestinal side effects. Therefore, the actions of GLP-1 and GIP, which include potentation of meal-induced insulin secretion and trophic effects on the beta-cell, have attracted a lot of interest. GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite. Two new drug classes based on the actions of the incretin hormones have recently been approved for therapy of T2DM; injectable long-acting stable analogues of GLP-1, incretin mimetics, and orally available inhibitors of dipeptidyl peptidase 4 (DPP4; the enzyme responsible for the rapid degradation of GLP-1 and GIP), the so-called incretin enhancers. This review article focuses on these two new classes of antidiabetic agents and will outline the scientific basis for the development of incretin mimetics and incretin enhancers, review clinical experience gathered so far and discuss future expectations for incretin-based therapy.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Molecular Mimicry

The single-tablet combination of vildagliptin and metformin addresses key defects of type 2 diabetes for improved glycemic control. By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, vildagliptin raises the levels of the active incretin hormones, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. This leads to increased synthesis and release of insulin from the pancreatic beta cells and decreased release of glucagon from the pancreatic alpha cells. The combination tablet also contains metformin, which addresses insulin resistance. The complementary mechanisms of action of the two agents in combination have been shown to provide additive and sustained reductions in hemoglobin A(1c) compared with metformin monotherapy. In active-controlled trials, the vildagliptin-metformin combination has been shown to produce equivalent reductions in hemoglobin A(1c) to pioglitazone-metformin and glimepiride-metformin combinations, without significant risk of hypoglycemia and without causing weight gain. In clinical trials, the overall incidence of any adverse event was similar in patients randomized to vildagliptin plus metformin and placebo plus metformin. Available data support the use of vildagliptin in combination with metformin as a promising second-line treatment for the management of type 2 diabetes and this is reflected in the latest UK National Institute for Health and Clinical Excellence draft guideline for consultation on new agents for blood glucose control in type 2 diabetes.

Topics: Adamantane; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipids; Metformin; Nitriles; Practice Guidelines as Topic; Pyrrolidines; Safety; Treatment Outcome; Vildagliptin

Type 2 diabetes mellitus (T2DM) is a global epidemic with increasing impact on individuals and healthcare providers. Available treatments (such as metformin, sulfonylureas, glitazones, and insulin) have proven unsatisfactory in producing a long-lasting impact on glycemic control. In addition, most of these treatments have undesirable side effects such as weight gain and hypoglycemia. As a result, exploring new treatment targets and new therapies is mandatory in order to treat this condition. The incretin pathway, in particular glucagon-like peptide (GLP-1), plays an important pathological role in the development of T2DM, and treatments targeting the incretin system have recently become available. These can mainly be divided into two broad categories; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase-4 (DPP-4; the enzyme responsible for rapid inactivation of incretins) inhibitors (sitagliptin, vildagliptin). Saxagliptin is a novel DPP-4 inhibitor that has recently completed phase 3 studies. Saxagliptin is a potent and specific inhibitor of DPP-4 (in comparison with other dipeptidyl peptidase enzymes) that is given once daily. Current data suggest that saxagliptin as monotherapy or in combination with metformin, glyburide, or a glitazone results in significant reductions in fasting and postprandial plasma glucose and hemoglobin A(1c) (HbA(1c)). Saxagliptin is well tolerated and does not increase hypoglycemia compared with the placebo, and is probably weight neutral. Saxagliptin will be a new effective drug in the currently available variety of antidiabetic medications for patients with T2DM.

Topics: Adamantane; Age Factors; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Sex Factors; Time Factors

Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying.. In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c

Topics: Blood Glucose; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Fasting; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Topics: Adamantane; Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Nitriles; Peptides; Pyrazines; Pyrrolidines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Type 2 diabetes mellitus is a multifactorial metabolic disorder. It is characterized by chronic hyperglycemia, insulin resistance, and a relative insulin secretion defect. The prevalence of type 2 diabetes mellitus has risen worldwide in large part because of an increase in obesity and sedentary lifestyles. The underlying pathophysiology and complications of type 2 diabetes mellitus are still being elucidated. Recent advances in diabetes research have helped us to gain a better understanding about insulin resistance and insulin secretion defects. The evolving understanding about the influence of the incretin effect, insulin signal transduction, adipose tissue, intra-islet cell communication, and inflammation is changing the way in which we view type 2 diabetes mellitus. This new understanding will eventually provide us with new treatment approaches to help patients who have type 2 diabetes mellitus. This article gives a review of the current and emerging concepts of the pathophysiology of type 2 diabetes mellitus.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Risk Factors

The incretins have emerged as key targets in the modern treatment of type 2 diabetes mellitus. Understanding the physiology of the incretins is essential to the physician's ability to appropriately use emerging pharmacotherapies that target this system. This review describes incretin physiology and discusses recent trials of drugs that modulate this system in the treatment of type 2 diabetes. A MEDLINE search using the terms "GLP-1" (ie, glucagon-like peptide 1), "incretins," "exenatide," and "DPP-IV inhibitors" (ie, dipeptidyl peptidase IV inhibitors) was performed, and pertinent articles from the past 10 years were reviewed. Articles describing incretin physiology and clinical trials with exenatide and dipeptidyl peptidase IV inhibitors were identified and discussed. As the articles show, new medications manipulating the incretin system are an important part of treating type 2 diabetes. The cost of these drugs and their potential side effects in comparison with existing agents must be considered when they are being selected as part of a treatment regimen. However, the evidence to date offers much promise and enthusiasm.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Peptides; Receptors, Glucagon; Treatment Outcome; Venoms

Bariatric surgery offers a safe and effective treatment of type II diabetes for morbidly obese persons with complete and permanent remission as well as a clear reduction in mortality. Current data suggest that surgical treatment could be extended to merely overweight and even slender diabetes patients. Bariatric surgery also offers invaluable new approaches for research into type II diabetes. Evidence that the foregut plays a decisive role in the pathogenesis of the disease opens promising opportunities for improved treatment of this serious disease.

Topics: Animals; Body Weight; Cost-Benefit Analysis; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Duodenum; Gastric Bypass; Germany; Humans; Incretins; Insurance Coverage; Jejunum; National Health Programs

Glucagon-like peptide-1 (GLP-1) is a gut hormone that plays an important role in regulating glucose homeostasis by both its pancreatic and extrapancreatic activity. Defects of GLP-1 characterize type 2 diabetes as a primary or perhaps consequent phenomenon, resulting in inappropriately low insulin secretion after oral ingestion of nutrients. The discovery that cleavage by the ubiquitous enzyme dipeptidyl peptidase-IV (DPP-IV) is the primary route of GLP-1 metabolism formed the rationale behind the proposal to prevent degradation of endogenously released GLP-1 by DPP-IV inhibition as a novel approach to the management of type 2 diabetes. Enhanced insulin secretion as well as delayed gastric emptying, reduced glucagon secretion, and inhibited apoptosis of beta cells resulting from blockade of incretin degradation, have been proposed as the major actions of DPP-IV inhibitors as antidiabetic agents. Clinical studies to date indicate that DPP-IV inhibitors effectively ameliorate islet dysfunction and improve glucose control in patients with type 2 diabetes. They appear to have excellent therapeutic effectiveness as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. Their pharmacokinetic and pharmacodynamic profiles support once-daily dosing, with relatively few adverse effects.

Topics: Administration, Oral; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Humans; Incretins

Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This Review highlights our current understanding of the mechanisms of action of incretin-based drugs, with an emphasis on the emerging clinical profile of new agents.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Receptors, Glucagon

In the next 10 years, major changes in the pharmacotherapy of diabetes can be expected. Both the currently used groups of drugs classified as dipeptidyl-peptidase IV blockers (gliptins) and so-called incretin mimetics (including both natural substances and incretin analogues) will be significantly expanded by up to ten new drugs. In addition, other completely new groups of drugs that act, for instance, via the hepatal mechanism or by influencing the metabolism of steroids will appear. Blocking the absorption of glucose in renal tubules by gliflozines seems to be very promising. In the treatment of diabetes complications, the inhibition of protein kinase C will probably mostly be applied. So-called insulinotropic peptides will very likely be applied by injection and substances reducing insulin resistance as well as new types of substances influencing PPAR nuclear receptors will be administered. In diabetology, antibodies against receptors will be used, too. However, modern pharmacotherapy will undoubtedly come up against the principles of so-called metabolic surgery and other successful technological procedures.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Sodium-Glucose Transport Proteins

This article aims to provide an overview of efficacy and safety data on glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes mellitus. Our goal is to differentiate the clinical profiles of GLP-1 receptor agonists and DPP-4 inhibitors, as well as the individual agents within each class. Additionally, we examine the utility of GLP-1 receptor agonists and DPP-4 inhibitors as these agents may be applied at different stages of type 2 diabetes therapy and discuss recently published clinical findings and their implications for treatment.

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Treatment Outcome

Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that is almost certain to worsen. Current therapies, which address glycemia and insulin resistance, have not adequately addressed the complications and treatment failures associated with this disease. New treatments based on the incretin hormones provide a novel approach to address some components of the complex pathophysiology of type 2 diabetes. The purpose of this review is to elucidate the science of the incretin hormones and describe the incretin effect and its regulatory role in beta-cell function, insulin secretion, and glucose metabolism. The key endogenous hormones of incretin system are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); a key enzymatic regulator of these hormones is dipeptidyl peptidase-4, which rapidly inactivates/degrades the incretin hormones. The roles of the incretin hormones in the regulation of glucose metabolism and other related physiologic processes such as gut motility and food intake are disturbed in type 2 diabetes. These disturbances--defects in the incretin system--contribute to the pathophysiology of type 2 diabetes in manifold ways. Consequently, therapies designed to address impairments to the effects of the incretin hormones have the potential to improve glucose regulation and other abnormalities (e.g., weight gain, loss of beta-cell function) associated with type 2 diabetes.

Topics: Animals; Biomedical Research; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Receptors, Glucagon

Impaired insulin secretion plays a major role in the pathogenesis of type 2 diabetes mellitus, and progressive loss of beta-cell function is a pathophysiologic hallmark of type 2 diabetes. Recent science has elaborated on the role of the incretin hormones on beta-cell function and insulin secretion, as well as the role that incretin-based pharmacotherapies may have on glycemic control and beta-cell function, possibly altering the progressive loss of beta-cell function and possibly reversing/halting disease progression. However, incretin-based therapies may also have benefits extending beyond glycemic control and insulin secretion. In this review we examine some of those "beyond-glycemic" benefits, including presentation of data on weight reduction, blood pressure lowering, beneficial changes in the lipid profile, and improvements in myocardial and endothelial function. We investigate how those effects may help ameliorate the cardiovascular burden in patients with diabetes.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Prognosis

Incretin-based therapies address the progressive nature of type 2 diabetes mellitus, not only by addressing glucose control but also with weight-neutral (i.e., dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin) and weight-reducing effects (i.e., glucagonlike peptide-1 [GLP-1] receptor agonists exenatide and liraglutide). Preclinical data suggest that incretin-based therapies may also preserve beta-cell function, holding promise of a truly disease-modifying therapy. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of these agents in routine clinical practice. We propose a systematic approach to treatment, addressing (1) patient selection, (2) optimal treatment combinations, and (3) timing and guidance for both initiation and intensification of therapy. The GLP-1 receptor agonists, for example, could be particularly beneficial in patients whose weight significantly increases cardiovascular risk. Early use of these agents may be effective in preventing diabetes in those at risk, or in halting or retarding disease progression in patients with frank diabetes. Additional clinical investigation will be required to test such hypotheses. Given the ever-increasing incidence of diabetes worldwide, the link between obesity and the development of type 2 diabetes, and the need for more effective, weight-focused, convenient and sustainable treatments, the data from such studies will be invaluable to further clarify the role of the incretins in the management of patients with type 2 diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Patient Selection; Treatment Outcome

Diabetes resolves in 80% of individuals undergoing successful Roux-en-Y gastric bypass. Absolute caloric restriction alone resulting from gastric anatomic changes indeed leads to weight loss; however, immediate effects in glycemic control often precede substantial weight loss typically associated with insulin sensitivity. One putative explanation relates to hormonal effects accompanying Roux-en-Y gastric bypass. We reviewed the existing and recent literature to investigate the hormonal changes accompanying Roux-en-Y gastric bypass.. Changes in levels of five candidate enteric hormones have been recently associated with early postoperative glycemic control following Roux-en-Y gastric bypass; the strongest effects are seen with variations in glucagon-like peptide-1, glucose-dependent insulinotropic peptide and ghrelin.. The unique hybridization of static anatomic restriction and dynamic absorptive bypass lends a duality to the beneficial effects of Roux-en-Y gastric bypass. This duality likely explains the short-term and long-term resolution of diabetes in patients undergoing Roux-en-Y gastric bypass.

Topics: Caloric Restriction; Diabetes Mellitus, Type 2; Energy Intake; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Incretins; Obesity, Morbid; Peptide Hormones; Weight Loss

The prevalence of diabetes is expected to rise together with an increase in morbidity and a reduction in life expectancy. A leading cause of death is cardiovascular disease, and hypertension and diabetes are additive risk factors for this complication. Selected treatment options should neither increase cardiovascular risk in patients with diabetes, nor increase risk of hyperglycaemia in patients with hypertension. The efficacy of present antihyperglycaemic agents is limited and new therapies, such as incretin-targeted agents, are under development. Even though most patients do not achieve glycated haemoglobin targets, trial data show that such interventions reduce the incidence of macrovascular events; however, intensive lowering may be detrimental in patients with existing cardiovascular disease. Currently available oral drugs do not address the key driver of type 2 diabetes--loss of functional beta-cell mass. In the future, new oral treatments must improve this, whilst providing durable blood glucose control and long-term tolerability.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Outbreaks; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypertension; Hypoglycemic Agents; Incretins; Male

This article aims to provide an overview of efficacy and safety data on glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes mellitus. Our goal is to differentiate the clinical profiles of GLP-1 receptor agonists and DPP-4 inhibitors, as well as the individual agents within each class. Additionally, we examine the utility of GLP-1 receptor agonists and DPP-4 inhibitors as these agents may be applied at different stages of type 2 diabetes therapy and discuss recently published clinical findings and their implications for treatment.

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Treatment Outcome

Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that is almost certain to worsen. Current therapies, which address glycemia and insulin resistance, have not adequately addressed the complications and treatment failures associated with this disease. New treatments based on the incretin hormones provide a novel approach to address some components of the complex pathophysiology of type 2 diabetes. The purpose of this review is to elucidate the science of the incretin hormones and describe the incretin effect and its regulatory role in beta-cell function, insulin secretion, and glucose metabolism. The key endogenous hormones of incretin system are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); a key enzymatic regulator of these hormones is dipeptidyl peptidase-4, which rapidly inactivates/degrades the incretin hormones. The roles of the incretin hormones in the regulation of glucose metabolism and other related physiologic processes such as gut motility and food intake are disturbed in type 2 diabetes. These disturbances--defects in the incretin system--contribute to the pathophysiology of type 2 diabetes in manifold ways. Consequently, therapies designed to address impairments to the effects of the incretin hormones have the potential to improve glucose regulation and other abnormalities (e.g., weight gain, loss of beta-cell function) associated with type 2 diabetes.

Topics: Animals; Biomedical Research; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Receptors, Glucagon

Impaired insulin secretion plays a major role in the pathogenesis of type 2 diabetes mellitus, and progressive loss of beta-cell function is a pathophysiologic hallmark of type 2 diabetes. Recent science has elaborated on the role of the incretin hormones on beta-cell function and insulin secretion, as well as the role that incretin-based pharmacotherapies may have on glycemic control and beta-cell function, possibly altering the progressive loss of beta-cell function and possibly reversing/halting disease progression. However, incretin-based therapies may also have benefits extending beyond glycemic control and insulin secretion. In this review we examine some of those "beyond-glycemic" benefits, including presentation of data on weight reduction, blood pressure lowering, beneficial changes in the lipid profile, and improvements in myocardial and endothelial function. We investigate how those effects may help ameliorate the cardiovascular burden in patients with diabetes.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Prognosis

Incretin-based therapies address the progressive nature of type 2 diabetes mellitus, not only by addressing glucose control but also with weight-neutral (i.e., dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin) and weight-reducing effects (i.e., glucagonlike peptide-1 [GLP-1] receptor agonists exenatide and liraglutide). Preclinical data suggest that incretin-based therapies may also preserve beta-cell function, holding promise of a truly disease-modifying therapy. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of these agents in routine clinical practice. We propose a systematic approach to treatment, addressing (1) patient selection, (2) optimal treatment combinations, and (3) timing and guidance for both initiation and intensification of therapy. The GLP-1 receptor agonists, for example, could be particularly beneficial in patients whose weight significantly increases cardiovascular risk. Early use of these agents may be effective in preventing diabetes in those at risk, or in halting or retarding disease progression in patients with frank diabetes. Additional clinical investigation will be required to test such hypotheses. Given the ever-increasing incidence of diabetes worldwide, the link between obesity and the development of type 2 diabetes, and the need for more effective, weight-focused, convenient and sustainable treatments, the data from such studies will be invaluable to further clarify the role of the incretins in the management of patients with type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Patient Selection; Treatment Outcome

To review the pharmacology, pharmacokinetics, efficacy, and safety of liraglutide, a glucagon-like peptide 1 (GLP-1) analog for the treatment of type 2 diabetes mellitus.. A MEDLINE search (1966-May 2009) was conducted for English-language articles using the terms glucagon-like peptide 1, incretin mimetic, NN2211, and liraglutide. Abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes annual meetings in 2006, 2007, and 2008 were also searched for relevant data.. Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of liraglutide were reviewed.. Liraglutide is a GLP-1 analog with pharmacokinetic properties suitable for once-daily administration. Clinical trial data from large, controlled studies demonstrate the effectiveness of liraglutide in terms of hemoglobin A(1c) (A1C) reduction, reductions in body weight, and the drug's low risk for hypoglycemic events when used as monotherapy. Data also support benefits of liraglutide therapy on beta-cell responsiveness to glucose, with animal and in vitro data indicating potential benefits in beta-cell mass and neogenesis with liraglutide treatment. Liraglutide has been studied as monotherapy and in combination with metformin, glimepiride, and rosiglitazone for the treatment of type 2 diabetes. Additionally, comparative data with insulin glargine and exenatide therapy are available from Phase 3 trials providing practitioners valuable clinical data on which to base clinical decision making. Overall, liraglutide is well tolerated with dose-dependent nausea, vomiting, and diarrhea being the most commonly reported adverse events in clinical trials.. Once-daily administration may provide a therapeutic advantage for liraglutide over twice-daily exenatide, with similar improvements in A1C and body weight observed when liraglutide was compared with exenatide. The glucose-dependent mechanism of insulin release with GLP-1 agonist therapy holds potential clinical significance in the management of postprandial hyperglycemic excursions, with minimal risk of hypoglycemia.

Topics: Animals; Blood Glucose; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.

Topics: Animals; Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Receptors, Glucagon

Postprandial glycaemia is now recognised as the major determinant of average glycaemic control in type 2 diabetes, as assessed by glycated haemoglobin. Therefore, an understanding of the factors influencing both the rise in blood glucose and insulin secretion after a meal is fundamental to the development of dietary and pharmacological approaches to optimise glycaemic control. The gastrointestinal tract regulates the rate at which carbohydrate and other nutrients are absorbed and is the source of regulatory peptides that stimulate pancreatic insulin secretion in the setting of elevated blood glucose levels. This article highlights the importance of the gastrointestinal tract in insulin secretion and glucose homeostasis and discusses potential strategies directed at modification of gastrointestinal function in order to improve glycaemic control in the management of diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Gastric Emptying; Gastrointestinal Tract; Humans; Incretins; Insulin; Insulin Secretion; Intestine, Small

The incretin effect, that is, the postprandial augmentation of insulin secretion by gastrointestinal hormones, mediates approximately 50-70% of the overall insulin responses after a mixed meal or glucose ingestion in healthy subjects. In patients with type 2 diabetes, the incretin effect is markedly reduced, and this has been attributed to defects in the secretion and insulinotropic action of the two main incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). It has been speculated that a reduced incretin effect might precede the onset of hyperglycaemia in patients with type 2 diabetes. However, the secretion and action of GIP and GLP-1 is relatively unaltered in normal glucose-tolerant individuals at high risk for type 2 diabetes (e.g., first-degree relatives) and a diminished incretin effect is also detectable in other types of diabetes, thereby arguing against such reasoning. This article will describe the defects in the incretin system in patients with type 2 diabetes, summarise their relevance in the development of hyperglycaemia and discuss the potential individual roles of GIP and GLP-1 in the pathogenesis of type 2 diabetes.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Postprandial Period; Prediabetic State

Incretin-based antidiabetic medications have been approved for clinical use for approximately two to three years. While their major clinical characteristics have been known from clinical trials, the discussion now focuses on the best clinical use of GLP-1 receptor agonists (incretin mimetics) and inhibitors of the protease dipeptidyl peptidase-4 (DPP-4). Any novel drug will not fully disclose its spectrum of beneficial and adverse activity before long-term trials with clinical endpoints are available. This, typically, will last 5-8 years. Nevertheless, there are convincing reasons to use incretin mimetics and DPP-4 inhibitors even in the absence of such results. This decision should be based on specific patient characteristics and (expected) treatment results, in comparison to other available treatment options. The present manuscript tries to describe the current state-of-the-art of using incretin mimetics and DPP-4 inhibitors in clinical practice, including an attempt to suggest their place in treatment algorithms for type 2-diabetic patients.

Topics: Algorithms; Animals; Biomimetics; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells

Type 2 diabetes is a chronic, progressive disease with a multi-faceted pathophysiology. Beyond the known defects of insulin resistance and beta-cell insufficiency, derangement of incretin hormones normally produced from the gut wall in response to food intake play an important role. In recent years, the 'incretin-based' therapies (IBTs) have been developed to address hyperglycemia through either mimicking the action of the endogenous incretin glucagon-like polypeptide (GLP-1) (GLP-1 receptor agonists) or by inhibiting the activity of the enzyme that degrades GLP-1 (the dipeptyl peptidase-4 inhibitors).. We reviewed available evidence on the glucose lowering and anti-atherogenic effects of IBT.. In addition to their glucose-lowering and weight-neutral or weight-reducing actions, IBT decrease systolic blood pressure and improve fasting and postprandial lipid parameters by reducing total-cholesterol, low-density lipoprotein-cholesterol and triglycerides concentrations, and increasing high-density lipoprotein-cholesterol values. Reduced high-sensitivity C-reactive protein levels and improved endothelial dysfunction have been reported too.. IBT have several beneficial effects on cardiovascular risk factors and, for this reason, it has been recently suggested to extend the use of these drugs in diabetic patients with cardiovascular complications. Yet, the long-term effects of IBT on subclinical or clinical atherosclerosis remain to be established by future studies.

Topics: Animals; Atherosclerosis; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Risk Factors

Type 2 diabetes mellitus is a common, chronic and progressive metabolic disorder, which accounts for 90% of diabetes cases worldwide. Approximately 60% of individuals with the disease do not achieve target glycosylated hemoglobin levels, despite the availability of many antidiabetic agents. The two most important needs in the present management of diabetes are the ability of antidiabetic agents to exhibit prolonged efficacy in reducing hyperglycemia and to preserve beta-cell function. The incretin effect appears to be reduced in patients with type 2 diabetes. Exenatide is the first in a novel class of antidiabetic drugs that improves glycemic control in patients with type 2 diabetes through several physiological glucoregulatory mechanisms which improve the incretin effect. Overall, mean glycosylated hemoglobin (HbA1c) reductions achieved in the exenatide phase III clinical trials were in the order of 1%. Long-term data from the uncontrolled open-label extension studies indicate that adjunctive exenatide therapy leads to sustained improvements in HbA1c and progressive weight loss for at least 3 years. The drug is generally well tolerated. The most common adverse events were gastrointestinal in nature and mild to moderate in severity. The objective of this review is to discuss the available published evidence on exenatide therapeutic efficacy and tolerability, and the role of this new drug in the treatment of type 2 diabetes.

Topics: Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Peptides; Venoms

Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Hyperglycemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially nerves and blood vessels. Diabetes causes about 5% of all deaths globally each year and is likely to increase by > 50% in the next 10 years without urgent action. In light of these alarming statistics, the pharmaceutical industry has been on a quest to characterize more promising molecular targets to satisfy stringent new criteria for anti-hyperglycemic agents introduced by the American Diabetes Association. On to this stage, G-protein-coupled receptor 119 (GPR119) has emerged as arguably one of the most exciting targets for the treatment of type 2 diabetes mellitus in the new millennium.. In this review, we outline the current clinical trial landscape and paint a detailed illustration of the key structural information realized from GPR119 agonist campaigns that have recently emerged in the Patent Cooperation Treaty literature.. GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon like peptide 1/glucose-dependent insulinotropic peptide levels in vivo. As a stand-alone therapy or in tandem with approved DPP-IV inhibitors, they could herald a brand new treatment paradigm for type 2 diabetes mellitus. With the passage of the first GPR119 agonist clinical candidates into Phase I trials (Arena/Ortho McNeil APD597; Metabolex MBX-2982; Prosidion/OSI PSN821) and confirmatory reports of clinical proof of concept with respect to glycemic control and incretin release, the spotlight has been set for this new class of therapeutic.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Drug Design; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Insulin; Molecular Structure; Patents as Topic; Receptors, G-Protein-Coupled; Signal Transduction; Structure-Activity Relationship; Treatment Outcome

As a consequence of excess abdominal adiposity and genetic predisposition, type 2 diabetes is a progressive disease, often diagnosed after metabolic dysfunction has taken hold of multiple organ systems. Insulin deficiency, insulin resistance and impaired glucose homeostasis resulting from beta-cell dysfunction characterize the disease. Current treatment goals are often unmet due to insufficient treatment modalities. Even when combined, these treatment modalities are frequently limited by safety, tolerability, weight gain, edema and gastrointestinal intolerance. Recently, new therapeutic classes have become available for treatment. This review will examine the new therapeutic classes of incretin mimetics and enhancers in the treatment of type 2 diabetes.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Treatment Outcome

Glycemic control remains an elusive goal for most patients with type 2 diabetes. Questions concerning glucose targets that have emerged from recent outcomes studies further complicate glucose control strategies. Navigating through these challenges requires an understanding of the relationship between hyperglycemia, glycemic variability, and risk, as well as how to combine antidiabetic agents safely and effectively to minimize complications. Relevant data were selected from recently published major outcomes studies and peer-reviewed articles discussing glycemic variability, incretins, and dipeptidyl peptidase-4 inhibition. Incretin hormones play a premier role in maintaining normal glucose homeostasis. In type 2 diabetes, however, incretin functioning is impaired and glucose homeostasis is disturbed, contributing to hyperglycemia and both acute and chronic glucose fluctuations. Glycemic control efforts should involve quarterly glycated hemoglobin assessments, routine monitoring of daily blood glucose values, and combination therapy that targets both fasting and postprandial hyperglycemia. Dipeptidyl peptidase-4 inhibitors, which enhance endogenous incretin function, are well suited for combination with other agents to promote daily glycemic control without increasing the risk of hypoglycemia or weight gain. Results of recent outcomes studies suggest that a lifetime strategy for diabetes management might involve aggressive efforts to control glycemia daily and early in type 2 diabetes, with less stringent glucose targets and avoidance of hypoglycemia as patients acquire comorbidities, such as advanced cardiovascular disease. Dipeptidyl peptidase-4 inhibitors have the potential to play a vital role in diabetes management at all stages of the disease.

Topics: Adamantane; Blood Glucose Self-Monitoring; Circadian Rhythm; Cost of Illness; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drug Therapy, Combination; Glycated Hemoglobin; Glycemic Index; Humans; Incretins; Pyrazines; Sitagliptin Phosphate; Treatment Failure; Triazoles

Patients with type 2 diabetes, approximately 85% of whom are overweight or obese, often have an increased incidence of cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia. Both type 2 diabetes and obesity are independent risk factors for CVD. Unfortunately, many therapies aimed at maintaining and improving glucose control are associated with weight gain. Among the older antidiabetes agents, most, including the insulin secretagogues and sensitizers, can lead to weight gain, except for metformin, which is weight-neutral. Among the newer agents, the dipeptidyl peptidase-4 inhibitors generally are weight-neutral in addition to lowering glucose, while the glucagon-like peptide-1 receptor agonists lead to weight reduction. Patients with type 2 diabetes are at an increased risk for both diabetes- and CV-related outcomes, and weight reduction is an important component of diabetes management. Weight gain in patients with type 2 diabetes can contribute to patient frustration and may negatively impact their compliance to therapeutic regimens. The selection of antidiabetes agents that not only improve glucose control but reduce or have a neutral effect on weight with beneficial effects on lipids are ideal options for managing patients with type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Exenatide; Glucagon-Like Peptide 1; Health Knowledge, Attitudes, Practice; Humans; Hypoglycemic Agents; Incretins; Motivation; Obesity; Patient Compliance; Peptides; Risk Management; Self Care; Venoms; Weight Gain

Obesity is associated with increased insulin resistance and is a well-recognized factor for the development of type 2 diabetes. Unfortunately, most diabetes therapies are associated with further weight gain, a most unwelcome characteristic, given the association of weight gain with deteriorating metabolic control, worsening cardiovascular profiles and decreased adherence to treatment. Therapies that effectively control glycaemia without weight gain or with concomitant weight loss are needed. The aim of this article was to review the existing preclinical and clinical evidences, showing that the family of glucagon-like peptide-1 (GLP-1)-based therapies fulfils these criteria by harnessing the beneficial properties of GLP-1, a naturally occurring incretin hormone with a strong blood glucose-lowering action and the ability to induce weight loss.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Obesity; Weight Loss

Type 2 diabetes is a progressive disease characterized by insulin resistance and impaired beta-cell function. Treatments that prevent further beta-cell decline are therefore essential for the management of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is known to stimulate glucose-dependent insulin secretion. Furthermore, GLP-1 appears to have multiple positive effects on beta cells. However, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which limits the clinical relevance of GLP-1 for the treatment of type 2 diabetes. Two main classes of GLP-1-based therapies have now been developed: DPP-4 inhibitors and GLP-1 receptor agonists. Liraglutide and exenatide are examples of GLP-1 receptor agonists that have been developed to mimic the insulinotropic characteristics of endogenous GLP-1. Both have demonstrated improved beta-cell function in patients with type 2 diabetes, as assessed by homoeostasis model assessment-B analysis and proinsulin : insulin ratio. Additionally, liraglutide and exenatide are able to enhance first- and second-phase insulin secretion and are able to restore beta-cell sensitivity to glucose. Preclinical studies have shown that both liraglutide and exenatide treatment can increase beta-cell mass, stimulate beta-cell proliferation, increase beta-cell neogenesis and inhibit beta-cell apoptosis. Clinical studies are needed to confirm these findings in humans. Replication of these data in humans could have important clinical implications for the treatment of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Liraglutide; Peptides; Venoms

Cardiovascular (CV) disease is the major cause of mortality and morbidity in individuals with diabetes. Individuals with diabetes often have a variety of factors such as hyperglycaemia, dyslipidaemia, hypertension, insulin resistance and obesity, which increase their risks of endothelial dysfunction and CV disease. The incretin hormones, such as glucagon-like peptide-1 (GLP-1), induce the glucose-dependent secretion of insulin, improve beta-cell function and induce slowing of gastric emptying and feelings of satiety - which result in reduced food intake and weight loss. Therapeutic treatments targeting the incretin system, such as GLP-1 receptor agonists, offer the potential to address beta-cell dysfunction (one the underlying pathogenic mechanisms of type 2 diabetes), as well as the resulting hyperglycaemia. Initial evidence now suggests that incretins could have beneficial effects on endothelial function and the CV system through both indirect effects on the reduction of hyperglycaemia and direct effects mediated through GLP-1 receptor-dependent and -independent mechanisms. If these initial findings are confirmed in larger clinical trials, GLP-1 receptor antagonists could help to address the major CV risks faced by patients with diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Weight Loss

To highlight the therapeutic promise of the incretin hormone glucagon-like peptide-1 (GLP-1), the consequent rationale for therapies acting through GLP-1-mediated pathways in type 2 diabetes mellitus (T2DM), and the emerging clinical role of the dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists.. The PubMed database was searched (using terms including incretins, GLP-1, GIP, DPP-4), along with recent ADA and EASD abstracts.. Many traditional drugs used for T2DM fail to achieve and maintain glycemic control, and possess limitations such as risk for hypoglycemia and weight gain. GLP-1 is a gut-derived hormone that glucose-dependently stimulates insulin secretion while simultaneously reducing gastric emptying and appetite. Other physiological actions of GLP-1 may benefit the cardiovascular system and beta-cell function. Recently developed drug therapies that mimic or prolong the action of this hormone, therefore, have great promise in the treatment of T2DM.. The GLP-1 receptor agonists and DPP-4 inhibitors are incretin-based therapies that are now becoming established as effective therapies for T2DM to be used either as monotherapy or added to other antidiabetes drugs. They enable improvements to be made in glycemic control without weight gain, with a low risk for hypoglycemia, and with potential additional clinical benefits.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

To update readers on developments in incretin therapies since the previous JAANP supplement in 2007; specifically, to describe clinical data for currently available incretin-based therapies as well as those under consideration by regulatory agencies.. Medline search for peer-reviewed publications.. Incretin-based therapies have pharmacologic properties that avoid some key limitations of previous treatments, such as hypoglycemia and weight gain. Certain agents also lower blood pressure and have the potential to reduce cardiovascular risk. The insulin-secreting action of incretin-based therapies only occurs under hyperglycemic conditions, thus minimizing the risk of hypoglycemia, unless combined with a sulfonylurea. The DPP-4 inhibitors are orally administered and demonstrate modest A1c reductions (0.6%-0.8%); the best results occur when combined with metformin. Glucagon-like peptide-1 (GLP-1) receptor agonists liraglutide and exenatide have shown greater A1c reductions (typically ≥ 1.1% and as high as 1.7%), and these agents have beneficial ancillary effects, including weight and systolic blood pressure reduction. Both DPP-4 inhibitors and GLP-1 receptor agonists have shown the ability to improve pancreatic beta-cell function in early studies.. Data are provided on the efficacy and tolerability of approved incretin therapies, and on treatments currently in regulatory review, in order to inform readers and guide their practice.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

To introduce the role of incretin therapies and suggest strategies for nurse practitioners to implement them in practice.. PubMed, Medline, summary of product characteristics/package inserts.. Incretin-based therapies offer a new alternative to currently available agents. They provide adequate levels of glycemic control and are associated with low incidence of hypoglycemia and weight gain. Dipeptidyl peptidase-4 inhibitors, for example sitagliptin, have a modest effect on A1c levels (-0.7%) as monotherapy; however, they reduce A1c to a greater extent when combined with metformin ( approximately 2.0%). Typical starting dose of sitagliptin is 100 mg; dose adjustments are required in subjects with renal complications. Glucagon-like peptide-1 receptor agonists, exenatide and liraglutide, reduce A1c levels (often in excess of 1.5%) and body weight. Exenatide has a starting dose of 5 mug and is not recommended for patients with hepatic impairment or severe/end-stage renal disease. Liraglutide has been found to benefit from a stepwise dose escalation (i.e., 0.6 mg weekly increments) until a 1.8-mg dose is reached. Unlike exenatide, dose adjustments in patients with renal and hepatic complications are not required.. Incretin-based therapies may help to overcome some of the drawbacks of current therapies used to treat type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Incretins; Nurse Practitioners; Nurse's Role; Patient Education as Topic; Receptors, Glucagon

Type 2 diabetes is a very common worldwide disorder, with major consequences for patients, society, and health care services. Good glycemic control is an important aspect of diabetes management because it has a significant impact on diabetes-related microvascular and possibly macrovascular complications. Based on our understanding of the pathogenesis of diabetes, multiple pharmacological interventions have been developed in the past 60 years. Although effective, none have had a lasting effect on glycemic control because of the progressive nature of type 2 diabetes requiring combination therapies and insulin treatment. In addition, several pharmacologic interventions have undesirable side effects, including hypoglycemia and weight gain. Drugs targeting the incretin pathway are the latest addition to the available antidiabetes agents. Incretin-based therapy is either delivered orally (dipeptidyl peptidase-4 [DPP-4]) inhibitors or injected subcutaneously (glucagon-like peptide-1 [GLP-1] mimetics and analogues). Dipeptidyl peptidase-4 inhibitors are effective either as a single or combination therapy in lowering glycated hemoglobin, fasting and postprandial glucose levels, with a low incidence of hypoglycemia and no weight gain. There are 3 DPP-4 inhibitors currently available (sitagliptin, saxagliptin, and vildagliptin), with more expected to be available in the future. In this article, we review the scientific background for incretin-based therapy and the available evidence regarding the role and efficacy of DPP-4 inhibitors in the treatment of patients with type 2 diabetes.

Topics: Adamantane; Administration, Oral; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

The incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), plays an important role in the regulation of insulin secretion in response to oral glucose. The discovery of deficiencies in incretin pathways associated with development of type 2 diabetes mellitus has propelled the growth of incretin-based therapies in patients with this disease. The basic rationale for incretin-based therapies, including both GLP-1-receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is reviewed, focusing on their roles in glucose regulation and potential therapeutic benefits. Increased awareness of the differences among incretin mimetics, GLP-1 analogs, and DPP-4 inhibitors, including their structures, half-lives, dosages, hemoglobin A(1c)-lowering capacities, effects on weight, and adverse events will help shape the future of these therapeutic agents. Improved understanding of the mechanism of action and clinical effects of incretin-based therapies will help advance their appropriate use within clinical practice.

Topics: Amino Acid Sequence; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Molecular Sequence Data; Structure-Activity Relationship

One of the challenges facing health care providers in the treatment of patients with type 2 diabetes mellitus is maintaining the balance between achieving hemoglobin A(1c) targets while simultaneously minimizing adverse events-most notably hypoglycemia and weight gain-that may negatively affect adherence to therapy and thus treatment outcomes. Incretin-based treatments, such as glucagon-like peptide-1 (GLP-1)-receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are the newest class of therapies for the management of patients with type 2 diabetes. Data from clinical trials in which liraglutide, exenatide, saxagliptin, or sitagliptin were employed as monotherapy or added to ongoing antidiabetic treatment indicate that the incretin-based therapies have very low risk for the development of hypoglycemia and either decrease body weight (GLP-1-receptor agonists) or are weight neutral (DPP-4 inhibitors). Decreased risk for hypoglycemia and weight gain may improve adherence. Avoiding weight gain, which is commonly associated with older oral antidiabetic agents and some insulins, also has the potential to decrease the risk for cardiovascular disease. Future pharmacoeconomic studies may demonstrate translation of these benefits into good cost-effectiveness for these therapies.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Incretins; Patient Compliance; Randomized Controlled Trials as Topic; Weight Gain

Nutrient intake stimulates the secretion of the gastrointestinal incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert glucose-dependent insulinotropic effects and assist pancreatic insulin and glucagon in maintaining glucose homeostasis. GLP-1 also suppresses glucose-dependent glucagon secretion, slows gastric emptying, increases satiety, and reduces food intake. An impaired incretin system, characterized by decreased responsiveness to GIP and markedly reduced GLP-1 concentration, occurs in individuals with type 2 diabetes mellitus (T2DM). The administration of GLP-1 improves glycemic control, but GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Exenatide, a DPP-4-resistant exendin-4 GLP-1 receptor agonist, exhibits the glucoregulatory actions of GLP-1 and reduces body weight in patients with T2DM. It may possess cardiometabolic actions with the potential to improve the cardiovascular risk profile of patients with T2DM. DPP-4 inhibitors such as sitagliptin and saxagliptin increase endogenous GLP-1 concentration and demonstrate incretin-associated glucoregulatory actions in patients with T2DM. DPP-4 inhibitors are weight neutral. A growing understanding of the roles of incretin hormones in T2DM may further clarify the application of incretin-based treatment strategies.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glutaminase; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Intracellular Signaling Peptides and Proteins; Peptides; Pyrazines; Signal Transduction; Sitagliptin Phosphate; Triazoles; Venoms

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Treatment Outcome

Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue that has received marketing approval from the European Commission, is a treatment for type 2 diabetes mellitus (DM) that is administered as a once-daily subcutaneous injection.. The aim of this review was to summarize the efficacy and safety data published about liraglutide, focusing on data from Phase III clinical trials.. Relevant English-language publications were identified through a search of MEDLINE and EMBASE (from 1948 to October 2009). The search terms included the following: GLP-1, incretin effect, liraglutide, NN2211, exenatide, sitagliptin, and vildagliptin. Original research papers about liraglutide that were published in peer-reviewed journals were considered.. The literature search identified 39 relevant publications. The efficacy and tolerability of oncedaily liraglutide at doses of 0.6, 1.2, and 1.8 mg for type 2 DM, in combination with, and compared with, other type 2 DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program. In the LEAD studies, consistent reductions in glycosylated hemoglobin (HbA(1c)) of up to 1.6% were seen with liraglutide, and up to 66% of patients achieved the HbA(1c) goal of <7%. Fasting and postprandial plasma glucose levels were also consistently reduced across the LEAD trials by up to 43 mg/dL (2.4 mmol/L) and 49 mg/dL (2.7 mmol/L), respectively. Hypoglycemia was reported at a rate of 0.03 to 1.9 events per patient annually. Liraglutide significantly improved beta-cell function, as measured by homeostasis model assessment for beta-cell function analysis (20%-44%) and by ratios of pro-insulin to insulin (-0.11 to 0.01). Consistent reductions in systolic blood pressure up to 6.7 mm Hg were also observed for liraglutide treatment. Liraglutide treatment, as monotherapy and in combination with oral antidiabetic drugs (OADs), was associated with weight loss of up to 3.24 kg. Overall, liraglutide was well tolerated. Nausea was the most common adverse event observed with liraglutide treatment, reported by 5% to 29% of patients; however, nausea was generally mild and transient.. Once-daily liraglutide was effective and well tolerated when used as monotherapy or in combination with OADs in patients with type 2 DM, and is therefore a promising new treatment option for the management of type 2 DM.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Liraglutide; Risk Factors

Many data are available on the epidemiology of type 2 diabetes in France (ENTRED 2007, DIABASIS 2008). It is currently estimated that 2.2 million people (3.8% of the population) have type 2 diabetes, with a higher prevalence among those with lower socioeconomic status. Ninety-five per cent of patients are over 45 years of age, 52% are male, 71% are overweight, 54% have hypertension, 18% have elevated LDL cholesterol, 19% have elevated triglyceride levels, and 13% are smokers. The main complications are cardiac (16.7%), retinal (16.6%), and renal disorders (elevated plasma creatinine in 19%), and foot ulcers (9.9%). HbA1c values exceed 7% in 41% of cases. Most patients are treated by general practitioners (93%), while 20% are followed by a diabetologist. Education is provided more often by hospital diabetologists (71%) than by general practitioners (11%). Nine out of ten patients are treated with oral antidiabetic drugs, consisting of metformin (62%), sulfonylurea (50%), glitazones (13%), glinides (8%), and alpha glucosidase inhibitors (8%), usually alone (43%) or in dual-agent combinations (29%). Insulin is prescribed to 17% of patients, an average of 13.8 years after initial diagnosis. Three-quarters of patients are prescribed antihypertensives, 47% statins and 40% antiplatelet drugs. One-third of patients are poorly adherent to their treatment and three-quarters experience adverse effects. Only one-quarter of patients follow dietary measures. The estimated annual per-patient cost of type 2 diabetes is 5400 euros, a sum that is fully reimbursed in 89% of cases. Patient management in France started to improve markedly in 2001 (ENTRED 2001), with more attention being paid to risk factors, and more widespread use of antihypertensive drugs, statins and antiplatelet agents. If the dramatic increase in the incidence of type 2 diabetes is to be reversed, patients at risk must be identified and managed earlier. In particular, plasma glucose levels must be determined regularly in all people over 45 years of age and in all subjects at risk of diabetes. Management of hyperglycemia and other risk factors must be more aggressive and adapted to disease progression. Patient follow-up must be improved, taking in account the entire healthcare infrastructure, and especially structures involved in the treatment of obesity and diabetes.

Topics: Adult; Aged; Bariatric Surgery; Combined Modality Therapy; Comorbidity; Cost of Illness; Diabetes Mellitus, Type 2; Diet, Diabetic; Exercise Therapy; Female; France; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidence; Incretins; Male; Metabolic Syndrome; Middle Aged; Obesity; Patient Compliance; Risk Factors; Socioeconomic Factors

A large percentage of critically ill adult inpatients have type 2 diabetes, which may be undiagnosed or uncontrolled during hospitalization. Hyperglycemia complicates the therapeutic management of inpatients and leads to adverse outcomes, and intensive glycemic control with insulin reduces morbidity and mortality. Insulin therapy, however, is labor-intensive and time-consuming. More important, long-standing protocols such as the sliding scale do not provide adequate glucose control. Although more research is needed to determine the best methods for treating hyperglycemia in-hospital, the importance of achieving better glycemic control while reducing the risk of hypoglycemia has been demonstrated. Post-discharge diabetes care is equally important, as it is essential in improving long-term outcomes after a hospital stay. Hospital care providers can play an important role in effective antihyperglycemic regimens in patients with diabetes prior to discharge. Post-discharge management is a formidable challenge because of the availability of an array of oral antidiabetes agents, including metformin, sulfonylureas, and thiazolidinediones, each with distinct therapeutic and adverse event profiles. Incretin-based therapies offer a potentially useful option for post-discharge therapy, and possibly for inpatient diabetes treatment. Incretins are effective, safe, and well-tolerated; they are easier for patients to use compared with insulin injections (eg, continual glucose monitoring is not required); and they may provide long-term improvement of cardiovascular parameters and beta-cell function. This review examines the challenges to achieving glycemic control in the hospital setting and summarizes clinical data on the efficacy and safety of incretin-based therapies in their use in the hospital and after discharge.

Topics: Adult; Aged; Ambulatory Care; Blood Glucose; Continuity of Patient Care; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Middle Aged; Outpatients; Patient Acceptance of Health Care; Patient Discharge; Practice Guidelines as Topic; Treatment Outcome

Beta cell dysfunction in type-2 diabetes mellitus holds an important role not just on its pathogenesis, but also on the progression of the disease. Until now, diabetes treatment cannot restore the reduced function of pancreatic beta cell. McIntyre et al stated that there is a factor from the intestine which stimulates insulin secretion as a response on glucose.This factor is known as incretin. It is a hormone which is released by the intestine due to ingested food especially those which contain carbohydrate and fat. Currently, there are 2 types of incretin hormones which have been identified, i.e.Glucose dependent insulinotropic polypeptide (GIP) and Glucagon like peptide-1 (GLP-1). These two hormones act by triggering insulin release immediately after food ingestion, inhibiting glucagon secretion, delaying stomach emptying, and suppressing hunger sensation. Several in vitro studies have demonstrated that these two incretin hormones may increase the proliferation of pancreatic beta cell.There is a decrease of GIP function and GLP-1 amount in type-2 diabetes mellitus; thus the attempt to increase both incretin hormones - in this case by using GLP-1 agonist and DPP-IV inhibitor - is one of treatment modalities to control the glucose blood level, either as a monotherapy or a combination therapy. Currently, there are two approaches of incretin utilization as one of type-2 diabetes mellitus treatment, which is the utilization of incretin mimetic/agonist and DPP-IV inhibitor.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin-Secreting Cells

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.

Topics: Adamantane; Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Humans; Hypoglycemic Agents; Incretins; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

Sitagliptin is a highly selective oral dipeptidyl peptidase-4 inhibitor. This drug increases the plasma concentration of active glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide. These two hormones then simulate the secretion of insulin in a glucose-dependent manner and inhibit glucagon secretion, thus reducing circulating glucose levels. In animal models, GLP-1 increases beta-cell mass.. To review the efficacy and safety of sitagliptin in combined therapies (as add on or initial combination treatment) in type 2 diabetes.. A Medline search on published clinical trials involving sitagliptin in combined therapies was performed; additional information from published papers and abstracts to congresses on preclinical and basic science issues was also included to support the mechanistic rationale of combinations.. In humans sitagliptin administration reduces fasting and postprandial glucose and A1c levels. Sitagliptin is as effective as glipizide (close to 0.7% mean A1c reduction), but has fewer hypoglycemic events than other oral insulin secretagogues. Since metformin reduces hepatic glucose production and increases GLP-1 release, combined therapy with sitagliptin becomes complementary and has been shown to have important additive effects. Sitagliptin combined with pioglitazone resulted in improved metabolic control when compared with pioglitazone plus placebo. Combined administration with insulin requires further studies. The weight neutral effect of sitagliptin, its glucose-dependent action (lower risk of hypoglycemia), the beneficial effects on beta-cell function and its eventual protective action on beta-cell mass makes it an excellent option for monotherapy or combined with metformin, glitazones or even sulfonylurea.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Peptide Fragments; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Type 2 diabetes is a progressive disease. The glucose control of persons with type 2 diabetes usually worsens over time. As seen in the UKPDS patients on one oral medication often fail. Treatment of this chronic, progressive disease usually requires multiple medications often in combination with insulin. However, despite the availability of many medications, the majority of people with type 2 diabetes are unable to maintain long-term glycemic control. The high prevalence of obesity compounds this problem as it may worsen hyperglycemia and insulin resistance. Ineffective implementation of existing pharmacotherapy is a significant factor contributing to suboptimal care. The efficacy of available therapies diminishes as the disease progresses because of a steady decline in pancreatic beta cell function. Innovative approaches to treatment are required and new agents are constantly being sought. Recent research has provided new insight to the role of alpha cells, glucagon and incretin hormones in the pathogenesis of type 2 diabetes. Recently several compounds became available for treatment. This is a review of incretin mimetics and enhancers and their clinical utility.

Topics: Amino Acid Sequence; Child; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Molecular Sequence Data

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by insulin resistance, a steady decline in glucose-induced insulin secretion (most likely caused by a progressive decrease in functional beta-cell mass), and inappropriately regulated glucagon secretion; in combination, these effects result in hyperglycemia. In 1958, sulfonylurea (SU) was introduced to the market as one of the first oral treatments for T2DM. Since then, the ability of SU to stimulate the release of insulin from pancreatic beta-cells by the closure of ATP-sensitive K+-channels has been employed as one of the most widespread treatment options for T2DM. However, SUs are associated with weight gain and a risk of hypoglycemia, and the one-track antidiabetic mechanism of SUs often results in patients being treated with additional antidiabetic drugs. In recent studies, SU has proven to be associated with increased beta-cell apoptosis, suggesting that SU may actually accelerate the progressive decrease in beta-cell mass, thereby promoting the need for insulin replacement. In contrast, the newly developed incretin-based therapies for T2DM employ the beta-cell-preserving properties of incretin hormones - glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). More importantly, incretin-based therapies potentiate glucose-stimulated insulin secretion and may restore reduced glucose-induced insulin secretion in T2DM. Furthermore, the insulinotropic effects of GLP-1 and GIP are glucose-dependent, reducing the risk of hypoglycemia. GLP-1 inhibits glucagon secretion and decreases gastrointestinal motility, in turn reducing food intake and body weight. This feature review focuses on the challenges and feasibilities of replacing SU with incretin-based therapy in patients with T2DM.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Molecular Mimicry; Sulfonylurea Compounds

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon.. The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin.. Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a sustained weight loss and glycosylated hemoglobin (HbA(1c)) reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 24-wk studies, sitagliptin reduces HbA(1c) by 0.6-0.8% as monotherapy, 1.8% as initial combination therapy with metformin, and 0.7% as add-on therapy to metformin. Vildagliptin monotherapy lowered HbA(1c) by 1.0-1.4% after 24 wk. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss, whereas sitagliptin and vildagliptin do not.. The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on beta-cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.

Topics: Amino Acid Sequence; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Models, Biological; Molecular Sequence Data

'Incretin effect' refers to increased insulin response to oral glucose as compared to i.v. glucose response. Incretin mimetics are a new class of antidiabetic drugs lowering hyperglycaemia. Incretin mimetics mimic the natural human hormones called 'incretins' with blood glucose regulating action. Exenatide is a synthetic analogue GLP-1 which is resistant to enzymatic degradation by DPP IV. Subcutaneously administered exenatide stimulates insulin secretion, suppresses glucagon secretion, slows down stomach evacuation and reduces the weight. Its administration is safe and the most frequent side effect is mild nausea.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Peptides; Venoms

Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was likely to be developed as a therapeutic agent for this disease.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Killer Cells, Natural; Proglucagon

The role of dipeptidyl peptidase-IV (DPP4) as both a regulatory enzyme and a signalling factor has been evaluated and described in many studies. DPP4 inhibition results in increased blood concentration of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). This causes an increase in glucose-dependent stimulation of insulin secretion, resulting in a lowering of blood glucose levels. Recent studies have shown that DPP4 inhibitors can induce a significant reduction in glycosylated haemoglobin (HbA(1c)) levels, either as monotherapy or as a combination with other antidiabetic agents. Research has also demonstrated that DPP4 inhibitors portray a very low risk of hypoglycaemia development. This review article focuses on the two leading agents of this category (sitagliptin and vildagliptin), providing an overview of their function along with the latest data regarding their clinical efficacy as antidiabetic agents.

Topics: Adamantane; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Postprandial Period

Treatment of type 2 diabetes (T2DM) is based on lifestyle changes and oral antidiabetic agents or insulin. The UKPDS study has confirmed metformin (Met) as the initial monotherapy. Accordingly, Met is widely regarded as the first drug of choice for most patients with T2DM. Safety and efficacy of sulphonylureas (SU) have been confirmed by several clinical trials. Recently, thiazolidinediones (TZD) have addressed some aspects of insulin-resistance that characterized several T2DM patients. However, SU and TZD are associated with various side effects that limit their use in many patients. New agents have been recently developed which potentiate the activity of the incretin (GLP1). GLP1, a gut hormone secreted in response to meal ingestion, is rapidly degraded by dipeptidylpeptidase-4 (DPP-4). GLP1 enhances insulin secretion and inhibits glucagon secretion in a glucose-dependent manner, delays gastric emptying and, in animal studies, preserves beta-cell mass by reducing apoptosis and stimulates of beta-cell proliferation. GLP1 levels are abnormally low in T2DM patients. Two classes of agents based on GLP1 have been launched: DPP-4 inhibitors and DPP-4 resistant GLP1 analogues. Randomized studies confirmed their efficacy to improve glycemic control in T2DM patients. Orally administered DPP-4 inhibitors reduce HbA1c by 0.5-1.1%, without hypoglycaemic events and no weight gain. The sub-cutaneous injected GLP1 analogues (exenatide and liraglutide) show larger reductions in HbA1c by 0.8-1.7% and weight loss but are associated with gastrointestinal side effects contributing to a significant treatment interruption. Several studies support the use of DPP-4 inhibitors in combination with Met as a promising second line treatment.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Metabolic Syndrome; Metformin; Piperidines; Pyrazoles; Rimonabant; Safety; Sulfonylurea Compounds; Thiazolidinediones

Topics: Diabetes Mellitus, Type 2; Drug Hypersensitivity; Economics, Pharmaceutical; Humans; Hypoglycemic Agents; Incretins; Models, Economic

Type 2 diabetes mellitus is a complex disease characterized by beta-cell failure in the setting of insulin resistance. In early stages of the disease, pancreatic beta-cells adapt to insulin resistance by increasing mass and function. As nutrient excess persists, hyperglycemia and elevated free fatty acids negatively impact beta-cell function. This happens by numerous mechanisms, including the generation of reactive oxygen species, alterations in metabolic pathways, increases in intracellular calcium and the activation of endoplasmic reticulum stress. These processes adversely affect beta-cells by impairing insulin secretion, decreasing insulin gene expression and ultimately causing apoptosis. In this review, we will first discuss the regulation of beta-cell mass during normal conditions. Then, we will discuss the mechanisms of beta-cell failure, including glucotoxicity, lipotoxicity and endoplasmic reticulum stress. Further research into mechanisms will reveal the key modulators of beta-cell failure and thus identify possible novel therapeutic targets. Type 2 diabetes mellitus is a multifactorial disease that has greatly risen in prevalence in part due to the obesity and inactivity that characterize the modern Western lifestyle. Pancreatic beta-cells possess the potential to greatly expand their function and mass in both physiologic and pathologic states of nutrient excess and increased insulin demand. beta-cell response to nutrient excess occurs by several mechanisms, including hypertrophy and proliferation of existing beta-cells, increased insulin production and secretion, and formation of new beta-cells from progenitor cells [1, 2]. Failure of pancreatic beta-cells to adequately expand in settings of increased insulin demand results in hyperglycemia and diabetes. In this review, we will first discuss the factors involved in beta-cell growth and then discuss the mechanisms by which beta-cell expansion fails and leads to beta-cell failure and diabetes (Fig. 1).

Topics: Animals; Apoptosis; Cell Proliferation; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Fatty Acids, Nonesterified; Glucose; Growth Hormone; Hepatocyte Growth Factor; Humans; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Parathyroid Hormone-Related Protein; Placental Lactogen; Prolactin; Somatomedins

This article reviews many of the key incretin clinical trials, with a focus on the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors compared with placebo and other glucose-lowering agents used as comparators. These agents have been tested either as monotherapy or in combination with one or more oral antidiabetic drugs (OADs). The article also discusses some of the important clinical differences between GLP-1 receptor agonists and DPP-4 inhibitors.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Insulin; Insulin Resistance; Treatment Outcome

The roles of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are rapidly evolving, despite limited recommendations on their use in current guidelines. This evolution is based on data from the large number of clinical trials demonstrating the clinical efficacy and favorable safety profile of these agents in individuals with type 2 diabetes mellitus (T2DM). This article focuses on factors to consider when implementing the GLP-1 receptor agonists and DPP-4 inhibitors as monotherapy or in combination with other agents in the treatment of T2DM.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Outcome Assessment, Health Care; Patient Education as Topic; Patient Selection

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells

The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inhibitors reduce elevated A1C, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. Collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with T2DM.

Topics: Adamantane; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fasting; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Nitriles; Peptides; Postprandial Period; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulfonylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women.Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on beta cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator

Topics: Amyloid; Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Islet Amyloid Polypeptide; Peroxisome Proliferator-Activated Receptors; Receptors, Cannabinoid

Glucagon-like peptide-1 (GLP-1), a gastrointestinal hormone mainly produced in the post-prandial state, reduces blood glucose through the stimulation of insulin secretion and the inhibition of glucagon release. Long-acting GLP-1 receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors which increase GLP-1 levels, are used as hypoglycemic treatments in type 2 diabetes. This paper aims at reviewing the potential benefit of those treatments in the prevention of cardiovascular risk in type 2 diabetic patients.. Experimental studies have shown that GLP-1 has several potentially beneficial actions on cardiovascular risk. Some of those, such as protection from myocardial ischemic damage and improvement of cardiac function, have also been demonstrated in humans. However, the equivalence of GLP-1 agonists and DPP-4 inhibitors with GLP-1, with respect to cardiovascular risk profile, cannot be assumed or taken for granted. Drugs of those two classes have been shown to effectively reduce glycated hemoglobin and to have a specific effect on post-prandial glucose; furthermore, they seem to reduce blood pressure and to have some favorable effects on lipid profiles. Additionally, GLP-1 agonists induce weight loss in diabetic patients.. The profile of action of GLP-1 receptor agonists and DPP-4 inhibitors suggests the possibility of an actual reduction in cardiovascular risk, which needs to be confirmed by large long-term clinical trials.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Rate; Humans; Incretins; Insulin Resistance; Myocardial Contraction; Myocardial Ischemia; Risk Factors

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

Type 2 diabetes mellitus is a metabolic disease leading to microvascular and macrovascular complications including coronary artery disease and stroke. Management of diabetes has been challenging, particularly in the presence of the enormous prevalence of obesity. In recent years, various inhibitors of the enzyme dipeptidyl peptidase (DPP)-4 have been developed to treat diabetes. The enzyme DPP-4 cleaves incretins, which, among other functions, stimulate insulin and suppresses glucagon. Inhibition of this enzyme results in an increase in the half-life and the sustained physiologic action of incretins, leading to an improvement in hyperglycemia. One such agent, namely sitagliptin (MK-04,310), has been introduced into the United States market, and another agent, vildagliptin (LAF237), is being used in Europe and elsewhere. This article is intended to evaluate the effectiveness of DPP-4 inhibitors as a therapeutic modality for managing type 2 diabetes. The authors conducted a literature search of various databases to identify the clinical trials involving the DPP inhibitors and concluded that the DPP-4 inhibitors, for example, sitagliptin and vildagliptin, are efficacious for managing diabetes as monotherapy or combination therapy.

Topics: Adamantane; Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

The increasing proportion of elderly persons in the global population, and the implications of this trend in terms of increasing rates of chronic diseases such as type 2 diabetes mellitus, continue to be a cause for concern for clinicians and healthcare policy makers. The diagnosis and treatment of type 2 diabetes in the elderly is challenging, as age-related changes alter the clinical presentation of diabetic symptoms. Once type 2 diabetes is diagnosed, the principles of its management are similar to those in younger patients, but with special considerations linked to the increased prevalence of co-morbidities and relative inability to tolerate the adverse effects of medication and hypoglycaemia. In addition, there are many underappreciated factors complicating diabetes care in the elderly, including cognitive disorders, physical disability and geriatric syndromes, such as frailty, urinary incontinence and pain. Available oral antihyperglycaemic drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin), alpha-glucosidase inhibitors and thiazolidinediones. Unfortunately, as type 2 diabetes progresses in older persons, polypharmacy intensification is required to achieve adequate glycaemic control with the attendant increased risk of adverse effects as a result of age-related changes in drug metabolism. The recent introduction of the incretins, a group of intestinal peptides that enhance insulin secretion after ingestion of food, as novel oral antihyperglycaemic treatments may prove significant in older persons. The two main categories of incretin therapy currently available are: glucagon-like peptide-1 (GLP-1) analogues and inhibitors of GLP-1 degrading enzyme dipeptidyl peptidase-4 (DPP-4). The present review discusses the effect of aging on metabolic control in elderly patients with type 2 diabetes, the current treatments used to treat this population and some of the more recent advances in the field of geriatric type 2 diabetes. In particular, we highlight the efficacy and safety of GLP-1 and DPP-4 inhibitors, administered as monotherapy or in combination with other oral antihyperglycaemic agents, especially when the relevant clinical trials included older persons. There is strong evidence that use of incretin therapy, in particular, the DPP-4 inhibitors, could offer significant advantages in older persons. Clinical evidence suggests that the DPP-4 inhibitors vildagliptin and sitagliptin are particularly suitable for f

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that play an important role in stimulating postprandial insulin release from pancreatic beta-cells. Agents that either mimic GLP-1 or prevent its degradation are now available for the treatment of Type 2 diabetes, and strategies to enhance endogenous GLP-1 release are under assessment. As intestinal peptides have a range of actions, including appetite regulation and coordination of fat metabolism, harnessing the enteric endocrine system is a promising new field for drug development.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin-Secreting Cells

Type 2 diabetes mellitus (T2DM) is a progressive disorder caused by a combination of insulin resistance and beta cell dysfunction. It is associated with an increased and premature risk of cardiovascular disease as well as specific microvascular complications such as retinopathy, nephropathy and neuropathy. In the last 5 years new glucose lowering drugs acting on novel pathways have been developed, licensed and launched, such as the glucagon-like peptide (GLP-1) agonists (exenatide) and dipeptidyl peptidase (DPP-IV) inhibitors such as sitagliptin and vildagliptin. This review looks at these new agents in terms of their mode of action, pharmacokinetics and use in clinical practice. This review also includes new agents in the area of weight loss that may have a positive effect for glucose management-for example, rimonabant.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Hypoglycemic Agents; Incretins; Piperidines; Pyrazoles; Rimonabant

GLP-1 analogues (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) represent new classes of anti-diabetic agents for the treatment of type 2 diabetes. The efficacy and safety of the incretin mimetic exenatide and of the DPP-4 inhibitors, sitagliptin and vildagliptin, have been clearly demonstrated by a very large number of clinical trials. Efficacy was demonstrated in terms of reduction of HbA1c, fasting and postprandial glucose. Moreover, exenatide showed a favourable effect on weight, while DPP-4 inhibitors were neutral with respect to this outcome. The low rate of hypoglycemic events seen in all studies confirms the glucose dependent action of incretins.

Topics: Adamantane; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Incretins; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

This paper briefly reviews the concept of incretins and describes the biological effects of the two incretins identified so far: the glucose-dependent insulinotropic polypeptide (GIP); and the glucagon-like peptide-1 (GLP-1). GIP is released by the Kcells of the duodenum, while GLP-1 is released by the Lcells of the distal ileum, in response to nutrient absorption. GIP and GLP-1 stimulate insulin biosynthesis and insulin secretion in a glucose-dependent manner. In addition, they increase beta-cell mass. GIP has a specific effect on adipose tissue to facilitate the efficient disposal of absorbed fat and, thus, may be involved in the development of obesity. GLP-1 has specific effects on pancreatic alpha cells, the hypothalamus, and gastrointestinal and cardiovascular systems. By inhibiting glucagon secretion and delaying gastric-emptying, GLP-1 plays an important role in glucose homoeostasis and, by inhibiting food intake, prevents the increase in body weight. As the metabolic effects of GIP are blunted in type 2 diabetes, this peptide cannot be used as an efficient therapy for diabetes. In contrast, GLP-1 effects are preserved at high concentrations in type 2 diabetes, making this peptide of great interest for the treatment of diabetes, a topic that will be discussed in the second part of this review.

Topics: Adipose Tissue; Body Weight; Diabetes Mellitus, Type 2; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Overweight; Receptors, Glucagon

Maintaining an adequate metabolic control is still a challenge in many patients with type 2 diabetes. Among the many factors advocated to explain the failure to achieve recommended goals, clinical inertia is increasingly recognised as a primary cause of poor glycaemic control. The existence of a "metabolic memory" strongly supports the adoption of a more aggressive treat-to-target approach, instead of waiting for treatment failure. This approach may be particularly important in the initial phases of the disease, to slow the progressive decline of beta-cell function and improve overall outcomes. The fear of hypoglycaemia and weight gain associated with most of the available treatments are among the main causes of clinical inertia, and strongly affect the attitudes of providers and patients toward therapy intensification. The incretin-based therapies represent a new potential goal-oriented treatment approach. Two classes of incretin-based drugs have been developed: GLP-1 mimetics (exenatide and liraglutide) and DPP-IV inhibitors (sitagliptin and vildagliptin). Incretino-mimetics have a peculiar mechanism of action that is associated with lack of hypoglycaemia and weight loss or neutrality; these characteristics may facilitate therapy intensification and help to attain established goals. Furthermore, they can induce benefits in terms of post-prandial hyperglicemia control and beta-cell function preservation. An early use of this class of drugs may show a positive impact on the disease progression and a delay in the need of insulin injections.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Middle Aged; Nurse Practitioners; Patient Selection; Primary Health Care

Topics: Algorithms; Decision Trees; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Nurse Practitioners; Nurse's Role; Nursing Assessment; Primary Health Care

Many patients with type 2 diabetes fail to achieve adequate glycaemic control with available treatments, even when used in combination, and eventually develop microvascular and macrovascular diabetic complications. Even intensive interventions to control glycaemia reduce macrovascular complications only minimally. There is, therefore, a need for new agents that more effectively treat the disease, as well as target its prevention, its progression, and its associated complications. One emerging area of interest is centred upon the actions of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which enhance meal-induced insulin secretion and have trophic effects on the beta-cell. GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite. Two new classes of agents have recently gained regulatory approval for therapy of type 2 diabetes; long-acting stable analogues of GLP-1, the so-called incretin mimetics, and inhibitors of dipeptidyl peptidase 4 (DPP-4, the enzyme responsible for the rapid degradation of the incretin hormones), the so-called incretin enhancers. This article focuses on DPP-4 inhibitors.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Enzyme Inhibitors; Gastric Inhibitory Polypeptide; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Mice; Rats

Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are intestinal hormones that are released in response to ingestion of nutrients, especially carbohydrate. They have a number of important biological effects, which include release of insulin, inhibition of glucagon and somatostatin, maintenance of beta-cell mass, delay of gastric emptying, and inhibition of feeding. These properties allow them to be potentially suitable agents for the treatment of type 2 diabetes (T2D). Incretin receptors are also present in other parts of the body including the brain, where their effects are beginning to be understood and their relevance to disorders of nutrition and ageing are being explored. There is currently a pandemic of obesity and diabetes, and existing treatments are largely inadequate in regard to efficacy as well as their ability to tackle important factors in the pathogenesis of T2D. There is increasing evidence that current treatments do not address the issue of progressive beta-cell failure in T2D. As obesity is the engine that is driving the epidemic of diabetes, it is disappointing that most treatments that succeed in lowering plasma glucose are also associated with weight gain. It is now well established that intensively treated T2D has a better outcome than standard treatment. Consequently, achieving better control of diabetes with lower HbA1c is the goal of optimal treatment. Despite the use of usual therapeutic agents in T2D, often in high doses and as combinations, such as metformin, sulphonylurea, alpha-glycosidase inhibitors, thiazolidinediones and a number of animal and human insulin preparations, optimal control of glycaemia is not achieved. The use of incretins as therapeutic agents offers a new approach to the treatment of T2D. Incretin metabolism is abnormal in T2D, evidenced by a decreased incretin effect, reduction in nutrient-mediated secretion of GIP and GLP-1 in T2D, and resistance to GIP. GLP-1, on the other hand, when administered intravenously in T2D is able to increase insulin secretion and improve glucose homeostasis. As GLP-1 has a very short half-life, due to rapid degradation by the enzyme dipeptidyl peptidase IV (DPPIV), analogues of GIP and GLP-1 that are resistant to the action of DPPIV have been developed and clinical trials have shown their effectiveness. Another novel agent, naturally resistant to DPPIV that is given by subcutaneous injection is a synthetic peptide called

Topics: Adipose Tissue; Amino Acid Sequence; Blood Glucose; Brain; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Liver; Molecular Sequence Data; United States

The aims of this review are (1) to examine the pathophysiologic relationship between type 2 diabetes and obesity, (2) to provide an overview of current and emerging treatments for type 2 diabetes and their effects on body weight.. A MEDLINE search was performed for literature published in the English language from 1966 to 2006. Abstracts and presentations from the American Diabetes Association Scientific Sessions (2002-2006) and the European Association for the Study of Diabetes Annual Meetings (1998-2006) were also searched for relevant studies. Preclinical and clinical data were selected for inclusion based on novelty and pertinence to treatment of the obese patient.. Recent guidelines suggest that all patients with type 2 diabetes should initially receive metformin as well as lifestyle intervention, followed by rapid administration of other oral anti-diabetic agents or insulin if glycemic goals are not met or maintained. Many oral anti-diabetic drugs, and insulin, are associated with weight gain. New agents with anti-diabetic activity that may be advantageous in obese patients with type 2 diabetes have recently become available. These include injectable incretin mimetics, which reduce blood glucose while reducing body weight but commonly cause nausea and vomiting. A new class of oral agents, the dipeptidyl peptidase-4 inhibitors, is weight-neutral and largely devoid of gastrointestinal side-effects. The cannabinoid receptor antagonist rimonabant is the first of a new class of anti-obesity agents that reduces central obesity and improves multiple aspects of vascular risk.. New agents offer the prospect of improved glycemic control without weight gain. However, the ultimate roles of these agents in the treatment of obese patients with type 2 diabetes remain to be established.

Topics: Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Obesity; Risk Factors

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antihyperglycemic agents that enhance the body's ability to regulate blood glucose by increasing the active levels of incretins, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). There are numerous DPP-4 inhibitors in development with sitagliptin as the first approved agent for the treatment of patients with type 2 diabetes.. The purpose of this review is to provide an overview of the clinical trial results with sitagliptin.. Clinical trials published between January 2005 (first sitagliptin publication) and November 2007 were included in this review. Medline was searched using the search terms: MK-0431 or sitagliptin.. Sitagliptin, an oral, once-daily, and highly selective DPP-4 inhibitor, has been evaluated in clinical trials as monotherapy, as add-on therapy, or as initial combination therapy with metformin. Sitagliptin provided effective fasting and postprandial glycemic control in a wide range of patients with type 2 diabetes. Markers of beta-cell function (HOMA-beta and proinsulin/insulin ratio) were improved with sitagliptin treatment. In these clinical trials, sitagliptin was generally well tolerated with an overall incidence of adverse experiences comparable to placebo, a low risk of hypoglycemia or gastrointestinal adverse experiences, and a neutral effect on body weight. The findings presented in this review are limited to the specific patient population enrolled in each clinical trial and for durations for up to 1 year. Future clinical studies should evaluate whether this class of agents has the potential to delay progression and/or prevent type 2 diabetes.. Sitagliptin has been shown to be effective and well-tolerated in various treatment regimens and may be considered for both initial therapy and as add-on therapy for patients with type 2 diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Metformin; Pyrazines; Sitagliptin Phosphate; Triazoles

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glucose; Homeostasis; Humans; Hypoglycemic Agents; Incretins

Progressive insulin secretory defects, due to either functional abnormalities of the pancreatic beta-cells or a reduction in beta-cell mass, are the cornerstone of type 2 diabetes. Incretin-based drugs hold the potential to improve glucose tolerance by immediate favorable effect on beta-cell physiology as well as by expanding or at least maintaining beta-cell mass, which may delay the progression of the disease. Long-term studies in humans are needed to elaborate on these effects.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin-Secreting Cells; Signal Transduction

Type 2 diabetes mellitus is associated with progressive decreases in pancreatic beta-cell function. Most patients thus require increasingly intensive treatment, including oral combination therapies followed by insulin. Fear of hypoglycemia is a potential barrier to treatment adherence and glycemic control, while weight gain can exacerbate hyperglycemia or insulin resistance. Administration of insulin can roughly mimic physiologic insulin secretion but does not address underlying pathophysiology. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released by the gut in response to meal intake that helps to maintain glucose homeostasis through coordinated effects on islet alpha- and beta-cells, inhibiting glucagon output, and stimulating insulin secretion in a glucose-dependent manner. Biological effects of GLP-1 include slowing gastric emptying and decreasing appetite. Incretin mimetics (GLP-1 receptor agonists with more suitable pharmacokinetic properties versus GLP-1) significantly lower hemoglobin A1c, body weight, and postprandial glucose excursions in humans and significantly improve beta-cell function in vivo (animal data). These novel incretin-based therapies offer the potential to reduce body weight or prevent weight gain, although the durability of these effects and their potential long-term benefits need to be studied further. This article reviews recent clinical trials comparing therapy with the incretin mimetic exenatide to insulin in patients with oral treatment failure, identifies factors consistent with the use of each treatment, and delineates areas for future research.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Receptors, Glucagon

In recent years new pharmacological agents have emerged, which enable us to widen the spectrum of diabetes management based on clear pathophysiological concepts. One should first of all mention the DPP4-inhibitors and the incretin mimetics, which have the potential of restoring the incretin effect in patients with type 2 diabetes mellitus. Moreover, it has been shown that the agent rimonabant, which was first used in order to achieve weight reduction, also contributed to the significant improvement of metabolic syndrome's parameters. Recent studies have shown that the dual alpha/gamma-PPAR-agonists have serious adverse effects. The thiazolidinediones (glitazones) significantly improve insulin sensitivity, diminish fat accumulation in the liver and increase circulating levels of adiponectin. Various adverse effects of glitazones have been described in recent studies. In the near future one should await the discovery of more oral antidiabetic agents acting through modulation of important enzymes in glucose metabolism and transport pathways.

Topics: Adverse Drug Reaction Reporting Systems; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Fractures, Spontaneous; Humans; Hypoglycemic Agents; Incretins; Male; Metabolic Syndrome; PPAR alpha; PPAR gamma; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

Among the challenges in improving outcomes in patients with diabetes is effectively implementing existing pharmacotherapies. However, current therapies for diabetes are often limited by adverse effects such as edema, hypoglycemia, and weight gain. Understanding the role of the incretin effect on the pathophysiology of diabetes has led to the development of new therapeutic agents. Exenatide is the first in a new class of agents termed "incretin mimetics," which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1. In clinical trials, patients with type 2 diabetes treated with exenatide demonstrate sustained improvements in glycemic control, with reductions in fasting and postprandial glucose levels and improvements in glycosylated hemoglobin levels. Improvements in glycemic control with exenatide are coupled with reductions in body weight. Lipid parameters, blood pressure, and C-reactive protein have been shown to improve favorably in patients treated with exenatide. The sustained glycemic improvements and progressive reduction in body weight with exenatide treatment support a shift toward a more favorable cardiovascular risk profile and may have a positive impact on decreasing the risk of associated long-term complications.

Topics: C-Reactive Protein; Comorbidity; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Obesity; Peptides; Protein Binding; Risk Factors; Venoms; Weight Loss

Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are intestinal postprandial hormones that stimulate insulin release from the pancreas as long as circulating glucose concentrations are raised. In addition to their effect on insulin secretion and consequent glucose lowering, GIP and GLP-1, especially the latter, have a number of physiological effects such as inhibition of glucagon release, gastric emptying and food intake, as well as a tropic action on pancreatic B-cell mass. There is currently a pandemic of obesity and diabetes, and existing treatments are largely inadequate both in regard to efficacy as well as their ability to tackle important factors in the pathogenesis of type 2 diabetes (T2D). There is increasing evidence that current treatments do not address the issue of progressive B-cell failure in T2D. Since obesity is the engine that is driving the epidemic of diabetes, it is disappointing that most treatments that succeed in lowering plasma glucose are also associated with weight gain. It is now well established that intensively treated T2D has a better outcome than standard treatment. Consequently, achieving better control of diabetes with lower HbA1c is the goal of optimal treatment. Despite the use of usual therapeutic agents in T2D, often in high doses and as combinations, such as metformin, sulphonylurea, alpha-glycosidase inhibitors, thiazolidinediones and a number of animal and human insulin preparations, optimal control of glycaemia is not achieved. The use of incretins as therapeutic agents offers a new approach to the treatment of T2D.

Topics: Amino Acid Sequence; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Molecular Sequence Data

Incidence of type 2 diabetes mellitus (T2DM) has increased in young people in recent years and new therapies are required for its effective treatment. Glucagon-like peptide 1 (GLP-1) is a potent blood glucose-lowering hormone produced in the L cells of the intestine. It may be potentially effective in the treatment of hyperglycemia in patients with T2DM.. PubMed database were searched with the terms "GLP-1", "incretins" and "diabetes".. GLP-1 is a product of the glucagon gene, and its secretion is controlled by both neural and endocrine signals. GLP-1 lowers plasma glucose by stimulating insulin and suppressing secretion of glucagons, thus inhibiting gastric emptying and reducing appetite. GLP-1 exerts these actions by the engagement of structurally distinct G-protein-coupled receptors (GPCRs). In patients with T2DM, GLP-1 increases insulin secretion and normalizes both fasting and postprandial blood glucose when given as a continuous intravenous infusion. However, the native hormone is unsuitable as a drug because it is broken down rapidly by dipeptidyl peptidase IV (DPP-4) and cleared by the kidneys. Fortunately, many GLP-1 agonists or analogues and DPP-4 inhibitors have been found or developed, such as exendin-4, exenatide, liraglutide, CJC1131, vidaliptin and P32/98. Clinical trials have shown their therapeutic functions in T2DM with little adverse reaction.. A GLP-1 based therapy will be safe and effective for the treatment of T2DM.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Genetic Therapy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Receptors, Glucagon

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive beta cell dysfunction as well as abnormalities in pancreatic alpha cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance. These strategies are typically used in a stepwise manner: employing oral glucose lowering agents, followed by insulin therapy. This traditional approach fails to address the progressive decline in beta cell function. Moreover, these therapies are often associated with weight gain in overweight or obese patients with type 2 diabetes. Both exogenous insulin and insulin secretagogues are associated with an increased risk of hypoglycemia. Recently, new treatments that leverage the glucoregulatory effects of incretin hormones, such as glucagon like peptide 1 have been introduced. Both incretin mimetics and DPP-4 inhibitors address both the underlying pathophysiology and overcome several of the limitations of established therapies by providing improvements in glycemia, and control of body weight with minimal risk of hypoglycemia.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incidence; Incretins; Insulin; Insulin Secretion; Life Style; Liraglutide; Obesity; Overweight; Peptides; Prevalence; Venoms

The gliptins, a new class of oral drugs for type 2 diabietes mellitus, lower blood glucose levels by a novel mechanism: ie, by inhibiting the enzyme dipeptidyl peptidase 4, thereby increasing the circulating levelsof incretins (gut hormones that can boost insulin levels). This article reviews the current evidence on the effectiveness of gliptins and suggests several ways in which these agents could be used in diabetes treatment.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins

Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet.. To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin.. Review of Phase III clinical trials based on Medline search published up to April 2008.. The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 - 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost.. Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.

Topics: Adamantane; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Nausea; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Vomiting

Diabetes mellitus affects 21 million Americans; an additional 41 million individuals in this country have impaired glucose tolerance. These individuals are at high risk for developing not only diabetes, but eventually dying from the cardiovascular complications associated with chronic exposure to hyperglycemia. Not only do patients with diabetes carry a 1.5- to 4.5-fold increased risk of cardiovascular mortality, any microvascular complications they develop such as retinopathy, neuropathy, and nephropathy can have a profoundly negative effect on their quality of life. Even mild hyperglycemia is associated with macrovascular disease. Similarly, hyperglycemia that occurs concurrently during an acute myocardial infarction or stroke is associated with worse outcomes. Therefore, evidence suggests that both chronic and acute hyperglycemia lead to higher morbidity and mortality. As people age, their 2-hour postchallenge blood glucose level typically increases, often independent of their fasting glucose level. At diagnosis, 25% of patients with type 2 diabetes have normal fasting glucose levels. The incidence of isolated impaired glucose tolerance is approximately 3 times greater than isolated impaired fasting glucose. Therefore, most patients with asymptomatic diabetes have isolated postchallenge hyperglycemia. A growing body of literature supports targeting postprandial hyperglycemia to lower glycosylated hemoglobin (A1C) levels and reduce microvascular and macrovascular complications associated with chronic hyperglycemia. This article will evaluate a typical patient case and strategies employed by the patient and health care provider.

Topics: Biomimetic Materials; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Family Practice; Hemoglobin A; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Male; Middle Aged; Patient Acceptance of Health Care; Peptides; Primary Health Care; Treatment Outcome; Venoms

Type 2 diabetes mellitus, which is increasingly prevalent in the United States and responsible for the bulk of diabetes-related healthcare costs, has not been adequately managed over the long term with the most commonly prescribed oral hypoglycaemic medications. Although there is evidence that successful management of type 2 diabetes must address both beta-cell deficiency and insulin resistance, most oral agents now prescribed do not prevent the progressive loss of beta-cell function that has traditionally continued during treatment. Increasingly aggressive management guidelines have led to the recommendation that metformin therapy be initiated along with lifestyle modification at the time of diagnosis. It seems unlikely, however, that this strategy will impede the progression of beta-cell dysfunction. Treatment paradigms are emerging that combine routinely used drug categories with newer agents based on the incretin pathway to achieve long-term glycaemic control. The current review discusses the clinical implications of these newer therapeutic alternatives, which enhance insulin secretion through glucose-dependent and physiologic mechanisms.

Topics: Anti-Obesity Agents; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Islets of Langerhans

The vast majority of patients with type 2 diabetes are overweight or obese. Lifestyle intervention to lose weight is recommended in most diabetic patients to improve glycaemic control and reduce associated risk factors for microvascular and macrovascular complications. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors, although achieving this level of weight reduction remains difficult for many patients. Complicating the matter, many agents used to target hyperglycaemia are associated with weight gain, making management of overweight or obese patients with type 2 diabetes quite challenging. Incretin-based therapies with the new classes of glucagon-like peptide-1 mimetics (e.g. exenatide, liraglutide) and dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g. sitagliptin, vildagliptin) may be of particular value in the treatment of overweight/obese type 2 diabetic patients because of their efficacy in improving glycaemic control and their favourable or neutral effects on body weight. In addition, DPP-4 inhibitors have a low risk for causing hypoglycaemia, undesirable gastrointestinal effects, or other prominent adverse effects that might limit their use. These classes of drugs hold promise for the treatment of type 2 diabetes, alone or in combination with other classes of antidiabetic agents.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Obesity; Overweight; Weight Gain

Management of elderly patients with type II diabetes is complicated by age-related changes in physiology, comorbidities, polypharmacy and heterogeneity of functional status. A minimum goal in antidiabetic treatment in this population is to achieve a level of glycaemic control that avoids acute complications of diabetes, adverse effects and reduction in quality of life. Hypoglycaemia is a particular problem in elderly patients, and many antidiabetic agents pose increased risk for hypoglycaemia. In addition, many standard agents pose risks for older patients because of reduced renal function and common comorbidities. Newer agents based on enhancing incretin activity, including the glucagon-like peptide-1 mimetics exenatide and liraglutide and the oral dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin, may offer particular advantages in elderly patients with diabetes.

Topics: Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Middle Aged

Dipeptidyl peptidase 4 (DPP-4) inhibition prevents the rapid degradation of the incretins, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. Incretins have beneficial effects on glycaemic control in patients with type 2 diabetes through their effects on both alpha- and beta-cells in the pancreas and possibly through additional non-pancreatic effects. Vildagliptin is a potent and selective oral DPP-4 inhibitor that has been studied both as monotherapy and in combination with other antidiabetic treatments. This agent has been shown to be well tolerated and is efficacious in reducing glycosylated haemoglobin, fasting plasma glucose and postprandial glucose levels in trials lasting up to 52 weeks. Vildagliptin is weight neutral, does not cause oedema and is associated with a very low incidence of hypoglycaemia. Recently reported clinical data have helped to further clarify the mechanisms of action and effects of vildagliptin. These results suggest that vildagliptin, as a member of the novel class of DPP-4 inhibitors, has the potential to significantly change the clinical management of diabetes. Future research will further define its use in various patient populations and its possible disease-modifying effects.

Topics: Adamantane; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Nitriles; Pyrrolidines; Vildagliptin

Incretins are gut peptides that potentiate nutrient-stimulated insulin secretion following meal ingestion. Activities of the dominant incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, include glucose-dependent stimulation of insulin secretion and, in preclinical models, improvement in islet beta-cell mass. GLP-1 additionally reduces glucagon secretion, inhibits gastric emptying and promotes satiety. Patients with type 2 diabetes mellitus (T2DM) exhibit reduced total and intact GLP-1 levels, and exogenous administration of the hormone via continuous infusion results in glucose profiles similar to those in non-diabetic subjects. Incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). Thus, strategies to enhance incretin activity have included development of GLP-1 receptor agonists resistant to the action of DPP-4 (e.g. exenatide and liraglutide) and DPP-4 inhibitors that act to increase concentrations of endogenous intact incretins (e.g. sitagliptin and vildagliptin). Clinical trials of these incretin-based therapies have shown them to be effective in improving glycaemic control in patients with T2DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Receptors, Glucagon

The epidemic of type 2 diabetes worldwide continues unabated. Despite a number of existing therapies, treatment goals are seldom fully achieved. While insulin resistance and beta cell failure remain important in the pathogenesis of the condition, the role of incretin hormones in glucose homeostasis has recently become clearer. Incretins have several glucoregulatory mechanisms, and a novel approach to the treatment of type 2 diabetes focuses on enhancing and prolonging the physiological actions of these hormones. Gliptins inhibit the enzyme dipeptidyl peptidase-IV (DPP-IV), which degrades incretin hormones. These drugs are a promising new class of oral hypoglycaemic medication, which appear to be weight-neutral and have few side-effects, although the published clinical studies are mainly regulatory licensing studies. As these drugs now are available for clinical use, we discuss the mechanism of action, efficacy and potential adverse effects of this new class of oral hypoglycaemic agent.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins

To review data from clinical trials of incretin mimetics in patients with type 2 diabetes.. Incretin mimetics are a new class of antidiabetic medication that mimic the actions of the hormone glucagon-like peptide-1. They exhibit several properties, including glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and induction of satiety, which result in improvements in glycemic control with weight loss in patients with type 2 diabetes. Recent 2-year data with exenatide, the only commercially available incretin mimetic, have demonstrated long-term sustained reductions in hemoglobin A1c with progressive weight loss. Glycemic and weight benefits were also recently reported in a 15-week study assessing once-weekly administration of long-acting release exenatide, a formulation currently in phase 3 of clinical development. Once-daily administration of liraglutide, also in phase 3 of development, has recently been shown to improve glycemic and weigh control as monotherapy, and in combination with metformin. The most common side effects of incretin mimetics are gastrointestinal in nature, particularly nausea.. The ability of incretin mimetics to improve glycemic control and reduce body weight is a unique property that fills an important void in the treatment of patients with type 2 diabetes.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Molecular Mimicry; Peptides; Venoms

Administration ofGLP-1 analogue resistant to DPPIV or therapeutic inhibition ofthe enzymes, allowing for an increase in the levels of GLP-1, are the very new approaches to the treatment of type 2 diabetes mellitus. Incretin therapy has an immense potential of improving unsatisfactory compensation in diabetic patients thus reducing the risk of manifestation of all arterial complications. Low fasting circulating levels of GLP-1 (and also GIP) grow rapidly after eating and are subsequently degraded to inactive forms by dipeptidyl peptidases IV (DPPIV). DPPIV are enzymes widely present in the body which proteolytically degrade GLP-1 and GIP (as well as other active substances). The preventing of their inactivation effect by administering DPPIV inhibitors allows for increasing the GLP-1 levels, which are reduced in type 2 diabetic patients, and subsequently improves glucose homeostasis in such patients. DPPIV inhibitors represent the principal new class of PAD, and their metabolic profile offers a number of unique clinical advantages for the treatment of patients with type 2 diabetes mellitus.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Insulin

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are physiological gut peptides with insulin-releasing and extrapancreatic glucoregulatory actions. Incretin analogues/mimetics activate GLP-1 or GIP receptors whilst avoiding physiological inactivation by dipeptidyl peptidase 4 (DPP-4), and they represent one of the newest classes of antidiabetic drug. The first clinically approved GLP-1 mimetic for the treatment of type-2 diabetes is exenatide (Byetta/exendin) which is administered subcutaneously twice daily. Clinical trials of liraglutide, a GLP-1 analogue suitable for once-daily administration, are ongoing. A number of other incretin molecules are at earlier stages of development. This review discusses the various attributes of GLP-1 and GIP for diabetes treatment and summarises current clinical data. Additionally, it explores the therapeutic possibilities offered by preclinical agents, such as non-peptide GLP-1 mimetics, GLP-1/glucagon hybrid peptides, and specific GIP receptor antagonists.

Topics: Amino Acid Sequence; Amino Acid Substitution; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Molecular Sequence Data; Peptides; Receptors, Gastrointestinal Hormone; Venoms

The prevalence of diabetes is growing in the United States and, for many patients, blood glucose continues to be poorly managed. Significantly, more than half of people with type 2 diabetes mellitus (T2DM) have hemoglobin A1Cs greater than 7%. Several factors contribute to the failure to achieve treatment goals, including clinical inertia (the failure to initiate or advance therapy in a patient who is not at the evidence-based therapeutic goal) and failure to address all components of disease pathophysiology. Newer classes of antihyperglycemic agents, the incretin-based therapies, have the potential to improve goal achievement.. To review incretin physiology and the latest clinical data on glucagon-like peptide-1 (GLP-1) mimetics and dipeptidyl peptidase-IV (DPP-4) inhibitors and to use this as a foundation to discuss the practical issues of disease management, including clinical inertia, clinical recommendations, and evaluation of the best fit for incretin-based therapies in current treatment paradigms.. Clinical inertia is an important contributing factor to T2DM treatment failure and may be improved through more specific diagnosis, more complete patient education, and an emphasis on earlier and more aggressive therapy in goal-oriented fashion. Based largely on the underlying pathophysiology of T2DM, newer ACE/AACE guidelines have been developed to facilitate this more aggressive approach. The incretin-based therapies can favorably impact some underlying elements in T2DM pathophysiology, including glucagon hypersecretion, rapid gastric emptying, postprandial hyperglycemia, and, possibly, chronic -cell dysfunction. When incorporated early into a long-term, treat-to-target management plan, incretin-based therapies have the potential to reduce the prevalence of treatment failure in T2DM and may positively impact disease progression.. Clinicians need to recognize and address the scope and impact of clinical inertia on T2DM patient outcomes. Better use of conventional treatment options and/or consideration of newer incretin-based therapies can contribute to improvements in patient health.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypolipidemic Agents; Incretins; Prevalence; Treatment Outcome; United States

Sitagliptin, distributed under the brand name of Januvia, has been the first and so far the only dipeptidyl peptidase IV (DPP-IV) inhibitor introduced in clinical practice. The results of published clinical studies clearly demonstrate its effectiveness and safety as an oral antidiabetic. Apart from increasing the insulin level, Sitagliptin reduces the level ofglucagon. The principal advantages of Sitagliptin from the clinical point of view are: a) the ability to reduce both fasting and non-fasting glycaemia and improve the HbA(1c) values, b) the fact that it does not provoke weight increase, c) the fact that the risk of hypoglycaemia is significantly lower as compared with sulfonylurea derivatives, d) good tolerability.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Pyrazines; Sitagliptin Phosphate; Triazoles

The optimal treatment of type 2 diabetes is currently uncertain. This article reviews a new class of oral hypoglycaemic agents: dipeptidyl peptidase-IV inhibitors. By potentiating the action of incretins they offer a more 'physiological' control of blood sugar with fewer side effects, and the possibility of ameliorating the decline in beta cell function.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome

Type 2 diabetes mellitus (DM) is associated with significantly increased risk of microvascular and macrovascular disease. Although most studies have focused on the microvascular complications of diabetes (eg, nephropathy, neuropathy, retinopathy), most patients with type 2 DM die from causes that are related to macrovascular disease (eg, myocardial infarction). Poor glycemic control increases the risk of future cardiovascular events, and prospective studies of patients with type 1 and type 2 DM have demonstrated that the incidence of vascular complications is reduced by lifestyle modifications or medications that reduce blood glucose concentrations.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Risk Reduction Behavior

Glucagon-like peptide-1 (GLP-1)-based therapy is a novel treatment for type 2 diabetes. It is executed either by GLP-1 mimetics or by dipeptidyl peptidase-IV inhibitors. In type 2 diabetes, the two strategies reduce hemoglobin A(1c) by 0.6% to 1.1% from baseline levels of 7.7% to 8.5%. They are efficient both in monotherapy and in combination with metformin or thiazolidinediones. Both treatments are well tolerated with low risk of hypoglycemia.

Topics: Adamantane; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Islets of Langerhans; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Type 2 diabetes is a heterogeneous, polygenic disorder in which dysfunction in a number of important metabolic pathways appears to play roles. Although it remains unclear exactly which event triggers the disorder, beta-cell dysfunction is a key element in the underlyingpathophysiology. Both impaired insulin secretion and insulin resistance contribute to the hyperglycemic state that causes the devastating cardiovascular, neurologic, and renal effects characteristic of type 2 diabetes. To prevent these complications, the American Diabetes Association recommends maintaining A1C levels below 7%. A1C has long been the target of diabetes therapy, and while this remains true in those with A1C levels above 8.4%, it is now apparent that in those with mild to moderate diabetes, postprandial glucose excursions may be of greater importance. Postprandial hyperglycemia occurs in 74% of those diagnosed with diabetes and 39% of those with optimal A1C levels. Involvement of impaired alpha-cell function has recently been recognized in the pathophysiology of type 2 diabetes. As a result of this dysfunction, glucagon and hepatic glucose levels that rise during fasting are not suppressed with a meal. Given inadequate levels of insulin and increased insulin resistance, hyperglycemia results. The incretins are important gut mediators of insulin release, and in the case of GLP-1, of glucagon suppression. Although GIP activity is impaired in those with type 2 diabetes, GLP-1 insulinotropic effects are preserved, and thus GLP-1 represents a potentially beneficial therapeutic option. However, like GIP, GLP-1 is rapidly inactivated by DPP-IV in vivo. Two therapeutic approaches to this problem have been developed: GLP-1 analogs with increased half-lives, and DPP-IV inhibitors, which prevent the breakdown of endogenous GLP-1 as well as GIP. Both classes of agent have shown promise, with potential not only to normalize fasting and postprandial glucose levels but also to improve beta-cell functioning and mass.

Topics: Diabetes Mellitus, Type 2; Disease Progression; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Incretins; Insulin-Secreting Cells; Pancreatic Diseases; Postprandial Period

Incretin therapeutics address an unmet need in diabetes by effectively treating postprandial glycemia. In addition, they present interesting possibilities for future therapy as they were suggested in preclinical studies to have effects on pancreatic beta-cell neogenesis. When used in combination with metformin, sulfonylureas, or TZDs, GLP-1 analogs such as exenatide and DPP-IV inhibitors such as sitagliptin reduce A1C, fasting glucose levels, and postprandial glucose levels with few additional adverse events. Incretin therapeutics is a relatively young field, and much remains to be discovered. It is to be hoped that as trial data accumulate they will demonstrate that these agents will improve overall glycemic control in those with type 2 diabetes. The possibility that they may also be able to affect the course of this devastating metabolic disorder should also be fully explored.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Metformin; Nitriles; Pyrrolidines; Vildagliptin

Glucagon-like peptide-1 (GLP-1) may contribute to the decreased incretin effect characterizing type 2 diabetes. Multiple actions other than insulin secretion stimulation give to GLP-1 a highly desirable profile for an antidiabetic agent. To overcome the need for continuous infusion of the native compound, which is rapidly degraded by dimethyl-peptidyl-peptidase-IV (DPP-IV), analogues with low affinity for this protease have been developed. A second major strategy is represented by DPP-IV inhibitors that act to increase endogenous GLP-1. On the basis of the promising results in clinical trials, the incretin-based therapy may offer an useful option for diabetes management.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Delivery Systems; Enzyme Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Maleimides; Peptides; Protein Processing, Post-Translational; Signal Transduction

Topics: alpha-Glucosidases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Metformin; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Treatment Outcome

Topics: Child; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Treatment Outcome

Due to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however, tirzepatide, a novel dual incretin receptor agonist (activating the GIP receptor and the glucagon-like peptide 1 (GLP-1) receptor) has demonstrated greater glucose and body weight-lowering properties as compared to GLP-1 receptor agonist therapy. The contribution of GIP receptor activation to effects of tirzepatide remains unknown. We will evaluate the glucose-lowering effect of exogenous GIP in the context of pharmacological GLP-1 receptor activation in patients with T2D.. In this randomised, double-blind, four-arm parallel, placebo-controlled trial, 60 patients with T2D will be included (18-74 of age; on diet and exercise and/or metformin therapy only; glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)). Participants will be randomised to an 8-week run-in period with subcutaneous (s.c.) placebo or semaglutide injections once-weekly (0.5 mg). Participants will then be randomised to 6 weeks' add-on treatment with continuous s.c. placebo or GIP infusion (16 pmol/kg/min). The primary endpoint is change in mean glucose levels (assessed by 14-day continuous glucose monitoring) from the end of the run-in period to end of trial.. The present study was approved by the Regional Committee on Health Research Ethics in the Capitol Region of Denmark (identification no. H-20070184) and by the Danish Medicines Agency (EudraCT no. 2020-004774-22). All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals.. NCT05078255 and U1111-1259-1491.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Incretins; Randomized Controlled Trials as Topic

Few studies exist on resistant starch in rice grains. The Okinawa Institute of Science and Technology Graduate University (OIST) has developed a new rice (OIST rice, OR) rich in resistant starch. This study aimed to clarify the effect of OR on postprandial glucose concentrations.. This single-center, open, randomized, crossover comparative study included 17 patients with type 2 diabetes. All participants completed two meal tolerance tests using OR and white rice (WR).. The median age of the participants was 70.0 [59.0-73.0] years, and the mean body mass index was 25.9±3.1 kg/m2. The difference in total area under the curve (AUC) of plasma glucose was -8223 (95% confidence interval [CI]: -10100 to -6346, p<0.001) mg·min/dL. The postprandial plasma glucose was significantly lower with OR than with WR. The difference in the AUC of insulin was -1139 (95% CI: -1839 to -438, p=0.004) µU·min/mL. The difference in the AUC of total gastric inhibitory peptide (GIP) and total glucagon-like peptide-1 (GLP-1) was -4886 (95% CI: -8456 to -1317, p=0.011) and -171 (95% CI: -1034 to 691, p=0.673) pmol·min/L, respectively.. OR can be ingested as rice grains and significantly reduced postprandial plasma glucose compared to WR independent of insulin secretion in patients with type 2 diabetes. OR could have escaped absorption not only from the upper small intestine but also from the lower small intestine.

Topics: Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin; Middle Aged; Oryza; Postprandial Period; Resistant Starch

Allulose is a rare monosaccharide with almost zero calories. There is no study of short-term allulose consumption in patients with type 2 diabetes (T2D). Thus, we aimed to study the effect of allulose consumption for 12 weeks on glucose homeostasis, lipid profile, body composition, incretin levels, and inflammatory markers in patients with T2D.. A double-blind, randomized, controlled crossover study was conducted on sixteen patients with T2D. Patients were randomly assigned to allulose 7 g twice daily or aspartame 0.03 g twice daily for 12 weeks. After a 2-week washout, patients were crossed over to the other sweetener for an additional 12 weeks. Oral glucose tolerance tests, laboratory measurements, and dual-energy X-ray absorptiometry were conducted before and after each phase.. This study revealed that short-term allulose consumption exerted no significant effect on glucose homeostasis, incretin levels, or body composition but significantly increased MCP-1 levels (259 ± 101 pg/ml at baseline vs. 297 ± 108 pg/mL after 12 weeks of allulose, p = 0.002). High-density lipoprotein cholesterol (HDL-C) significantly decreased from 51 ± 13 mg/dl at baseline to 41 ± 12 mg/dL after 12 weeks of allulose, p < 0.001.. Twelve weeks of allulose consumption had a neutral effect on glucose homeostasis, body composition, and incretin levels. Additionally, it decreased HDL-C levels and increased MCP-1 levels.. This trial was retrospectively registered on the Thai Clinical Trials Registry (TCTR20220516006) on December 5, 2022.

Topics: Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Homeostasis; Humans; Incretins

Low cognitive scores are risk factors for cardiovascular outcomes. Whether this relationship is stronger using novel cognitive indices is unknown.. Participants in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial who completed both the Montreal Cognitive Assessment (MoCA) score and Digit Substitution Test (DSST) at baseline (N = 8772) were included. These scores were used to identify participants with baseline substantive cognitive impairment (SCI), defined as a baseline score on either the MoCA or DSST ≥ 1.5 SD below either score's country-specific mean, or SCI-GM, which was based on a composite index of both scores calculated as their geometric mean (GM), and defined as a score that was ≥ 1.5 SD below their country's average GM. Relationships between these measures and incident major adverse cardiovascular events (MACE), and either stroke or death were analyzed.. Compared with 7867 (89.7%) unaffected participants, the 905 (10.3%) participants with baseline SCI had a higher incidence of MACE (unadjusted hazard ratio [HR] 1.34; 95% CI 1.11, 1.62; P = 0.003), and stroke or death (unadjusted HR 1.60; 95% CI 1.33, 1.91; P < 0.001). Stronger relationships were noted for SCI-GM and MACE (unadjusted HR 1.61; 95% CI 1.28, 2.01; P < 0.001), and stroke or death (unadjusted HR 1.85; 95% CI 1.50, 2.30; P < 0.001). For SCI-GM but not SCI, all these relationships remained significant in models that adjusted for up to 10 SCI risk factors.. Country-standardized SCI-GM was a strong independent predictor of cardiovascular events in people with type 2 diabetes in the REWIND trial.

Topics: Cardiovascular Diseases; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Risk Factors; Stroke

Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors improve glycemic control in type 2 diabetes, but the importance of protecting GIP from degradation for their clinical effects is unknown. We included 12 patients with type 2 diabetes (mean ± SD BMI 27 ± 2.6 kg/m2, HbA1c 7.1 ± 1.4% [54 ± 15 mmol/mol]) in this double-blind, placebo-controlled, crossover study to investigate the contribution of endogenous GIP to the effects of the DPP-4 inhibitor sitagliptin. Participants underwent two randomized, 13-day treatment courses of sitagliptin (100 mg/day) and placebo, respectively. At the end of each treatment period, we performed two mixed-meal tests with infusion of the GIP receptor antagonist GIP(3-30)NH2 (1,200 pmol/kg/min) or saline placebo. Sitagliptin lowered mean fasting plasma glucose by 1.1 mmol/L compared with placebo treatment. During placebo treatment, postprandial glucose excursions were increased during GIP(3-30)NH2 compared with saline (difference in area under the curve ± SEM 7.3 ± 2.8%) but were unchanged during sitagliptin treatment. Endogenous GIP improved β-cell function by 37 ± 12% during DPP-4 inhibition by sitagliptin. This was determined by the insulin secretion rate/plasma glucose ratio. We calculated an estimate of the absolute sitagliptin-mediated impact of GIP on β-cell function as the insulinogenic index during sitagliptin treatment plus saline infusion minus the insulinogenic index during sitagliptin plus GIP(3-30)NH2. This estimate was expressed relative to the maximal potential contribution of GIP to the effect of sitagliptin (100%), defined as the difference between the full sitagliptin treatment effect, including actions mediated by GIP (sitagliptin + saline), and the physiological response minus any contribution by GIP [placebo treatment + GIP(3-30)NH2]. We demonstrate insulinotropic and glucose-lowering effects of endogenous GIP in patients with type 2 diabetes and that endogenous GIP contributes to the improved β-cell function observed during DPP-4 inhibition.

Topics: Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Receptors, Gastrointestinal Hormone; Sitagliptin Phosphate

Topics: Anti-Obesity Agents; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Humans; Hypoglycemic Agents; Incretins; Weight Loss

Gastrointestinal-mediated glucose disposal (GIGD) during oral glucose tolerance test (OGTT) reflects the percentage of glucose disposal caused by mechanisms elicited by the oral route of glucose administration. GIGD is reduced in patients with type 2 diabetes (T2D) due to a reduced incretin effect and possibly also due to inappropriate suppression of glucagon after oral glucose. We investigated the effect of glucagon receptor antagonism on GIGD, the incretin effect and glucose excursions in patients with T2D and controls without diabetes.. A double-blind, randomised, placebo-controlled crossover study was conducted.. Ten patients with T2D and 10 gender-, age- and BMI-matched controls underwent two 50 g OGTTs and 2 isoglycaemic i.v. glucose infusions, succeeding (~10 h) single-dose administration of 100 mg of the glucagon receptor antagonist LY2409021 or placebo, respectively.. Compared to placebo, LY2409021 reduced fasting plasma glucose in patients with T2D and controls. Plasma glucose excursions after oral glucose assessed by baseline-subtracted area under the curve were increased by LY2409021 compared to placebo in both groups, but no effect of LY2409021 on GIGD or the incretin effect was observed. LY2409021 increased fasting glucagon concentrations three-fold compared to placebo concentrations.. Glucagon receptor antagonism with LY2409021 had no effect on the impaired GIGD or the impaired incretin effect in patients with T2D and did also not affect these parameters in the controls. Surprisingly, we observed reduced oral glucose tolerance with LY2409021 which may be specific for this glucagon receptor antagonist.

Topics: Biphenyl Compounds; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Glucagon; Glucose; Humans; Incretins; Insulin; Receptors, Glucagon

People with diabetes are at high risk for cardiovascular events including heart failure (HF). We examined the effect of the glucagon-like peptide 1 agonist dulaglutide on incident HF events and other cardiovascular outcomes in those with or without prior HF in the randomized placebo-controlled Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial.. The REWIND major adverse cardiovascular event (MACE) outcome was the first occurrence of a composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes). In this post-hoc analysis, a HF event was defined as an adjudication-confirmed hospitalization or urgent evaluation for HF. Of the 9901 participants studied over a median follow-up of 5.4 years, 213/4949 (4.3%) randomly assigned to dulaglutide and 226/4952 (4.6%) participants assigned to placebo experienced a HF event (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.77-1.12; p = 0.456). In the 853 (8.6%) participants with HF at baseline, there was no change in either MACE or HF events with dulaglutide as compared to participants without HF (p = 0.44 and 0.19 for interaction, respectively). Combined cardiovascular death and HF events were marginally reduced with dulaglutide compared to placebo (HR 0.88, 95% CI 0.78-1.00; p = 0.050) but unchanged in patients with and without HF at baseline (p = 0.31).. Dulaglutide was not associated with a reduction in HF events in patients with type 2 diabetes regardless of baseline HF status over 5.4 years of follow-up.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease.. In a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS).. In total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism.. Compared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted.. NCT01425580.

Topics: Aged; Biomarkers; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Lipidomics; Lipids; Liraglutide; Male; Metabolome; Metabolomics; Metformin; Middle Aged; Spectrometry, Mass, Electrospray Ionization; Sulfonylurea Compounds; Time Factors; Treatment Outcome

To evaluate the efficacy and treatment satisfaction of dapagliflozin and liraglutide in T2DM patients with glucose poorly controlled after triple therapy.. In addition to the original therapeutic regimen, dapagliflozin (n=83) and liraglutide (n=89) once a day were added, respectively. Height, body weight, waist circumference, and blood pressure were recorded. FBG, 2hPBG, HbA1c, fasting C-peptide, HOMA-IR, blood lipid, eGFR, BUA and DTSQ were detected before the treatment and after 24 weeks of treatment.. At the end of 24 weeks of treatment, a follow-up visit was completed for 79 patients in the dapagliflozin group and 77 patients in the liraglutide group. The body weight of the patients in the dapagliflozin group and the liraglutide group decreased significantly (P<0.05). The HbA1c level in the dapagliflozin group decreased from 8.96 ± 1.23% to 7.03 ±0.74% (P< 0.01), more than that in the liraglutide group, namely, from 8.99 ± 1.34% to 7.24 ±0.77% (P< 0.01). After 12 weeks of treatment, eGFR in the dapagliflozin group first decreased and then increased after 12 weeks of treatment. The percentages of patients achieving combined endpoints in the two groups were of no statistical significance (P=0.204). And there were mild adverse events in both groups.. The add-on treatment of dapagliflozin and liraglutide had promising clinical outcomes in patients with T2DM and poorly controlled glucose after triple therapy, which include the improvement in blood glucose, insulin resistance, SBP, and renal function. However, the overall treatment satisfaction was higher in the dapagliflozin group.

Topics: Aged; Benzhydryl Compounds; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucosides; Glycated Hemoglobin; Glycemic Control; Humans; Incretins; Liraglutide; Male; Middle Aged; Patient Satisfaction; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome

Pinolenic acid, a major component (~20%) of pine nut oil, is a dual agonist of the free fatty acid receptors, FFA1 and FFA4, which may regulate release of incretins and ghrelin from the gut. Here, we investigated the acute effects of hydrolyzed pine nut oil (PNO-FFA), delivered to the small intestine by delayed-release capsules, on glucose tolerance, insulin, incretin and ghrelin secretion, and appetite.. In two cross-over studies, we evaluated 3 g unhydrolyzed pine nut oil (PNO-TG) or 3 g PNO-FFA versus no oil in eight healthy, non-obese subjects (study 1), and 3 g PNO-FFA or 6 g PNO-FFA versus no oil in ten healthy, overweight/obese subjects (study 2) in both studies given in delayed-release capsules 30 min prior to a 4-h-oral glucose tolerance test (OGTT). Outcomes were circulating levels of glucose, insulin, GLP-1, GIP, ghrelin, appetite and gastrointestinal tolerability during OGTT.. Both 3 g PNO-FFA in study 1 and 6 g PNO-FFA in study 2 markedly increased GLP-1 levels (p < 0.001) and attenuated ghrelin levels (p < 0.001) during the last 2 h of the OGTT compared with no oil. In study 2, these effects of PNO-FFA were accompanied by an increased satiety and fullness (p < 0.03), and decreased prospective food consumption (p < 0.05). PNO-FFA caused only small reductions in glucose and insulin levels during the first 2 h of the OGTT.. Our results provide evidence that PNO-FFA delivered to the small intestine by delayed-release capsules may reduce appetite by augmenting GLP-1 release and attenuating ghrelin secretion in the late postprandial state.. NCT03062592 and NCT03305367.

Topics: Adult; Aged; Appetite; Blood Glucose; C-Peptide; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hydrolysis; Incretins; Insulin; Intestine, Small; Linolenic Acids; Male; Middle Aged; Pinus; Plant Oils; Seeds

Recent cardiovascular outcome trials have shown significant reductions in major cardiovascular (CV) events with glucagon-like peptide (GLP)-1 receptor agonists. Additionally, adjunctive surrogates for cardiovascular risk validated by some studies include arterial stiffness and endothelial function indexes. To date, no randomized trial has addressed the possible effects of antidiabetic interventional drugs such as GLP1 agonists on endothelial and arterial stiffness indexes as surrogate markers of vascular damage.. We aimed to evaluate metabolic efficacy and surrogate vascular efficacy endpoints of once-weekly dulaglutide (1.5 mg) plus traditional antidiabetic treatment compared with traditional antidiabetic treatment alone in subjects with type 2 diabetes.. Men and women (aged ≥ 50 years) with established or newly detected type 2 diabetes whose HbA1c level was 9.5% or less on stable doses of up to two oral glucose- lowering drugs with or without basal insulin therapy were eligible for randomization. Subcutaneous dulaglutide was initiated at the full dose (1.5 mg/day weekly). Arterial stiffness (PWV: pulse wave velocity and augmentation index) and endothelial function (RHI: reactive hyperaemia index) were evaluated at baseline and at three-month and nine-month examination visits. At each visit (at 3 and 9 months), the subjects were also evaluated for glycaemic variables such as fasting plasma glucose (FPG) and HbA1c and lipid variables such as total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels.. At the three-month follow-up, the subjects treated with dulaglutide showed significantly lower serum levels of FPG and HbA1c than control subjects treated with conventional therapy. At the 9-month follow-up, subjects treated with dulaglutide showed significant lower values of the mean diastolic blood pressure, BMI, total serum cholesterol, LDL cholesterol, FPG, HbA1c and PWV and higher mean RHI values than control subjects treated with conventional therapy.. Our randomized trial showed that subjects with type 2 diabetes treated with conventional therapy plus 1.5 mg/day of subcutaneous dulaglutide compared with subjects treated with conventional therapy alone showed favourable metabolic effects associated with positive effects on vascular health markers such as arterial stiffness and endothelial function markers. These findings are consistent with previous study findings indicating the strict relationship between cardiovascular risk factors such as systolic blood pressure, total serum cholesterol and LDL levels and cardiovascular events and vascular health surrogate markers.

Topics: Aged; Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Italy; Lipids; Male; Middle Aged; Recombinant Fusion Proteins; Time Factors; Treatment Outcome; Vascular Stiffness; Vasodilation

Patients with type 2 diabetes experience resolution of hyperglycemia within days after Roux-en-Y gastric bypass (RYGB) surgery. This is attributed, in part, to enhanced secretion of hindgut factors following exclusion of the gastric remnant and proximal intestine during surgery. However, evidence of the mechanisms of remission remain limited due to the challenges of metabolic evaluation during the early postoperative period. The purpose of this investigation was to determine the role of foregut exclusion in the resolution of type 2 diabetes after RYGB.. Patients with type 2 diabetes (n = 15) undergoing RYGB had a gastrostomy tube (G-tube) placed in their gastric remnant at time of surgery. Patients were randomized to receive a mixed meal tolerance test via oral or G-tube feeding immediately prior to and 2 weeks after surgery in a repeated measures crossover design. Plasma glucose, insulin, C-peptide, incretin responses, and indices of meal-stimulated insulin secretion and sensitivity were determined.. Body weight, fat mass, fasting glucose and insulin, and circulating lipids were significantly decreased 2 weeks after surgery. The glycemic response to feeding was reduced as a function of total area under the curve but not after adjustment for the reduction in fasting glucose. Oral feeding significantly enhanced insulin and incretin secretion after RYGB, which was entirely ablated by G-tube feeding.. Foregut exclusion accounts for the rise in incretin and insulin secretion but may not fully explain the early improvements in glucose metabolism after RYGB surgery.

Topics: Adolescent; Adult; Area Under Curve; Blood Glucose; Body Composition; Cross-Over Studies; Diabetes Mellitus, Type 2; Enteral Nutrition; Feeding Methods; Female; Gastric Bypass; Gastric Stump; Glycemic Control; Humans; Incretins; Insulin Secretion; Intention to Treat Analysis; Male; Meals; Middle Aged; Postoperative Period; Prospective Studies; Treatment Outcome; Young Adult

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown.. In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks.. The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide.. In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Male; Metformin; Middle Aged; Nausea; Weight Loss

The mechanism behind the cardiovascular protection observed with human GLP-1 RA (glucagon-like peptide-1 receptor agonists) in type 2 diabetes is unknown. We hypothesized that treatment with the GLP-1 RA liraglutide had a positive effect on vascular inflammation.

Topics: Aged; Biomarkers; Blood Glucose; Carotid Artery Diseases; Carotid Intima-Media Thickness; Coronary Angiography; Coronary Artery Disease; Denmark; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fluorodeoxyglucose F18; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Predictive Value of Tests; Radiopharmaceuticals; Time Factors; Treatment Outcome; Vasculitis

GIP was proposed to play a key role in the development of non- alcoholic fatty liver disease (NAFLD) in response to sugar intake. Isomaltulose, is a 1,6-linked glucose-fructose dimer which improves glucose homeostasis and prevents NAFLD compared to 1,2-linked sucrose by reducing glucose-dependent insulinotropic peptide (GIP) in mice. We compared effects of sucrose vs. isomaltulose on GIP and glucagon-like peptide-1 (GLP-1) secretion, hepatic insulin clearance (HIC) and insulin sensitivity in normal (NGT), impaired glucose tolerant (IGT) and Type 2 diabetes mellitus (T2DM) participants. A randomized crossover study was performed in 15 NGT, 10 IGT and 10 T2DM subjects. In comparison to sucrose, peak glucose concentrations were reduced by 2.3, 2.1 and 2.5 mmol/l (all p < 0.05) and insulin levels were 88% (p < 0.01, NGT), 32% (p < 0.05, IGT) and 55% (T2DM) lower after the isomaltulose load. Postprandial GIP

Topics: Adult; Case-Control Studies; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Isomaltose; Liver; Male; Middle Aged; Sucrose

Several studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes.. In a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide -52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (-0.4 ± 1.7%; P = 0.447) compared to placebo (-0.4 ± 1.4%; P = 0.420; between group P = 0.911).. Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss.. NCT01761318.

Topics: Adipose Tissue, Brown; Adiposity; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Energy Metabolism; Female; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Middle Aged; Netherlands; Prospective Studies; Time Factors; Treatment Outcome; Weight Loss

Cardiovascular morbidity and mortality are a major burden in patients with type 2 diabetic mellitus. In a landmark study, semaglutide (an injectable glucagon like peptide-1 receptor agonist) has been shown to significantly reduce cardiovascular events, however, the mechanism of benefit is still unknown. The primary hypothesis of our current study is to assess the effect of semaglutide to reduce progression of noncalcified coronary atherosclerotic plaque volume as measured by serial coronary CTA as compared to placebo in persons with diabetes over 1 year.. One hundred forty patients will be enrolled after signing informed consent and followed up for 12 months and with a phone call 30 days after medical discontinuation. All the participants will undergo coronary artery calcium scoring and coronary computed tomography angiography at our center at baseline and 12 months. Eligible participants will be randomly assigned to semaglutide 2 mg/1.5 ml (1.34 mg/ml) prefilled pen for subcutaneous (SC) injection or placebo 1.5 ml, pen-injector for SC injection in a 1:1 fashion as add-on to their standard of care.. As of July 2019, the study was approximately 30% enrolled with an estimated enrollment completion by first quarter of 2020 and end of study by first quarter 2021. Thirty patients were enrolled as of 23 July 2019. Preliminary data of demographics and clinical characteristics were summarized.. Our current study will provide important imaging-derived data that may add relevance to the clinically derived outcomes from liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results and semaglutide and cardiovascular outcomes in patients with type 2 diabetic mellitus 6 trials.

Topics: Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 2; Disease Progression; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Incretins; Plaque, Atherosclerotic; Randomized Controlled Trials as Topic; Treatment Outcome; Vascular Calcification

Topics: Adult; Aged; Arterial Pressure; Arteries; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Endothelial Cells; Female; Glucagon-Like Peptide-1 Receptor; Glucosides; Glycocalyx; Greece; Humans; Incretins; Insulin; Liraglutide; Male; Metformin; Middle Aged; Recovery of Function; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome; Vascular Stiffness; Ventricular Function, Left

Exenatide, a glucagon like peptide 1 analog, has been suggested to reduce the cardiovascular disease risk factors, such as body weight, blood pressure and subclinical atherosclerosis in patients with type 2 diabetes mellitus (T2DM). This was the first randomized, open-label, controlled trial to compare the effects of exenatide versus insulin on subclinical atherosclerosis, as assessed by carotid-intima media thickness (CIMT), in patients with T2DM.. A total of 66 patients with T2DM admitted from March 10, 2015 to June 20, 2017 in the Department of Endocrinology, Beijing Hospital were randomized to receive twice-daily exenatide or aspartate 70/30 insulin for 52 weeks. The primary endpoint was change from baseline in CIMT, and secondary endpoints included changes at week 52 from baseline in body weight, glycemic markers, lipid metabolism markers, blood pressure, C-reactive protein, fibrinogen, 8-hydroxydeoxyguanosine, irisin, and brain natriuretic peptide.. Exenatide more significantly reduced the CIMT from baseline compared with insulin after 52 weeks, with a mean difference of - 0.14 mm (95% interval confidence: - 0.25, - 0.02; P = 0.016). Weight and body mass index were both significantly reduced in the exenatide group over 52 weeks. Exenatide reduced total lipoprotein and low-density lipoprotein cholesterol levels more significantly than insulin at weeks 16 and 40. Correlation analyses showed that CIMT was positively correlated with low-density lipoprotein cholesterol.. Twice-daily exenatide could prevent atherosclerosis progression in patients with T2DM over a 52-week treatment period compared with insulin therapy. Trial registration Chinese Clinical Trial Registry ChiCTR-1800015658.

Topics: Adult; Aged; Beijing; Blood Glucose; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Disease Progression; Drug Administration Schedule; Exenatide; Female; Humans; Hypoglycemic Agents; Incretins; Insulin Aspart; Male; Middle Aged; Predictive Value of Tests; Time Factors; Treatment Outcome; Young Adult

The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants METHODS: We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models.. Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82-0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80-0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87-0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82-0.99) p = 0.028].. These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk.. https://www.clinicaltrials.gouv . Unique Identifier NCT01394952).

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Male; Middle Aged; Recombinant Fusion Proteins; Risk Assessment; Time Factors; Treatment Outcome

Type 2 diabetes is associated with cognitive dysfunction and an increased dementia risk, particularly in individuals with concomitant cardiovascular and/or kidney disease. Incretin therapies may modulate this risk via glycemic and nonglycemic pathways. We explored if the dipeptidyl peptidase 4 inhibitor linagliptin could prevent cognitive decline in people with type 2 diabetes with cardiorenal disease.. The CArdiovascular and Renal Microvascular outcomE study with LINAgliptin (CARMELINA)-COG substudy was an integral part of CARMELINA (NCT01897532) that randomized participants with cardiorenal disease to linagliptin 5 mg or placebo once daily (1:1), in addition to standard of care. The primary cognitive outcome was the occurrence of accelerated cognitive decline at the end of treatment, defined as a regression-based index score ≤16th percentile on the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning and analyzed in participants with a baseline MMSE ≥24. Effects across subgroups by baseline factors, as well as absolute cognitive changes, were also assessed.. In a large international cardiovascular outcome trial in people with type 2 diabetes and cardiorenal disease, linagliptin did not modulate cognitive decline over 2.5 years.

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Cognition; Cognitive Dysfunction; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Humans; Incretins; Kidney; Kidney Diseases; Linagliptin; Male; Middle Aged; Treatment Outcome

Recent trials have identified anti-diabetes mellitus agents that lower major adverse cardiovascular event (MACE) rates, although some increase rates of lower-extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of diabetes mellitus and risk for LEA, prompting this investigation of clinical outcomes in patients with diabetes mellitus and PAD in the EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering).. EXSCEL evaluated the effects of once-weekly exenatide (a GLP-1 [glucagon-like peptide-1] receptor agonist) versus placebo on the rates of the primary composite MACE end point (cardiovascular death, myocardial infarction, or stroke) among patients with type 2 diabetes mellitus. In this post hoc analysis, we assessed the association of baseline PAD with rates of MACE, LEA, and the effects of exenatide versus placebo in patients with and without PAD.. EXSCEL included 2800 patients with PAD (19% of the trial population). These individuals had higher unadjusted and adjusted rates of MACE compared with patients without PAD (13.6% versus 11.4%, respectively) as well as a higher adjusted hazard ratio (adjusted hazard ratio, 1.13 [95% CI, 1.00-1.27];. EXSCEL participants with PAD had higher rates of all-cause mortality and LEA compared with those without PAD. There were no differences in MACE or LEA rates with exenatide versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Topics: Aged; Cause of Death; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome

Short-term intensive insulin therapy (IIT) and gastric bypass surgery are both interventions that can improve beta-cell function, reduce insulin resistance and induce remission of type 2 diabetes. Whereas gastric bypass yields an enhanced glucagon-like peptide-1 (GLP-1) response that may contribute to its metabolic benefits, the effect of short-term IIT on the incretin response is unclear. Thus, we sought to evaluate the impact of IIT on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion in early type 2 diabetes.. In this study, 63 patients (age 59±8.3 years, baseline A1c 6.8±0.7%, diabetes duration 3.0±2.1 years) underwent 4 weeks of IIT (basal insulin detemir and pre-meal insulin aspart). GLP-1, GIP and glucagon responses were assessed by the area-under-the-curve (AUC) of these hormones on oral glucose tolerance tests at baseline and 1-day after the completion of therapy. Beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), with insulin resistance measured by Homeostasis Model Assessment (HOMA-IR).. Despite improving beta-cell function, insulin resistance and glucagonemia, short-term IIT does not change GLP-1 secretion and decreases the GIP response to an oral glucose challenge in early type 2 diabetes. Thus, the beneficial impact of this therapy on glucose homeostasis is not attributable to its effects on incretin secretion.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Early Diagnosis; Early Medical Intervention; Female; Humans; Incretins; Insulin; Male; Middle Aged; Treatment Outcome

Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM).. Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3-. In both groups, blood glucose and serum 3-. The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Routes; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Healthy Volunteers; Humans; Incretins; Insulin; Intestine, Small; Male; Middle Aged; Postprandial Period

Topics: Adult; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet, Vegan; Energy Intake; Humans; Incretins; Insulin; Male; Meals; Meat; Middle Aged; Nutrients; Vegetables

We aimed to explore the relationship between GLP-1 receptor (GLP-1R) expression in adipose tissue (AT) and incretin secretion, glucose homeostasis and weight loss, in patients with morbid obesity and type 2 diabetes undergoing bariatric surgery. RNA was extracted from subcutaneous (SAT) and visceral (VAT) AT biopsies from 40 patients randomized to metabolic gastric bypass, sleeve gastrectomy or greater curvature plication. Biochemical parameters, fasting plasma insulin, glucagon and area under the curve (AUC) of GLP-1 following a standard meal test were determined before and 1 year after bariatric surgery. GLP-1R expression was higher in VAT than in SAT. GLP-1R expression in VAT correlated with weight (r = -0.453, p = 0.008), waist circumference (r = -0.494, p = 0.004), plasma insulin (r = -0.466, p = 0.007), and systolic blood pressure (BP) (r = -0.410, p = 0.018). At 1 year, GLP-1R expression in VAT was negatively associated with diastolic BP (r = -0.361, p = 0.039) and, following metabolic gastric bypass, with the increase of GLP-1 AUC, (R

Topics: Adipose Tissue; Adolescent; Adult; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Male; Middle Aged; Obesity, Morbid; Stomach; Weight Loss; Young Adult

This study compared the efficacy and safety of lixisenatide with placebo as add-on therapy to basal insulin (BI) in adults aged ≥70 years with type 2 diabetes (T2D), with or without moderate renal insufficiency.. This post hoc analysis evaluated data from non-frail patients with T2D inadequately controlled on BI with or without oral antidiabetic drugs (n = 108), randomized to once-daily lixisenatide 20 μg or placebo for 24 weeks (GetGoal-O Study). The primary endpoint was the change in HbA1c from baseline to Week 24. Secondary endpoints included changes from baseline in fasting plasma glucose, 2-hour postprandial plasma glucose (PPG), average seven-point self-monitored plasma glucose (SMPG), area under the curve for SMPG, daily BI dose, body weight, proportion of patients achieving HbA1c > 0.5%, and composite endpoints. Safety outcomes included the incidence of documented symptomatic hypoglycemia (plasma glucose <60 mg/dL) and gastrointestinal treatment-emergent adverse events (TEAEs). Outcomes were also analyzed by the occurrence of moderate renal insufficiency.. Compared with placebo, lixisenatide-treated patients had significantly greater reductions in HbA1c, 2-hour PPG, average seven-point SMPG, and body weight. Documented symptomatic hypoglycemia was approximately two-fold higher in patients treated with placebo than lixisenatide (12.7% vs 5.7%). GI TEAEs occurred more frequently in the lixisenatide- than placebo-treated group (34% vs 9.1%). Moderate renal insufficiency (estimated glomerular filtration rate between ≥30 and <60 mL/min/1.73 m. Add-on therapy with lixisenatide in non-frail patients aged ≥70 years with T2D uncontrolled with BI is effective, safe, and well tolerated and should be considered in this population.. 背景: 这项研究在伴有或不伴中度肾功能不全的≥70岁2型糖尿病(type 2 diabetes, T2D)成人患者中, 比较了利西那肽与安慰剂作为基础胰岛素(basal insulin, BI)添加治疗的疗效及安全性。 方法: 这项事后分析所评估的数据来自经BI联合或者不联合口服降糖药治疗后血糖仍控制不佳的非脆性T2D患者(n=108), 将其随机分配至每日一次20 μg利西那肽治疗组或安慰剂组, 治疗24周(GetGoal-O研究)。主要终点为从基线至第24周的HbA1c变化。次要终点包括空腹血糖、餐后2小时血糖、平均7点自我监测血糖(self-monitored plasma glucose, SMPG)、SMPG曲线下面积、每日BI剂量、体重、HbA1c降幅>0.5%的患者比例以及复合终点相对于基线的变化。安全性结局包括记录的症状性低血糖(血糖<60 mg/dl)及治疗期间胃肠道不良事件(treatment-emergent adverse events, TEAEs)的发生率。还通过中度肾功能不全的发生对结果进行了分析。 结果: 与安慰剂组相比, 利西那肽治疗组的HbA1c、餐后2小时血糖、平均7点SMPG以及体重下降均更显著。安慰剂组中记录的症状性低血糖发生率大约是利西那肽治疗组患者的2倍(分别为12.7%与5.7%)。利西那肽治疗组的胃肠道TEAEs发生率高于安慰剂组(分别为34%与9.1%)。中度肾功能不全(估算的肾小球滤过率≥30至<60 ml/min/1.73 m

Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin Glargine; Male; Peptides; Time Factors; Treatment Outcome

Topics: Anti-Obesity Agents; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Combinations; Drug Monitoring; Drug Resistance, Multiple; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Metformin; Obesity; Overweight; Weight Gain; Weight Loss

To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID).. This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments.. A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m. Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.

Topics: Cardiovascular Diseases; Cohort Studies; Combined Modality Therapy; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Jet; Intention to Treat Analysis; Male; Middle Aged; Patient Dropouts; Peptides; Risk Factors; Severity of Illness Index; Suspensions; United States; Venoms

To assess the safety and efficacy of monotherapy with once-weekly subcutaneous (s.c.) semaglutide vs sitagliptin in Japanese people with type 2 diabetes (T2D).. In this phase IIIa randomized, open-label, parallel-group, active-controlled, multicentre trial, Japanese adults with T2D treated with diet and exercise only or oral antidiabetic drug monotherapy (washed out during the run-in period) received once-weekly s.c. semaglutide (0.5 or 1.0 mg) or once-daily oral sitagliptin 100 mg. The primary endpoint was number of treatment-emergent adverse events (TEAEs) after 30 weeks.. Overall, 308 participants were randomized and exposed to treatment, with similar baseline characteristics across the groups. In total, 2.9% of participants in both the semaglutide 0.5 mg and the sitagliptin group prematurely discontinued treatment, compared with 14.7% in the semaglutide 1.0 mg group. The majority of discontinuations in the semaglutide 0.5 and 1.0 mg groups were attributable to adverse events (AEs). More TEAEs were reported in semaglutide- vs sitagliptin-treated participants (74.8%, 71.6% and 66.0% in the semaglutide 0.5 mg, semaglutide 1.0 mg and sitagliptin groups, respectively). AEs were mainly mild to moderate. Gastrointestinal AEs, most frequently reported with semaglutide, diminished in frequency over time. The mean glycated haemoglobin (HbA1c [baseline 8.1%]) decreased by 1.9% and 2.2% with semaglutide 0.5 and 1.0 mg, respectively, vs 0.7% with sitagliptin (estimated treatment difference [ETD] vs sitagliptin -1.13%, 95% confidence interval [CI] -1.32; -0.94, and -1.44%, 95% CI -1.63; -1.24; both P < .0001). Body weight (baseline 69.3 kg) was reduced by 2.2 and 3.9 kg with semaglutide 0.5 and 1.0 mg, respectively (ETD -2.22 kg, 95% CI -3.02; -1.42 and -3.88 kg, 95% CI -4.70; -3.07; both P < .0001).. In Japanese people with T2D, more TEAEs were reported with semaglutide than with sitagliptin; however, the semaglutide safety profile was similar to that of other glucagon-like peptide-1 receptor agonists. Semaglutide significantly reduced HbA1c and body weight compared with sitagliptin.

Topics: Administration, Oral; Constipation; Diabetes Mellitus, Type 2; Diarrhea; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Incretins; Injections, Subcutaneous; Japan; Nausea; Patient Dropouts; Severity of Illness Index; Sitagliptin Phosphate; Weight Loss

An elevated level of urinary albumin to creatinine ratio (UACR) is a marker of renal dysfunction and predictor of kidney failure/death in patients with type 2 diabetes. The prognostic use of UACR in established cardiac biomarkers is not well described.. To evaluate whether UACR offers incremental prognostic benefit beyond risk factors and established plasma cardiovascular biomarkers.. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 study was performed from May 2010 to May 2013 and evaluated the safety of saxagliptin vs placebo in patients with type 2 diabetes with overt cardiovascular disease or multiple risk factors. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years).. Patients were randomized to saxagliptin vs placebo plus standard care.. Baseline UACR was measured in 15 760 patients (95.6% of the trial population) and categorized into thresholds.. Of 15 760 patients, 5205 were female (33.0%). The distribution of UARC categories were: 5805 patients (36.8%) less than 10 mg/g, 3891 patients (24.7%) at 10 to 30 mg/g, 4426 patients (28.1%) at 30 to 300 mg/g, and 1638 patients (10.4%) at more than 300 mg/g. When evaluated without cardiac biomarkers, there was a stepwise increase with each higher UACR category in the incidence of the primary composite end point (cardiovascular death, myocardial infarction, or ischemic stroke) (3.9%, 6.9%, 9.2%, and 14.3%); cardiovascular death (1.4%, 2.6%, 4.1%, and 6.9%); and hospitalization for heart failure (1.5%, 2.5%, 4.0%, and 8.3%) (adjusted P < .001 for trend). The net reclassification improvement at the event rate for each end point was 0.081 (95% CI, 0.025 to 0.161), 0.129 (95% CI, 0.029 to 0.202), and 0.056 (95% CI, -0.005 to 0.141), respectively. The stepwise increased cardiovascular risk associated with a UACR of more than 10 mg/g was also present within each chronic kidney disease category. The UACR was associated with outcomes after including cardiac biomarkers. However, the improvement in discrimination and reclassification was attenuated; net reclassification improvement at the event rate was 0.022 (95% CI, -0.022 to 0.067), -0.008 (-0.034 to 0.053), and 0.043 (-0.030 to 0.052) for the primary end point, cardiovascular death, and hospitalization for heart failure, respectively.. In patients with type 2 diabetes, UACR was independently associated with increased risk for a spectrum of adverse cardiovascular outcomes. However, the incremental cardiovascular prognostic value of UACR was minimal when evaluated together with contemporary cardiac biomarkers.. clinicaltrials.gov Identifier: NCT01107886.

Topics: Adamantane; Albuminuria; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glomerular Filtration Rate; Heart Failure; Hospitalization; Humans; Incretins; Male; Renal Insufficiency, Chronic

Incretin-based therapies are used in the treatment of type 2 diabetes mellitus (T2DM) and obesity. We investigated the changes in arterial stiffness and left ventricular (LV) myocardial deformation after 6-month treatment with the GLP-1 analogue liraglutide in subjects with newly diagnosed T2DM.. We randomized 60 patients with newly diagnosed and treatment-naive T2DM to receive either liraglutide (n = 30) or metformin (n = 30) for 6 months. We measured at baseline and after 6-month treatment: (a) carotid-femoral pulse wave velocity (PWV) (b) LV longitudinal strain (GLS), and strain rate (GLSR), peak twisting (pTw), peak twisting velocity (pTwVel) and peak untwisting velocity (pUtwVel) using speckle tracking echocardiography. LV untwisting was calculated as the percentage difference between peak twisting and untwisting at MVO (%dpTw-Utw. After 6-months treatment, subjects that received liraglutide presented with a reduced PWV (11.8 ± 2.5 vs. 10.3 ± 3.3 m/s), MDA (0.92 [0.45-2.45] vs. 0.68 [0.43-2.08] nM/L) and NT-proBNP (p < 0.05) in parallel with an increase in GLS (- 15.4 ± 3 vs. - 16.6 ± 2.7), GLSR (0.77 ± 0.2 vs. 0.89 ± 0.2), pUtwVel (- 97 ± 49 vs. - 112 ± 52°, p < 0.05), %dpTw-Utw. Six-month treatment with liraglutide improves arterial stiffness, LV myocardial strain, LV twisting and untwisting and NT-proBNP by reducing oxidative stress in subjects with newly diagnosed T2DM. ClinicalTrials.gov Identifier NCT03010683.

Topics: Adult; Biomarkers; Biomechanical Phenomena; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Female; Glucagon-Like Peptide-1 Receptor; Greece; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Middle Aged; Myocardial Contraction; Natriuretic Peptide, Brain; Oxidative Stress; Peptide Fragments; Time Factors; Treatment Outcome; Vascular Stiffness; Ventricular Function, Left

After digestion, dietary triacylglycerol stimulates incretin release in humans, mainly through generation of 2-monoacylglycerol, an agonist for the intestinal G protein-coupled receptor 119 (GPR119). Enhanced incretin release may have beneficial metabolic effects. However, dietary fat may promote weight gain and should therefore be restricted in obesity. We designed C4-dietary oil (1,3-di-butyryl-2-oleoyl glycerol) as a 2-oleoyl glycerol (2-OG)-generating fat type, which would stimulate incretin release to the same extent while providing less calories than equimolar amounts of common triglycerides, e.g., olive oil.. We studied the effect over 180 min of (a) 19 g olive oil plus 200 g carrot, (b) 10.7 g C4 dietary oil plus 200 g carrot and (c) 200 g carrot, respectively, on plasma responses of gut and pancreatic hormones in 13 overweight patients with type 2 diabetes (T2D). Theoretically, both oil meals result in formation of 7.7 g 2-OG during digestion.. Both olive oil and C4-dietary oil resulted in greater postprandial (P ≤ 0.01) glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses (incremental area under curve (iAUC)): iAUC. C4-dietary oil enhanced secretion of GLP-1 and GIP to almost the same extent as olive oil, in spite of liberation of both 2-OG and oleic acid, which also may stimulate incretin secretion, from olive oil. Thus, C4-dietary oil is more effective as incretin releaser than olive oil per unit of energy and may be useful for dietary intervention.

Topics: Aged; Area Under Curve; Diabetes Mellitus, Type 2; Dietary Fats, Unsaturated; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycerides; Glycerol; Humans; Incretins; Male; Meals; Middle Aged; Obesity; Oleic Acid; Olive Oil; Overweight; Postprandial Period; Prodrugs; Receptors, G-Protein-Coupled; Single-Blind Method; Triglycerides

To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin.. This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose.. Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events.. Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.

Topics: Aged; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Male; Middle Aged; Obesity; Weight Loss

Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP-1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and HDL cholesterol from baseline to week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (-0.70%; paired t test, P < .001). Significant changes were also observed in FPG (-34.7 mg/dL), body weight (-4.46%), SBP (-7.90 mm Hg), and HDL cholesterol (7.60%; all P < .001). The incidence of AEs, adverse drug reactions and hypoglycaemia was 71.8%, 32.4% and 9.9%, respectively. All hypoglycaemic events were mild. These findings suggest that the long-term combination of canagliflozin with a GLP-1RA is effective and well tolerated in Japanese patients with T2DM.

Topics: Aged; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Cholesterol, HDL; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Incretins; Japan; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

It has been suggested that liraglutide could have an impact on glucose and lipid metabolism disorder and adhesion molecule activation, which may play important roles in the vascular damage of diabetes. In this study, we examined the effects of liraglutide versus metformin on non-esterified free fatty acids, beta-cell insulin secretion, and adhesion molecule levels in patients with recent-onset type 2 diabetes mellitus.. In this study, 60 patients newly diagnosed with type 2 diabetes mellitus (mean age 33.97 ± 5.67 years) were randomly assigned to receive once-daily subcutaneous liraglutide or oral metformin. Before the study and after the 8-week treatment period, a 75 g oral glucose tolerance test was performed. Plasma glucose, lipids and lipoprotein, plasma insulin, glycaemic and insulin responses, non-esterified free fatty acids (NEFA), and soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were evaluated.. After 8 weeks, 120 min of NEFA (155 ± 125 vs 99 ± 73 µmol/L, P = 0.026) and the levels of sVCAM-1 (465 ± 136 vs 382 ± 131 ng/ml, P = 0.013) significantly decreased, while the early phase insulin secretion index (24.94 [7.78, 38.89] vs. 31.13 [17.67, 59.09], P = 0.031), fasting plasma insulin (104 [51, 123] vs 113 [54, 171] mIU/L, P = 0.015), 60 min plasma insulin (326 [165, 441] vs 471 [334, 717] mIU/L, P = 0.005), 120 min plasma insulin (401 [193, 560] vs 500 [367, 960] mIU/L, P = 0.047), and insulin area under the curve (AUCins) (648 [321, 742] vs 738 [451, 1118] mIU/L, P = 0.005) remarkably increased for patients in the liraglutide treatment group. The levels of sVCAM-1 dramatically decreased after 8 weeks of liraglutide treatment (503 ± 182 vs 382 ± 131 ng/ml, P = 0.046) compared to that of the metformin treatment group. At the same time, the differences before and after liraglutide treatment in 120 min of NEFA (- 32 [- 96, - 5] vs 5 [- 35, 38] µmol/L, P = 0.033) and AUCins (738 [451, 1118] vs 594 [357, 1216] mIU/L, P = 0.014) were remarkably enhanced compared to that of the metformin therapy. Nevertheless, there were no significant differences in fasting NEFA after liraglutide or metformin treatment. The reduction of 120 min NEFA (ΔNEFA) was positively correlated with the decrease of sVCAM-1 (ΔsVCAM-1) after 8 weeks of liraglutide treatment (r = 0.523, P = 0.003).. Our results demonstrate that liraglutide administration is more effective than metformin in reducing 120 min NEFA and suppressing sVCAM-1 levels for recent-onset type 2 diabetes mellitus. We suggest that this outcome may be because liraglutide is associated with potentiating insulin secretion capacity, inhibiting vascular inflammatory cytokines, and antagonizing atherosclerosis.

Topics: Administration, Oral; Adult; Biomarkers; China; Diabetes Mellitus, Type 2; Down-Regulation; Fatty Acids, Nonesterified; Female; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Metformin; Time Factors; Treatment Outcome; Vascular Cell Adhesion Molecule-1

Animal studies demonstrated that glucagon-like peptide-1 receptor agonists reduce myocardial necrosis following regional ischaemia induction. This effect may improve cardiovascular outcomes after myocardial infarction. Risk of cardiovascular death or hospitalisation for heart failure after myocardial infarction was evaluated in patients with type 2 diabetes at high cardiovascular risk in the LEADER trial.. Data from patients randomised to liraglutide or placebo, in addition to standard of care, in Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) (NCT01179048) were analysed post hoc. Cox regression, with myocardial infarction as a time-dependent covariate, was used to analyse time from randomisation to a composite of cardiovascular death or hospitalisation for heart failure.. Patients who experienced myocardial infarction had a sevenfold higher risk of the composite endpoint (with myocardial infarction: n = 148, 25.0%; without myocardial infarction: n = 716, 8.2%; hazard ratio: 7.0; 95% confidence interval: 5.8, 8.4). The risk of the composite endpoint after myocardial infarction was not significantly lower in the liraglutide group ( n = 63, 23.0%) compared with placebo ( n = 85, 26.7%; hazard ratio: 0.91; 95% confidence interval: 0.66, 1.26).. The data demonstrated that having myocardial infarction significantly increased the risk of subsequent cardiovascular death or hospitalisation for heart failure. However, we did not find evidence for a reduced risk in these cardiovascular outcomes following myocardial infarction in patients treated with liraglutide versus placebo.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Myocardial Infarction; Proportional Hazards Models; Risk Factors; Time Factors; Treatment Outcome

Albiglutide is a long-acting glucagon-like peptide-1 receptor agonist that improves glycemic control in patients with type 2 diabetes mellitus (T2DM). Harmony Outcomes is a randomized, double-blind, placebo-controlled trial of the effect of albiglutide on major adverse cardiovascular (CV) events in patients with T2DM and established CV disease.. The trial was designed to recruit 9,400 patients aged ≥40 years with T2DM, prior atherosclerotic CV disease, and suboptimal glycemic control. Participants were assigned in a 1:1 ratio to albiglutide 30 mg (potentially increasing to 50 mg) or matching placebo administered once weekly by subcutaneous injection. The trial will continue until ≥611 confirmed primary outcome events (CV death, myocardial infarction, or stroke) occur over a median follow-up of at least 1.5 years.. A total of 9,463 patients were enrolled at 611 sites in 28 countries between July 2015 and December 2016. The mean age was 64.1 years; duration of T2DM, 13.8 years; and glycated hemoglobin, 8.7%. The percentage of patients with prior coronary artery disease was 70.5%; peripheral arterial disease, 25.0%; stroke, 17.7%; heart failure, 20.2%; and chronic kidney disease, 22.6%.. Harmony Outcomes will assess the CV safety of albiglutide in patients with T2DM and CV disease. Trials of other agents in the glucagon-like peptide-1 receptor agonist class have shown CV benefit for only some of these medications, possibly due to differences in trial design or instead due to differences in drug structure or metabolism. Harmony Outcomes will provide information critical to our understanding of this heterogenous class of glucose-lowering agents.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidence; Incretins; Italy; Male; Middle Aged; Ontario; Survival Rate; Treatment Outcome; United Kingdom; United States

A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM).. LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.. LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.. Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.

Topics: Adult; Animals; Appetite; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diarrhea; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Male; Mice; Mice, Inbred C57BL; Middle Aged; Receptors, Gastrointestinal Hormone; Vomiting

Short-term studies have demonstrated potential therapeutic efficacy of dipeptidyl peptidase 4 inhibitors (DPP4 inhibitors) in patients with poorly controlled T1DM. In this study we evaluated the effect of DPP4 inhibitor, linagliptin, on glycaemic control and variability, and incretinaxis in well controlled T1DM patients to mitigate the effect of glucotoxicity on incretin secreting cells.. Twenty T1DM patients were randomized to receive either linagliptin (10 patients, dose-5 mg/day) or placebo (10 patients), in addition to insulin for 3 months. HbA1C, continuous glucose monitoring (CGM) and mixed meal test (MMT) were performed before and at the end of the study period.. HbA1C reduction and change in glycaemic variability and insulin requirement in the linagliptin group did not attain the level of statistical significance. The increase in AUC GLP1 (Area under curve for GLP1) and decrease in AUC glucagon (Area under curve for glucagon) during the MMT in linagliptin group were also statistically insignificant.. Linagliptin is not effective in reducing HbA1C and glycaemic variability in relatively well controlled T1DM patients.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Purines; Quinazolines; Treatment Outcome

Multiple bloodglucose-lowering agents have been linked to cardiovascular events. Preliminary studies showed improvement in left ventricular (LV) function during glucagon-like peptide-1 receptor agonist administration. Underlying mechanisms, however, are unclear. The purpose of this study was to investigate myocardial perfusion and oxidative metabolism in type 2 diabetic (T2DM) patients with LV systolic dysfunction as compared to healthy controls. Furthermore, effects of 26-weeks of exenatide versus insulin glargine administration on cardiac function, perfusion and oxidative metabolism in T2DM patients with LV dysfunction were explored.. Twenty-six T2DM patients with LV systolic dysfunction (cardiac magnetic resonance (CMR) derived LV ejection fraction (LVEF) of 47 ± 13%) and 10 controls (LVEF of 59 ± 4%, P < 0.01 as compared to patients) were analyzed. Both myocardial perfusion during adenosine-induced hyperemia (P < 0.01), and coronary flow reserve (P < 0.01), measured by [. T2DM patients with LV systolic dysfunction did not have altered myocardial efficiency as compared to healthy controls. Exenatide or insulin glargine had no effects on cardiac function, perfusion or oxidative metabolism. Trial registration NCT00766857.

Topics: Aged; Coronary Circulation; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Energy Metabolism; Exenatide; Female; Humans; Hypoglycemic Agents; Incretins; Insulin Glargine; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardial Perfusion Imaging; Myocardium; Netherlands; Oxidation-Reduction; Oxygen Consumption; Peptides; Positron Emission Tomography Computed Tomography; Recovery of Function; Stroke Volume; Systole; Time Factors; Treatment Outcome; Venoms; Ventricular Dysfunction, Left; Ventricular Function, Left

We have previously reported that once-weekly albiglutide was noninferior to thrice-daily lispro for glycemic lowering, with decreased weight and risk of hypoglycemia, in patients inadequately controlled on basal insulin over 26 weeks. Findings after 52 weeks reveal similar responses to albiglutide as an add-on to insulin glargine.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Insulin Glargine; Insulin Lispro; Meals; Risk; Weight Gain; Weight Loss

Bariatric surgery, incretin-based therapy (glucagon-like peptide-1 analogues), and sodium-glucose co-transporter 2 (SGLT2) inhibitors have antidiabetic properties in morbidly obese patients. However, their comparative efficacy in treating type 2 diabetes mellitus (T2DM) in class I obese patients specifically in Indian has not been studied yet. This study evaluates and compares the efficacy and side effect of surgical and advanced medical management of T2DM in class I obese patients.. T2DM patients with body mass index ranging from 30 to 35 kg/m. There was statistically significant lowering of HbA1c and FPG after 12 months in all the three groups. However, this lowering was clinically insignificant in GLP-1 and SGLT2 groups. There was also improvement in lipid profile values in all the three groups with significantly higher percentage change in bariatric surgery group when compared to other modalities.. Bariatric surgery is a safe and effective procedure to treat T2DM in class I obese patients. It is also superior to advance medical treatment modalities such as GLP-1 analogues and SGLT2 inhibitors.

Topics: Adult; Bariatric Surgery; Body Mass Index; Combined Modality Therapy; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Obesity; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors.. Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (P. Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.

Topics: Aged; Biomarkers; Blood Glucose; Case-Control Studies; Denmark; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Models, Biological; Time Factors

To determine the effect of the glucagon-like peptide-1 analogue liraglutide on left ventricular function in chronic heart failure patients with and without type 2 diabetes.. LIVE was an investigator-initiated, randomised, double-blinded, placebo-controlled multicentre trial. Patients (n = 241) with reduced left ventricular ejection fraction (LVEF ≤45%) were recruited (February 2012 to August 2015). Patients were clinically stable and on optimal heart failure treatment. Intervention was liraglutide 1.8 mg once daily or matching placebo for 24 weeks. The LVEF was similar at baseline in the liraglutide and the placebo group (33.7 ± 7.6% vs. 35.4 ± 9.4%). Change in LVEF did not differ between the liraglutide and the placebo group; mean difference (95% confidence interval) was -0.8% (-2.1, 0.5; P = 0.24). Heart rate increased with liraglutide [mean difference: 7 b.p.m. (5, 9), P < 0.0001]. Serious cardiac events were seen in 12 (10%) patients treated with liraglutide compared with 3 (3%) patients in the placebo group (P = 0.04).. Liraglutide did not affect left ventricular systolic function compared with placebo in stable chronic heart failure patients with and without diabetes. Treatment with liraglutide was associated with an increase in heart rate and more serious cardiac adverse events, and this raises some concern with respect to the use of liraglutide in patients with chronic heart failure and reduced left ventricular function. More data on the safety of liraglutide in different subgroups of heart failure patients are needed.

Topics: Acute Coronary Syndrome; Aged; Atrial Fibrillation; Chronic Disease; Diabetes Mellitus, Type 2; Disease Progression; Double-Blind Method; Echocardiography; Female; Heart Failure; Heart Rate; Humans; Incretins; Liraglutide; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Stroke Volume; Tachycardia, Ventricular; Treatment Outcome; Ventricular Function, Left; Walk Test

To characterize gastrointestinal adverse events (AEs) with different glucagon-like peptide-1 receptor agonists (GLP-1RAs).. Two retrospective intention-to-treat analyses of 6-month patient-level data were conducted. Data from three studies comparing exenatide once weekly (n = 617) with exenatide twice daily (n = 606) were pooled, and one (DURATION-6) comparing exenatide once weekly (n = 461) with liraglutide (n = 450) was analysed separately. Patient-reported gastrointestinal AEs were classified as upper or lower, AE incidences and timing were determined, subgroups were analysed, and associations of gastrointestinal AEs with efficacy were examined.. Nausea was the most common gastrointestinal AE for all treatments. Fewer exenatide once-weekly-treated vs exenatide twice-daily- or liraglutide-treated patients reported gastrointestinal AEs (34% vs 45% and 25% vs 41%, respectively; both P  < .0001). Fewer exenatide once-weekly-treated patients reported upper plus lower events than liraglutide-treated patients ( P  < .001); the difference between exenatide once weekly and twice daily was not significant. Within each group, more women than men reported gastrointestinal AEs. Events occurrred early and were predominantly mild. Glycated haemoglobin reductions were similar for patients with or without gastrointestinal AEs. Weight loss was greater for patients with gastrointestinal AEs with exenatide once weekly and exenatide twice daily ( P  < .05); no difference was observed in DURATION-6.. Gastrointestinal AEs were less frequent with exenatide once weekly vs exenatide twice daily or liraglutide, and combined upper and lower events occurred less often. Gastrointestinal AEs were typically mild and occurred early. Gastrointestinal AEs did not affect glycaemic control but may be associated with greater weight loss.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Gastrointestinal Diseases; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Incidence; Incretins; Intention to Treat Analysis; Liraglutide; Male; Nausea; Patient Dropouts; Peptides; Retrospective Studies; Self Report; Severity of Illness Index; Sex Factors; Venoms; Weight Loss

Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUC

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Enteroendocrine Cells; Enzyme-Linked Immunosorbent Assay; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin-Secreting Cells; Liraglutide; Time Factors

Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors treat type 2 diabetes through incretin-signaling pathways. This study compared the efficacy and safety of the glucagon-like peptide-1 receptor agonist exenatide once-weekly (Miglyol) suspension for autoinjection (QWS-AI) with the dipeptidyl peptidase-4 inhibitor sitagliptin or placebo.. In this open-label, multicentre study of patients with type 2 diabetes who had suboptimal glycaemic control on metformin monotherapy, 365 patients were randomized to receive exenatide 2.0 mg QWS-AI, sitagliptin 100 mg once daily or oral placebo (3:2:1 ratio). The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to 28 weeks.. At 28 weeks, exenatide QWS-AI significantly reduced HbA1c from baseline compared to sitagliptin (-1.13% vs -0.75% [baseline values, 8.42% and 8.50%, respectively]; P  = .02) and placebo (-0.40% [baseline value, 8.50%]; P = .001). More exenatide QWS-AI-treated patients achieved HbA1c <7.0% than did sitagliptin- or placebo-treated patients (43.1% vs 32.0% and 24.6%; both P  < .05). Exenatide QWS-AI and sitagliptin reduced fasting plasma glucose from baseline to 28 weeks (-21.3 and -11.3 mg/dL) vs placebo (+9.6 mg/dL), with no significant difference between the 2 active treatments. Body weight decreased with both active treatments (-1.12 and -1.19 kg), but not with placebo (+0.15 kg). No improvement in blood pressure was observed in any group. The most common adverse events with exenatide QWS-AI were gastrointestinal events and injection-site reactions.. This study demonstrated that exenatide QWS-AI reduced HbA1c more than sitagliptin or placebo and was well tolerated.

Topics: Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Drug Therapy, Combination; Excipients; Exenatide; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incidence; Incretins; Injections, Jet; Male; Metformin; Middle Aged; Peptides; Sitagliptin Phosphate; Triglycerides; United States; Venoms

To evaluate the efficacy and safety of fasiglifam, an orally active G-protein-coupled receptor 40 agonist, in combination with the dipeptidyl peptidase-4 inhibitor sitagliptin, in patients with type 2 diabetes inadequately controlled with diet/exercise (± metformin).. In this randomized, double-blind, phase II study, 368 patients received once-daily placebo, sitagliptin 100 mg, fasiglifam 25 or 50 mg, or the combination of sitagliptin 100 mg plus fasiglifam 25 or 50 mg. The primary endpoint was change from baseline glycated haemoglobin (HbA1c) at 12 weeks; a key secondary endpoint was change in fasting plasma glucose (FPG).. The fasiglifam 25 and 50 mg combination regimens produced significantly greater HbA1c reductions than sitagliptin (treatment differences of -0.45% and -0.61%; P < .01, respectively) or respective doses of fasiglifam monotherapy (-0.43% and -0.48%; P < .01) and significantly greater FPG reductions than sitagliptin (-1.1 mmol/L for both combination regimens; P < .01). Improved glycaemic control occurred by week 1 for FPG and week 4 for HbA1c in all groups. Hypoglycaemia rates were low (≤3.3%) and similar across treatments. Liver enzymes >3 × upper limit of normal occurred in four patients (fasiglifam 25 mg, n = 1; fasiglifam 50 mg, n = 2; 1 fasiglifam/sitagliptin 50/100 mg, n = 1).. Combination of fasiglifam and sitagliptin provided significant additional effects on glycaemic control, with hypoglycaemia rates similar to placebo with or without metformin. This study provides supportive clinical evidence for the complementary mechanism of actions of this GPR40 agonist and DPP-4 inhibitor.

Topics: Benzofurans; Combined Modality Therapy; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Hemoglobins, Abnormal; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Male; Metformin; Middle Aged; Receptors, G-Protein-Coupled; Sitagliptin Phosphate; Sulfones; United States

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) stimulate the incretin system and lower glycaemic parameters in type 2 diabetes mellitus (T2DM). This analysis of clinical studies of up to 3years evaluated the safety of albiglutide, a GLP-1 RA, in people with T2DM.. Integrated safety analysis included seven phase-3 T2DM studies of albiglutide compared with placebo and/or active comparators (a dipeptidyl peptidase-4 inhibitor, GLP-1 RA, insulin, sulphonylurea, and thiazolidinedione).. Studies of 32months (HARMONY 7), 1year (HARMONY 6), and 3years (HARMONY 1-5), reported similar rates of adverse events (AEs) (84.8%, 82.3%), and serious AEs (13.1%, 12.9%) between albiglutide and all comparators, respectively. AEs that did not differ between the groups included symptomatic or severe hypoglycaemia as well as nausea (12.0%, 11.3%) and vomiting (5.3%, 4.7%) for albiglutide and all comparators, respectively. According to the Medical Dictionary for Regulatory Activities preferred terms, only diarrhoea (13.7%, 9.9%), injection-site reaction (9.0%, 2.0%), and peripheral oedema (4.5%, 6.8%) had at least 2% difference between the albiglutide and all-comparator groups. In a similar integrated analysis, pancreatitis occurred more often with albiglutide (0.3%, 0.1%). Renal and cardiac function did not differ between the two groups.. In an integrated analysis of seven phase 3 clinical trials, albiglutide-treated patients experienced frequencies of AEs (including cardiovascular and renal) similar to the all-comparators group treated with other T2DM medications or placebo. Albiglutide treatment was associated with higher rates of diarrhoea and injection-site reactions, but not increased nausea and vomiting, versus all comparators.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections; Insulin; Male; Middle Aged; Sulfonylurea Compounds

The aim of this study was to evaluate the efficacy and safety of sitagliptin administered to elderly patients with type 2 diabetes mellitus (T2DM) for 1 year as compared with glimepiride. Patients aged ≥60 years with T2DM and inadequately controlled blood glucose were randomly assigned to sitagliptin 50 mg once daily or glimepiride 0.5 mg once daily for 52 weeks. The primary efficacy endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 52. Secondary efficacy endpoints included self-monitored blood glucose and weight. Safety endpoints were adverse events including hypoglycaemia. Administration of sitagliptin or glimepiride to elderly patients with T2DM resulted in a significant decrease in HbA1c change from baseline. At 52 weeks, the least squares mean difference between the treatments was 0.11% (95% confidence interval [CI] -0.02 to 0.24; P = .087) (1.2 mmol/mol [-0.2 to 2.6]). The upper limit of the CI was below the predefined non-inferiority margin (0.3% [3.3 mmol/mol]), demonstrating non-inferiority of sitagliptin to glimepiride for the primary endpoint. Sitagliptin resulted in a significantly lower incidence rate of non-serious hypoglycaemia than glimepiride during the 52 weeks (4.7% vs 16.1%; P = .002); thus, sitagliptin is a useful therapeutic option for elderly patients with T2DM.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Aging; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Equivalence Trials as Topic; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Japan; Middle Aged; Reproducibility of Results; Severity of Illness Index; Sitagliptin Phosphate; Sulfonylurea Compounds; Weight Loss

To compare the addition of weekly dulaglutide vs the addition of placebo to titrated glargine in patients with type 2 diabetes (T2D) with sub-optimum glycated haemoglobin (HbA1c) concentration.. Patients (N = 300) from this phase III, double-blind, parallel-arm, placebo-controlled study were randomized to weekly subcutaneous injections of dulaglutide 1.5 mg or placebo with titrated daily glargine (mean ± standard deviation baseline dose: 39 ± 22 U), with or without metformin (≥1500 mg/d). The primary endpoint was superiority of dulaglutide/glargine to placebo/glargine with regard to change from baseline in HbA1c level at 28 weeks.. Least squares (LS) mean ± standard error (s.e.) HbA1c changes from baseline were -1.44 ± 0.09% (-15.74 ± 0.98 mmol/mol) with dulaglutide/glargine and -0.67 ± 0.09% (-7.32 ± 0.98 mmol/mol) with placebo/glargine at 28 weeks (LS mean difference [95% confidence interval] -0.77% [-0.97, -0.56]; P < .001). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -2.41 ± 0.39 kg; P < .001). Increases from baseline in mean glargine dose were significantly smaller with dulaglutide/glargine vs placebo/glargine (13 ± 2 U [0.1 ± 0.02 U/kg] vs 26 ± 2 U [0.3 ± 0.02 U/kg], respectively; P < .001; LS mean ± s.e. final dose: dulaglutide/glargine, 51 ± 2 U; placebo/glargine, 65 ± 2 U). The hypoglycaemia rate (≤3.9 mmol/L threshold) was 7.69 ± 15.15 and 8.56 ± 16.13 events/patient/year, respectively (P = .488). One episode of severe hypoglycaemia occurred in the dulaglutide/glargine group. Common gastrointestinal adverse events with dulaglutide were nausea (12.0%), diarrhoea (11.3%) and vomiting (6.0%).. Weekly dulaglutide 1.5 mg added to basal insulin is an efficacious and well tolerated treatment option for patients with T2D.

Topics: Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Injections, Subcutaneous; Insulin Glargine; Intention to Treat Analysis; Male; Middle Aged; Patient Dropouts; Recombinant Fusion Proteins

Patients with diabetes mellitus are at high risk for developing coronary artery disease (CAD), even if they are treated with statins. Several studies have shown the beneficial effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on the cardiovascular system in an animal model. However, recent clinical trials using DPP-4 inhibitors have shown that these inhibitors fail to reduce the occurrence of cardiovascular events. Therefore, this study will be performed to evaluate the effects of sitagliptin, a DPP-4 inhibitor, on coronary atherosclerosis in patients with type 2 diabetes. This study will be a prospective, open-label, randomized multicenter trial performed in 6 centers in Japan. Stable CAD patients with type 2 diabetes who have undergone successful percutaneous coronary intervention under integrated backscatter (IB)-intravascular ultrasound (IVUS) guidance will be studied. They will be randomly assigned to either the sitagliptin group or a control group. After 48 weeks' treatment, the IVUS examination will be repeated in the same coronary artery as at baseline. The primary end point will be the percentage change in plaque volume measured using grayscale IVUS from baseline to the 48-week follow-up. This study will be the first multicenter trial to evaluate the effects of a DPP-4 inhibitor on coronary atherosclerosis evaluated using IB-IVUS, and the findings will clarify the anti-atherogenic effects of sitagliptin.

Topics: Clinical Protocols; Coronary Artery Disease; Coronary Vessels; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Japan; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Predictive Value of Tests; Prospective Studies; Research Design; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Ultrasonography, Interventional

To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist].. CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18.. Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues.. In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition.

Topics: Aged; Biomimetics; Blood Pressure; Canagliflozin; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Urologic Diseases; Weight Loss

The effect of saxagliptin on cardiovascular outcomes according to different hemoglobin A1c (HbA1c) levels has not been described. Thus, we analyzed the SAVOR-TIMI 53 trial to compare the cardiovascular effects of saxagliptin vs placebo according to baseline HbA1c.. A total of 16,492 patients with type 2 diabetes (HbA1c 6.5%-12.0% in the 6 months before randomization) and either a history of established cardiovascular disease or multiple risk factors for atherosclerosis were randomized to saxagliptin or placebo in addition to usual care. Patients were followed for a median of 2.1 years. The primary endpoint was cardiovascular death, myocardial infarction, or ischemic stroke.. Patients were stratified by HbA1c at randomization into the following prespecified groups: <7%, 7%-<8%, 8%-<9%, and ≥9%. Baseline HbA1c ≥7% was associated with increased risk of cardiovascular death, myocardial infarction, or ischemic stroke (adjusted hazard ratio [HR(adj)] 1.35; 95% confidence interval [CI], 1.17-1.58) but not hospitalization for heart failure (HR(adj) 1.09; 95% CI, 0.88-1.36). Saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic stroke in patients with HbA1c <7% (HR 1.01; 95% CI, 0.78-1.31), 7%-<8% (HR 0.98; 95% CI, 0.80-1.20), 8%-<9% (HR 1.09; 95% CI, 0.85-1.39), ≥9% (HR 0.95; 95% CI, 0.77-1.18) (P-interaction = .89).. Baseline HbA1c is associated with increased risk of macrovascular events but not hospitalization for heart failure. There was no heterogeneity in the effect of saxagliptin on cardiovascular events by baseline HbA1c, with cardiovascular death, myocardial infarction, or ischemic stroke neither increased nor decreased across the spectrum of baseline HbA1c values.

Topics: Adamantane; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Double-Blind Method; Female; Glycated Hemoglobin; Heart Failure; Hospitalization; Humans; Incretins; Male; Middle Aged; Myocardial Infarction; Risk; Stroke

Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis.. This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119.. Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]).. Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.. Wellcome Trust, National Institute of Health Research, and Novo Nordisk.

Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Incretins; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome; Young Adult

Investigation of dietary therapy for diabetes has focused on meal size and composition; examination of the effects of meal sequence on postprandial glucose management is limited. The effects of fish or meat before rice on postprandial glucose excursion, gastric emptying and incretin secretions were investigated.. The experiment was a single centre, randomised controlled crossover, exploratory trial conducted in an outpatient ward of a private hospital in Osaka, Japan. Patients with type 2 diabetes (n = 12) and healthy volunteers (n = 10), with age 30-75 years, HbA1c 9.0% (75 mmol/mol) or less, and BMI 35 kg/m(2) or less, were randomised evenly to two groups by use of stratified randomisation, and subjected to meal sequence tests on three separate mornings; days 1 and 2, rice before fish (RF) or fish before rice (FR) in a crossover fashion; and day 3, meat before rice (MR). Pre- and postprandial levels of glucose, insulin, C-peptide and glucagon as well as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide were evaluated. Gastric emptying rate was determined by (13)C-acetate breath test involving measurement of (13)CO2 in breath samples collected before and after ingestion of rice steamed with (13)C-labelled sodium acetate. Participants, people doing measurements or examinations, and people assessing the outcomes were not blinded to group assignment.. FR and MR in comparison with RF ameliorated postprandial glucose excursion (AUC-15-240 min-glucose: type 2 diabetes, FR 2,326.6 ± 114.7 mmol/l × min, MR 2,257.0 ± 82.3 mmol/l × min, RF 2,475.6 ± 87.2 mmol/l × min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 1,419.8 ± 72.3 mmol/l × min, MR 1,389.7 ± 69.4 mmol/l × min, RF 1,483.9 ± 72.8 mmol/l × min) and glucose variability (SD-15-240 min-glucose: type 2 diabetes, FR 1.94 ± 0.22 mmol/l, MR 1.68 ± 0.18 mmol/l, RF 2.77 ± 0.24 mmol/l [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 0.95 ± 0.21 mmol/l, MR 0.83 ± 0.16 mmol/l, RF 1.18 ± 0.27 mmol/l). FR and MR also enhanced GLP-1 secretion, MR more strongly than FR or RF (AUC-15-240 min-GLP-1: type 2 diabetes, FR 7,123.4 ± 376.3 pmol/l × min, MR 7,743.6 ± 801.4 pmol/l × min, RF 6,189.9 ± 581.3 pmol/l × min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 3,977.3 ± 324.6 pmol/l × min, MR 4,897.7 ± 330.7 pmol/l × min, RF 3,747.5 ± 572.6 pmol/l × min [p < 0.05 for MR vs RF and MR vs FR]). FR and MR delayed gastric emptying (Time50%: type 2 diabetes, FR 83.2 ± 7.2 min, MR 82.3 ± 6.4 min, RF 29.8 ± 3.9 min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 66.3 ± 5.5 min, MR 74.4 ± 7.6 min, RF 32.4 ± 4.5 min [p < 0.05 for FR vs RF and MR vs RF]), which is associated with amelioration of postprandial glucose excursion (AUC-15-120 min-glucose: type 2 diabetes, r = -0.746, p < 0.05; healthy, r = -0.433, p < 0.05) and glucose variability (SD-15-240 min-glucose: type 2 diabetes, r = -0.578, p < 0.05; healthy, r = -0.526, p < 0.05), as well as with increasing GLP-1 (AUC-15-120 min-GLP-1: type 2 diabetes, r = 0.437, p < 0.05; healthy, r = 0.300, p = 0.107) and glucagon (AUC-15-120 min-glucagon: type 2 diabetes, r = 0.399, p < 0.05; healthy, r = 0.471, p < 0.05). The measured outcomes were comparable between the two randomised groups.. Meal sequence can play a role in postprandial glucose control through both delayed gastric emptying and enhanced incretin secretion. Our findings provide clues for medical nutrition therapy to better prevent and manage type 2 diabetes.. UMIN Clinical Trials Registry UMIN000017434.. Japan Society for Promotion of Science, Japan Association for Diabetes Education and Care, and Japan Vascular Disease Research Foundation.

Topics: Adult; Aged; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Japan; Male; Meals; Middle Aged; Postprandial Period

We evaluated whether patients with histologically verified nonalcoholic fatty liver disease (NAFLD) have an impaired incretin effect and hyperglucagonaemia.. Four groups matched for age, sex and body mass index were studied: (i) 10 patients with normal glucose tolerance and NAFLD; (ii) 10 patients with type 2 diabetes and NAFLD; (iii) eight patients with type 2 diabetes and no liver disease; and (iv) 10 controls. All participants underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycaemic intravenous glucose infusion (IIGI). We determined the incretin effect by relating the beta cell secretory responses during the OGTT and IIGI. Data are presented as medians (interquartile range), and the groups were compared by using the Kruskal-Wallis test.. Controls exhibited a higher incretin effect [55% (43-73%)] compared with the remaining three groups (P < 0.001): 39% (44-71%) in the nondiabetic NAFLD patients, 20% (-5-50%) in NAFLD patients with type 2 diabetes, and 2% (-8-6%) in patients with type 2 diabetes and no liver disease. We found fasting hyperglucagonaemia in NAFLD patients with [7.5 pmol L(-1) (6.8-15 pmol L(-1))] and without diabetes [7.5 pmol L(-1) (5.0-8.0 pmol L(-1))]. Fasting glucagon levels were lower but similar in patients with type 2 diabetes and no liver disease [4.5 pmol L(-1) (3.0-6.0 pmol L(-1))] and controls [3.4 pmol L(-1) (1.8-6.0 pmol L(-1) )]. All groups had similar glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide responses.. Patients with NAFLD have a reduced incretin effect and fasting hyperglucagonaemia, with the latter occurring independently of glucose (in)tolerance.

Topics: Adult; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Incretins; Insulin; Male; Middle Aged; Non-alcoholic Fatty Liver Disease

Nutrient "preloads" given before meals can attenuate postprandial glycemic excursions, at least partly by slowing gastric emptying and stimulating secretion of the incretins (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). This study was designed to evaluate whether a protein preload could improve the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin to increase incretin concentrations, slow gastric emptying, and lower postprandial glycemia in type 2 diabetes.. Twenty-two patients with type 2 diabetes treated with metformin were studied on four occasions, receiving either 50 mg vildagliptin (VILD) or placebo (PLBO) on both the evening before and the morning of each study day. The latter dose was followed after 60 min by a preload drink containing either 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a (13)C-octanoate-labeled mashed potato meal. Plasma glucose and hormones, and gastric emptying, were evaluated.. Compared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact incretins, and slowed gastric emptying but suppressed plasma glucagon and total incretins (P < 0.05 each). Compared with both PLBO/WHEY and VILD/CTRL, VILD/WHEY was associated with higher plasma intact GLP-1 and GIP, slower gastric emptying, and lower postprandial glycemia (P < 0.05 each).. In metformin-treated type 2 diabetes, a protein preload has the capacity to enhance the efficacy of vildagliptin to slow gastric emptying, increase plasma intact incretins, and reduce postprandial glycemia.

Topics: Adamantane; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Metformin; Middle Aged; Nitriles; Postprandial Period; Pyrrolidines; Vildagliptin; Whey Proteins

Hydroxycitric acid (HCA), derived from the fruit Garcinia cambogia, reduces the rate of glucose absorption and lowers postprandial glycemia in rodents, but its effect in humans is unknown. The aim of this study was to investigate the effects of small intestinal perfusion with HCA on glucose absorption, as well as the incretin and glycemic responses to a subsequent intraduodenal glucose infusion, in both healthy individuals and patients with type 2 diabetes.. Twelve healthy participants and 8 patients with type 2 diabetes received an intraduodenal infusion of HCA (2800 mg in water) or control (water) over 60 min, followed by an intraduodenal infusion of 60 g glucose over 120 min, in a double-blind, randomized crossover design. In healthy individuals, 5 g 3-O-methylglucose (3-OMG) was co-infused with glucose as a marker of glucose absorption. Blood was sampled frequently.. In healthy individuals, blood glucose was lower with HCA than control, both before and during the intraduodenal glucose infusion (P < 0.05 for each). Plasma glucose-dependent insulinotropic polypeptide (GIP; P = 0.01) and glucagon (P = 0.06) were higher with HCA, but there were no differences in plasma glucagon-like peptide (GLP)-1, insulin, or serum 3-OMG concentrations. In patients with type 2 diabetes, blood glucose, and plasma GIP, GLP-1, and insulin did not differ between HCA and control either before or after intraduodenal glucose, but during glucose infusion, plasma glucagon was higher with HCA (P = 0.04).. In healthy individuals, small intestinal exposure to HCA resulted in a modest reduction in glycemia and stimulation of plasma GIP and glucagon, but no effect on plasma GLP-1 or insulin, or on glucose absorption. HCA had no effect on glycemia in patients with type 2 diabetes.

Topics: 3-O-Methylglucose; Adult; Aged; Biomarkers; Citrates; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Supplements; Double-Blind Method; Duodenum; Female; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Intestinal Absorption; Intestinal Mucosa; Intubation, Gastrointestinal; Male; Middle Aged

Liraglutide 3.0 mg, an acylated GLP-1 analogue approved for weight management, lowers body weight through decreased energy intake. We conducted exposure-response analyses to provide important information on individual responses to given drug doses, reflecting inter-individual variations in drug metabolism, absorption and excretion.. We report efficacy and safety responses across a wide range of exposure levels, using data from one phase II (liraglutide doses 1.2, 1.8, 2.4 and 3.0 mg), and two phase IIIa [SCALE Obesity and Prediabetes (3.0 mg); SCALE Diabetes (1.8; 3.0 mg)] randomized, placebo-controlled trials (n = 4372).. There was a clear exposure-weight loss response. Weight loss increased with greater exposure and appeared to level off at the highest exposures associated with liraglutide 3.0 mg in most individuals, but did not fully plateau in men. In individuals with overweight/obesity and comorbid type 2 diabetes, there was a clear exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased with higher plasma liraglutide concentration (plateauing at ∼21 nM); however, for individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No exposure-response relationship was identified for any safety outcome, with the exception of gastrointestinal adverse events (AEs). Individuals with gallbladder AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not have higher liraglutide exposure compared with the overall population.. These analyses support the use of liraglutide 3.0 mg for weight management in all subgroups investigated; weight loss increased with higher drug exposure, with no concomitant deterioration in safety/tolerability besides previously known gastrointestinal side effects.

Topics: Appetite Depressants; Body Mass Index; Cohort Studies; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Reducing; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Middle Aged; Obesity; Overweight; Prediabetic State; Sex Characteristics; Weight Loss

To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake.. On four separate days, nine patients with type 2 diabetes, and 10 matched healthy control subjects received bolus instillations of (i) CDCA, (ii) colesevelam, (iii) CDCA + colesevelam or (iv) placebo. At baseline and for 180 min after instillation, blood was sampled.. In both the type 2 diabetes group and the healthy control group, CDCA elicited an increase in GLP-1 levels compared with colesevelam, CDCA + colesevelam and placebo, respectively (p < 0.05). The interventions did not affect plasma glucose, insulin or C-peptide concentrations in any of the groups. CDCA elicited a small increase in plasma insulin : glucose ratio compared with colesevelam, CDCA + colesevelam and placebo in both groups. Compared with colesevelam, CDCA + colesevelam and placebo, respectively, CDCA increased glucagon and delayed gastric emptying in both groups.. CDCA increased GLP-1 and glucagon secretion, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which, in turn, may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans.

Topics: Aged; Bile Acids and Salts; Blood Glucose; C-Peptide; Chenodeoxycholic Acid; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged; Placebos

Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon-like peptide 1 (GLP-1) during fasting and hyperglycemic conditions, respectively.. Renal transplant recipients with (n = 12) and without (n = 12) PTDM underwent two separate experimental days with 3-h intravenous infusions of GLP-1 (0.8 pmol/kg/min) and saline, respectively. After 1 h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp.. Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups. In PTDM patients, glucose-induced glucagon suppression was significantly less pronounced (maximal suppression from baseline: 43 ± 12 vs. 65 ± 12%, P < 0.001), while first- and second-phase insulin secretion were significantly lower. The PTDM group also exhibited a significantly lower insulin response to arginine (P = 0.01) but similar glucagon and proinsulin responses compared with control subjects. In the preclamp phase, GLP-1 lowered fasting plasma glucose to the same extent in both groups but reduced glucagon only in PTDM patients. During hyperglycemic clamp, GLP-1 reduced glucagon concentrations and increased first- and second-phase insulin secretion in both groups.. PTDM is characterized by reduced glucose-induced insulin secretion and attenuated glucagon suppression during a hyperglycemic clamp. Similar to the case in type 2 diabetes, GLP-1 infusion seems to improve (insulin) or even normalize (glucagon) these pathophysiological defects.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Infusions, Intravenous; Insulin; Insulin Secretion; Kidney Transplantation; Male; Middle Aged; Proinsulin

To investigate the effect of exenatide treatment on serum ghrelin levels in obese female patients with type 2 diabetes mellitus.. Fourteen female patients with type 2 diabetes mellitus being treated with metformin and exenatide were enrolled. A mixed meal test was applied to the patients while continuing with their daily medications. Blood samples were taken before and at 60, 120, and 180 minutes following mixed meal test to measure serum total ghrelin, glucose, and insulin levels. The following week, exenatide treatment of the patients was paused for 24 hours and the same experimental procedures were repeated.. Serum ghrelin levels were suppressed significantly at 180 minutes with exenatide treatment compared with baseline (294.4 ± 57.5 versus 234.5 ± 59.4 pg/mL) (p < 0.001). Serum ghrelin levels at 180 minutes were statistically different when percentage change in serum ghrelin levels after mixed meal tests with and without exenatide usage were compared (p = 0.001). Estimated total area under the curve values for serum ghrelin concentrations was also significantly lower with exenatide compared with omitted treatment (p = 0.035).. These results suggest that the effect of exenatide on weight loss may be related with the suppression of serum ghrelin levels, which is an orexigenic peptide.

Topics: Adult; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Down-Regulation; Drug Therapy, Combination; Eating; Exenatide; Female; Ghrelin; Humans; Hypoglycemic Agents; Incretins; Metformin; Middle Aged; Obesity; Peptides; Postprandial Period; Prospective Studies; Time Factors; Treatment Outcome; Venoms; Weight Loss

Apart from the mean level of glycemic control, the extent of glucose excursions is another important issue to consider in type 2 diabetes mellitus (T2DM) management. Studies have showed that fluctuations of glucose seem to have more deleterious effects than sustained hyperglycemia in the development of diabetic complications as acute glucose swings activate the oxidative stress. However, until now, no randomized controlled trials have been conducted with the primary aim to evaluate glycemic fluctuation in the comparison between twice-daily exenatide and other treatment paradigms (for example, biphasic insulin aspart 30).. This multicenter, open-label, randomized, parallel trial includes a 1-week screening period and a 16-week treatment period. After the screening period, 150 patients with confirmed type 2 diabetes who are treated with stable, maximum-tolerated doses of metformin will be randomly assigned to one of two groups for antihyperglycemic therapies: exenatide and biphasic insulin aspart 30. The treatment with exenatide will be initiated at a low dose of 5 μg twice a day for 4 weeks and then titrated up to a standard dose of 10 ug twice a day until the completion of the study. The adjustment of insulin dose is instructed to achieve an optimal balance between glycemic control and the risk of hypoglycemia as dictated by clinical practice. The primary outcome is the absolute change of mean amplitude of glycemic excursion from baseline to week 16, which is calculated based on a real-time continuous glucose monitoring system (CGMS).. This is the first randomized controlled trial using a CGMS to evaluate glycemic fluctuation between twice-daily exenatide and insulin aspart 30, which will provide beneficial evidence of exenatide usage in patients with T2DM.. NCT02449603 . Date of registration: 11 May 2015.

Topics: Adolescent; Adult; Aged; Biomarkers; Biphasic Insulins; Blood Glucose; China; Clinical Protocols; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Incretins; Insulin Aspart; Insulin, Isophane; Male; Middle Aged; Peptides; Pilot Projects; Research Design; Time Factors; Treatment Outcome; Venoms; Young Adult

To assess the effects of glucagon-like peptide (GLP)-1-based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus.. We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m(2); HbA1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo (P>0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P<0.05). After the meal, exenatide increased endothelial domain power (P<0.05). In the 12-week study, no effects on vasomotion were observed.. Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1-based therapies on glucose are not mediated through microvascular responses.

Topics: Adult; Aged; Blood Flow Velocity; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Incretins; Laser-Doppler Flowmetry; Liraglutide; Male; Microcirculation; Microscopic Angioscopy; Microscopy, Video; Microvessels; Middle Aged; Netherlands; Peptides; Regional Blood Flow; Signal Transduction; Sitagliptin Phosphate; Skin; Time Factors; Treatment Outcome; Venoms

Liraglutide, a GLP-1 analogue, exerts several beneficial non-glycemic effects in patients with type-2 diabetes (T2DM), such as those on body weight, blood pressure, plasma lipids and inflammation markers. However, the effects of liraglutide on cardiovascular (CV) risk markers in subjects with the metabolic syndrome (MetS) are still largely unknown. We herein explored its effects on various cardio-metabolic risk markers of the MetS in subjects with T2DM.. We performed an 18-month prospective, real-world study. All subjects had T2DM and the MetS based on the AHA/NHLBI criteria. Subjects with a history of a major CV event were excluded. One hundred-twenty-one subjects (71 men and 50 women; mean age: 62 ± 9 years) with T2DM and the MetS, who were naïve to incretin-based therapies and treated with metformin only, were included. Liraglutide (1.2 mg/day) was added to metformin (1500-3000 mg/day) for the entire study. Fasting plasma samples for metabolic parameters were collected and carotid-intima media thickness (cIMT) was assessed by B-mode real-time ultrasound at baseline and every 6 months thereafter.. There was a significant reduction in waist circumference, body mass index, fasting glycemia, HbA1c, total- and LDL-cholesterol, triglycerides, and cIMT during the 18-month follow-up. Correlation analysis showed a significant association between changes in cIMT and triglycerides (r = 0.362; p < 0.0001). The MetS prevalence significantly reduced during the study, and the 26% of subjects no longer fulfilled the criteria for the MetS after 18 months.. Liraglutide improves cardio-metabolic risk factors in subjects with the MetS in a real-world study. Trial Registration ClinicalTrials.gov: NCT01715428.

Topics: Aged; Biomarkers; Carotid Artery Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Echocardiography, Doppler, Color; Female; Humans; Hypoglycemic Agents; Incretins; Italy; Liraglutide; Male; Metabolic Syndrome; Metformin; Middle Aged; Predictive Value of Tests; Prevalence; Prospective Studies; Risk Factors; Treatment Outcome

Patients with type 2 diabetes are generally treated in primary care setting and as a final treatment step to obtain good glycaemic control, multiple daily insulin injections (MDI) are generally used. The aim of this study is to evaluate the effect of GLP-1 analogue liraglutide on glycaemic control in patients with type 2 diabetes treated with MDI with inadequate glycaemic control.. Overweight and obese patients with type 2 diabetes and impaired glycaemic control treated with MDI were randomised to liraglutide or placebo over 24 weeks. Masked continuous glucose monitoring was performed at baseline and during the trial. The primary endpoint was the change in haemoglobin A1c from baseline to week 24. Additional endpoints include changes in weight, fasting glucose, glycaemic variability, treatment satisfaction, insulin dose, hypoglycaemias, blood pressure and blood lipid levels.. Recruitment occurred between February 2013 and February 2014. A total of 124 patients were randomised. Study completion is anticipated in August 2014.. It is expected that the results of this study will establish whether adding liraglutide to patients with type 2 diabetes treated with MDI will improve glycaemic control, lower body weight, and influence glycaemic variability.

Topics: Biomarkers; Blood Glucose; Clinical Protocols; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Injections; Insulin; Liraglutide; Patient Selection; Research Design; Sample Size; Sweden; Time Factors; Treatment Outcome

Few studies have focused on postprandial incretin responses to different carbohydrate meals. Therefore, we designed a study to compare the different effects of two carbohydrates (75 g oral glucose, a monosaccharide and 100 g standard noodle, a polysaccharide, with 75 g carbohydrates equivalently) on postprandial glucose, insulin and incretin responses in different glucose tolerance groups.. This study was an open-label, randomized, two-way crossover clinical trial. 240 participants were assigned to take two carbohydrates in a randomized order separated by a washout period of 5-7 days. The plasma glucose, insulin, c-peptide, glucagon and active glucagon-like peptide-1 (AGLP-1) were measured. The incremental area under curve above baseline from 0 to 120 min of insulin (iAUC(0 -120 min)- INS) and AGLP-1(iAUC(0 -120 min)- AGLP-1) was calculated.. Compared with standard noodles, the plasma glucose and insulin after consumption of oral glucose were higher at 30 min (both P < 0.001) and 60 min (both P < 0.001), while lower at 180 min (both P < 0.001), but no differences were found at 120 min. The glucagon at 180 min was higher after consumption of oral glucose (P = 0.010). The AGLP-1 response to oral glucose was higher at 30 min (P < 0.001), 60 min (P < 0.001) and 120 min (P = 0.022), but lower at 180 min (P = 0.027). In normal glucose tolerance (NGT), oral glucose elicited a higher insulin response to the corresponding AGLP-1 (P < 0.001), which was represented by iAUC(0 -120 min) -INS /iAUC(0 -120 min)- AGLP-1, while in type 2 diabetes mellitus (T2DM), standard noodles did (P = 0.001).. Monosaccharide potentiated more rapid and higher glycemic and insulin responses. Oral glucose of liquid state would elicit a more potent release of AGLP-1. The incretin effect was amplified after consumption of standard noodles in T2DM.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Glucose; C-Peptide; China; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Postprandial Period; Predictive Value of Tests; Time Factors; Young Adult

CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (NCT01243424) is an ongoing, randomized trial in subjects with early type 2 diabetes and increased cardiovascular risk or established complications that will determine the long-term cardiovascular impact of linagliptin versus the sulphonylurea glimepiride. Eligible patients were sulphonylurea-naïve with HbA1c 6.5%-8.5% or previously exposed to sulphonylurea (in monotherapy or in a combination regimen <5 years) with HbA1c 6.5%-7.5%. Primary outcome is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina. A total of 631 patients with primary outcome events will be required to provide 91% power to demonstrate non-inferiority in cardiovascular safety by comparing the upper limit of the two-sided 95% confidence interval as being below 1.3 for a given hazard ratio. Hierarchical testing for superiority will follow, and the trial has 80% power to demonstrate a 20% relative cardiovascular risk reduction. A total of 6041 patients were treated with median type 2 diabetes duration 6.2 years, 40.0% female, mean HbA1c 7.2%, 66% on 1 and 24% on 2 glucose-lowering agents and 34.5% had previous cardiovascular complications. The results of CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes may influence the decision-making process for selecting a second glucose-lowering agent after metformin in type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Protocols; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Incretins; Linagliptin; Male; Middle Aged; Patient Selection; Research Design; Risk Factors; Sample Size; Sulfonylurea Compounds; Treatment Outcome

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Echocardiography, Doppler; Electrocardiography; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycated Hemoglobin; Heart Function Tests; Humans; Incretins; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Nitriles; Pyrrolidines; Reference Values; Risk Assessment; Stroke Volume; Treatment Outcome; Vildagliptin

The role of the incretin hormones in the pathophysiology of maturity onset diabetes of the young (MODY) is unclear.. We studied the postprandial plasma responses of glucagon, incretin hormones (glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)) and dipeptidyl-peptidase 4 (DPP4) enzymatic activity in patients with glucokinase (GCK) diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A) diabetes (MODY3) as well as in matched healthy individuals (CTRLs).. Ten patients with MODY2 (mean age ± S.E.M. 43 ± 5 years; BMI 24 ± 2 kg/m(2); fasting plasma glucose (FPG) 7.1 ± 0.3 mmol/l: HbA1c 6.6 ± 0.2%), ten patients with MODY3 (age 31 ± 3 years; BMI 24 ± 1 kg/m(2); FPG 8.9 ± 0.8 mmol/l; HbA1c 7.0 ± 0.3%) and ten CTRLs (age 40 ± 5 years; BMI 24 ± 1 kg/m(2); FPG 5.1 ± 0.1 mmol/l; HbA1c 5.3 ± 0.1%) were examined with a liquid test meal.. All of the groups exhibited similar baseline values of glucagon (MODY2: 7 ± 1 pmol/l; MODY3: 6 ± 1 pmol/l; CTRLs: 8 ± 2 pmol/l, P=0.787), but patients with MODY3 exhibited postprandial hyperglucagonaemia (area under the curve (AUC) 838 ± 108 min × pmol/l) as compared to CTRLs (182 ± 176 min × pmol/l, P=0.005) and tended to have a greater response than did patients with MODY2 (410 ± 154 min × pmol/l, P=0.063). Similar peak concentrations and AUCs for plasma GIP and plasma GLP1 were observed across the groups. Increased fasting DPP4 activity was seen in patients with MODY3 (17.7 ± 1.2 mU/ml) vs CTRLs (13.6 ± 0.8 mU/ml, P=0.011), but the amount of activity was similar to that in patients with MODY2 (15.0 ± 0.7 mU/ml, P=0.133).. The pathophysiology of MODY3 includes exaggerated postprandial glucagon responses and increased fasting DPP4 enzymatic activity but normal postprandial incretin responses both in patients with MODY2 and in patients with MODY3.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Fasting; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Male; Middle Aged; Postprandial Period

Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release of glucagon-like peptides (GLP)-1 and -2.. A prospective, double-blind, randomized trial was performed in 21 glucose-tolerant humans (11 lean: age 49 ± 7 years, BMI 23.6 ± 1.7 kg/m(2); 10 obese: age 51 ± 7 years, BMI 35.5 ± 4.9 kg/m(2)). Participants ingested 10(10) b.i.d. L. reuteri SD5865 or placebo over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess incretin effect and GLP-1 and GLP-2 secretion, and euglycemic-hyperinsulinemic clamps with [6,6-(2)H2]glucose were used to measure peripheral insulin sensitivity and endogenous glucose production. Muscle and hepatic lipid contents were assessed by (1)H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays.. In glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2 release by 76% (P < 0.01) and 43% (P < 0.01), respectively, compared with placebo, along with 49% higher insulin (P < 0.05) and 55% higher C-peptide secretion (P < 0.05). However, the intervention did not alter peripheral and hepatic insulin sensitivity, body mass, ectopic fat content, or circulating cytokines.. Enrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may serve as a novel therapeutic approach to improve glucose-dependent insulin release.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Limosilactobacillus reuteri; Male; Middle Aged; Obesity; Oxidative Stress; Pilot Projects; Probiotics; Prospective Studies; Protein Precursors

Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM).. In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments.. In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 μmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain -18.1 ± 6.6 versus -15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia.. In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM.. http://www.isrctn.org . Unique identifier ISRCTN69686930.

Topics: Aged; Biomarkers; Biomechanical Phenomena; Blood Glucose; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Echocardiography, Doppler, Color; Echocardiography, Stress; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Incretins; Infusions, Intravenous; Insulin; Male; Middle Aged; Myocardial Contraction; Peptide Fragments; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Maturity onset diabetes of the young (MODY) designates monogenic forms of non-autoimmune diabetes characterised by autosomal dominant inheritance, non-insulin dependent diabetes at onset and diagnosis often before 25 years of age. MODY constitutes genetically and clinically heterogeneous forms of diabetes. More than 8 different genes are known to cause MODY, among which hepatocyte nuclear factor 1 alpha (HNF1A) (MODY3) and glucokinase (GCK) (MODY2) mutations are the most common. Both forms of MODY are characterised by specific beta cell dysfunction, with patients with HNF1A-diabetes having a reduced insulin secretory capacity, while patients with GCK-diabetes have a glucose-sensing defect, but preserved insulin secretory capacity. Patients with MODY are effectively treated with sulphonylurea (SU) due to very high sensitivity to these drugs, but they are also prone to develop hypoglycaemia. The objectives of this thesis were to study the pathophysiology of GCK-diabetes and HNF1A-diabetes by investigating the incretin effect, the physiological response to food ingestion and to estimate the treatment potential of a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with HNF1A-diabetes. In Study I we investigated the incretin effect and the responses of islet hormones and incretin hormones to oral glucose tolerance test (OGTT) and isoglycaemic IV glucose infusion (IIGI) in patients with GCK-diabetes, in patients with HNF1A-diabetes, and in BMI and age matched healthy individuals (CTRLs). In Study II we investigated responses of islet hormones and incretin hormones to a more physiological stimulus consisting of a standardised meal test in patients with GCK-diabetes, in patients with HNF1A--diabetes, and in BMI and age matched CTRLs. In Study III we conducted a randomised, double-blind, crossover trial investigating the glucose lowering effect and risk of hypoglycaemia during 6 weeks of treatment with the GLP-1RA, liraglutide compared to the SU, glimepiride in 16 patients with HNF1A-diabetes. At baseline and at the end of each treatment period a standardised meal test followed by a light bicycling test was performed. The results of the studies showed that patients with HNF1A-diabetes were less glucose tolerant than patients with GCK-diabetes, but both groups were more glucose intolerant than CTRLs. In spite of glucose intolerance patients with GCK-diabetes showed normal incretin effect, whereas patients with HNF1A-diabetes showed an impaired increti

Topics: Academic Dissertations as Topic; Adult; Blood Glucose; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Islets of Langerhans; Male; Postprandial Period

The risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes; thus, it is important to determine whether glucose-lowering therapy affects this risk over time. Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily (a glucagon-like peptide-1 receptor agonist) or glimepiride (a sulfonylurea) added to metformin in the EURopean EXenAtide (EUREXA) study.. Patients with type 2 diabetes failing metformin were randomized to add-on exenatide twice daily (n = 515) or glimepiride (n = 514) until treatment failure defined by hemoglobin A1C. Anthropomorphic measures, blood pressure (BP), heart rate, lipids, and high-sensitivity C-reactive protein (hsCRP) over time were evaluated.. Over 36 months, twice-daily exenatide was associated with improved body weight (-3.9 kg), waist circumference (-3.6 cm), systolic/diastolic BP (-2.5/-2.6 mmHg), high-density lipoprotein (HDL)-cholesterol (0.05 mmol/L), triglycerides (-0.2 mmol/L), and hsCRP (-1.7 mg/L). Heart rate did not increase (-0.3 beats/minute), and low-density lipoprotein-cholesterol (0.2 mmol/L) and total cholesterol (0.1 mmol/L) increased slightly. Between-group differences were significantly in favor of exenatide for body weight (P < 0.0001), waist circumference (P < 0.001), systolic BP (P < 0.001), diastolic BP (P = 0.023), HDL-cholesterol (P = 0.001), and hsCRP (P = 0.004). Fewer patients randomized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive (20.4 vs 26.4%; P = 0.026) or lipid-lowering medication (8.4 vs 12.8%; P = 0.025).. Add-on exenatide twice daily was associated with significant, sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride.. NCT00359762, http://www.ClinicalTrials.gov.

Topics: Aged; Biomarkers; Blood Glucose; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Europe; Exenatide; Female; Glycated Hemoglobin; Heart Rate; Humans; Hypoglycemic Agents; Incretins; Lipids; Male; Metformin; Middle Aged; Peptides; Risk Factors; Sulfonylurea Compounds; Time Factors; Treatment Outcome; Venoms

Incretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from glucose-lowering, these agents exhibit pleiotropic actions that may have favourable and unfavourable clinical consequences. Incretin-based therapies have been associated with heart rate acceleration, heart failure, acute renal failure and acute pancreatitis. Conversely, these agents may reduce blood pressure, glomerular hyperfiltration, albuminuria and hepatic steatosis. While large-sized cardiovascular safety trials can potentially identify the clinical significance of some of these pleiotropic actions, small-sized mechanistic studies are important to understand the (patho)physiological rationale of these findings. The current protocol describes a mechanistic study to assess cardiovascular, renal and gastrointestinal effects, and mechanisms of incretin-based therapies in type 2 diabetes.. 60 patients with type 2 diabetes will undergo acute and prolonged randomised, double-blind, intervention studies. The acute intervention will consist of intravenous administration of the GLP-1 receptor agonist exenatide or placebo. For the prolonged intervention, patients will be randomised to 12-week treatment with the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebos. For each examined organ system, a primary end point is defined. Primary cardiovascular end point is change in resting heart rate variability assessed by beat-to-beat heart rate monitor and spectral analyses software. Primary renal end point is change in glomerular filtration rate assessed by the classic inulin clearance methodology. Primary gastrointestinal end points are change in pancreatic exocrine function assessed by MRI-techniques (acute intervention) and faecal elastase-1 levels (12-week intervention). Secondary end points include systemic haemodynamics, microvascular function, effective renal plasma flow, renal tubular function, pancreatic volume and gallbladder emptying-rate.. The study is approved by the local Ethics Review Board (VU University Medical Center, Amsterdam) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.. NCT01744236.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Exenatide; Female; Gastrointestinal Tract; Heart; Humans; Hypoglycemic Agents; Incretins; Kidney; Liraglutide; Male; Middle Aged; Peptides; Research Design; Sitagliptin Phosphate; Treatment Outcome; Venoms

Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent degradation of incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), whereas metformin may increase GLP-1 levels. We examined, in a four-period crossover trial, the influence of metformin (2,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly augmented insulin secretion, in monotherapy and as an add-on to metformin. The incretin effect was not changed numerically with any of the treatments. In conclusion, sitagliptin increased intact GLP-1 and GIP through DPP-4 inhibition but reduced total GLP-1 and GIP (feedback inhibition) without affecting the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic agents besides GLP mediating the antidiabetic effects of DPP-4 inhibition.

Topics: Administration, Intravesical; Administration, Oral; Adult; Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Gene Expression Regulation; Glucose; Humans; Incretins; Insulin; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Triazoles

Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼ 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼ 50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles

The PDY6797 study evaluated efficacy, safety and pharmacodynamics of lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus (T2DM) insufficiently controlled with sulphonylureas with/without metformin.. This randomized, double-blind, placebo-controlled trial comprised a single-dose assessment of lixisenatide 5 and 10 µg, and a 5- to 6-week repeated dose-escalation assessment of lixisenatide 5 to 30 µg once (QD) or twice daily (BID). The primary endpoint was change in postprandial plasma glucose (PPG) area under the curve (AUC)[0:29-4:30 h] after a standardized breakfast at the highest tolerated lixisenatide dose. Change from baseline in glycated haemoglobin (HbA1c), 2-h PPG and fasting plasma glucose (FPG) were assessed, as were adverse events.. Change from baseline in PPG AUC[0:29-4:30 h] with lixisenatide QD and BID was significantly greater than placebo (p < 0.0001 for all study populations), with particularly prominent effects in Japanese patients. Greater reductions in PPG AUC[0:29-4:30 h] were seen with lixisenatide QD versus BID, while the totality of evidence suggested that the lixisenatide 20 µg dose was optimal. In the overall population, changes from baseline for 2-h PPG, HbA1c and FPG were significant with lixisenatide QD and BID versus placebo (p < 0.01 for all). Lixisenatide was well tolerated.. Lixisenatide significantly reduced PPG AUC[0:29-4:30 h] versus placebo at the highest well-tolerated dose in patients with T2DM treated with sulphonylureas with/without metformin and had a good safety and tolerability profile. Japanese patients experienced particular benefits with lixisenatide in terms of reductions in PPG excursions.

Topics: Adult; Aged; Asian People; Cohort Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Japan; Male; Metformin; Middle Aged; Peptides; Receptors, Glucagon; Sulfonylurea Compounds; White People; Young Adult

In this study, we examined whether inhibition of postprandial hyperglycemia by combination therapy with two drugs for reducing postprandial hyperglycemia, i.e., α-glucosidase inhibitor miglitol and dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin, improves glycemic control and reduces the risk of cardiovascular disease (CVD) development.. We enrolled 32 type 2 diabetic Japanese patients with hemoglobin A1c (HbA1c) levels ranging from 6.9% to 10.5%, who had been treated for at least 2 months with 50mg miglitol (t.i.d.) or 50 mg sitagliptin (q.d.). Following a monotherapy period with either miglitol (Group-M) or sitagliptin (Group-S) for 1 month, the patients were subjected to combination therapy with sitagliptin and miglitol for 3 months. Meal tolerance tests were performed at the end of the monotherapy and combination therapy.. Combination therapy for 3 months after monotherapy reduced HbA1c (changes: Group-M: -1.3%±0.7%, P<0.001; Group-S: -0.6%±0.5%, P<0.001) and glycoalbumin levels and increased 1,5-anhydroglucitol concentrations in the blood. In the meal tolerance tests, circulating active glucagon-like peptide-1 levels were elevated in both groups, while active glucose-dependent insulinotropic polypeptide levels were reduced by combination therapy in the group with add-on miglitol therapy. The plasma protein concentrations of interleukin (IL)-8 and adhesion molecules (sE-selectin and sVCAM-1) were reduced by switching to the combination therapy, in particular with the add-on miglitol therapy.. Our results suggest that combination therapy with miglitol and sitagliptin improves glycemic control and reduces the circulating protein concentrations of IL-8, sE-selectin, and sVCAM-1 in type 2 diabetic Japanese patients.

Topics: 1-Deoxynojirimycin; Adult; Aged; Asian People; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; E-Selectin; Female; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Interleukin-8; Japan; Male; Middle Aged; Prospective Studies; Pyrazines; Risk Factors; Sitagliptin Phosphate; Triazoles; Vascular Cell Adhesion Molecule-1

The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Energy Intake; Gastric Inhibitory Polypeptide; Gastrointestinal Motility; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins; Male; Metformin; Obesity; Pyrazines; Sitagliptin Phosphate; Triazoles

Subjects with type 2 diabetes (T2D) and their nondiabetic first-degree relatives (REL) have increased risk of cardiovascular disease (CVD). Postprandial triglyceridemia (PPL), influenced by diet, is an independent risk factor for CVD. Dietary fat elicits increased PPL in T2D compared with nondiabetic controls, but our knowledge of PPL responses to fat in REL is sparse. Our aim was to test the hypothesis that REL respond to a monounsaturated fatty acid (MUFA) challenge with a higher PPL response compared with controls who have no family history of T2D (CON) and that MUFAs exert a differential impact on incretin responses and on the expression of genes involved in carbohydrate and lipid metabolism in muscle and adipose tissues of REL and CON.. A total of 17 REL and 17 CON consumed a meal with 72 energy percent derived from MUFAs (macadamia nut oil). Plasma triglycerides, free fatty acids, insulin, glucose, glucagon-like peptide 1, glucose-dependent insulintropic peptide and ghrelin were measured at baseline and regular intervals until 4 h postprandially. Muscle and adipose tissue biopsies were collected at baseline and at 210 min after the meal.. The MUFA-rich meal did not elicit different responses (P>0.05) in PPL, insulin, glucose, incretins or ghrelin in REL and CON. Several genes were differentially regulated in muscle and adipose tissues of REL and CON.. A MUFA-rich meal elicits similar PPL, insulin and incretin responses in REL and CON. MUFAs have a differential impact on gene expression in muscle and adipose tissues in a pattern pointing toward early defects in lipid metabolism in REL.

Topics: Adipose Tissue; Adult; Diabetes Mellitus, Type 2; Family; Fatty Acids, Monounsaturated; Female; Gene Expression; Humans; Hyperlipidemias; Incretins; Insulin; Lipid Metabolism; Macadamia; Male; Meals; Middle Aged; Muscles; Postprandial Period; Triglycerides

To estimate the impact of aging and diabetes on insulin sensitivity, beta-cell function, adipocytokines, and incretin production.. Hyperglycemic clamps, arginine tests and meal tolerance tests were performed in 50 non-obese subjects to measure insulin sensitivity (IS) and insulin secretion as well as plasma levels of glucagon, GLP-1 and GIP. Patients with diabetes and healthy control subjects were divided into the following groups: middle-aged type 2 diabetes (MA-DM), aged Type 2 diabetes (A-DM) and middle-aged or aged subjects with normal glucose tolerance (MA-NGT or A-NGT).. IS, as determined by the homeostasis model assessment, glucose infusion rate, and oral glucose insulin sensitivity, was reduced in the aged and DM groups compared with MA-NGT, but it was similar in the MA-DM and A-DM groups. Insulinogenic index, first and second phase insulin secretion and the disposition indices, but not insulin response to arginine, were reduced in the aged and DM groups. Postprandial glucagon production was higher in MA-DM compared to MA-NGT. Whereas the GLP-1 production was reduced in A-DM, no differences between groups were observed in GIP production.. In non-obese subjects, diabetes and aging impair insulin sensitivity. Insulin production is reduced by aging, and diabetes exacerbates this condition. Aging associated defects superimposed diabetic physiopathology, particularly regarding GLP-1 production. On the other hand, the glucose-independent secretion of insulin was preserved. Knowledge of the complex relationship between aging and diabetes could support the development of physiopathological and pharmacological based therapies.

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Aging; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Down-Regulation; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Pancreas; Postprandial Period; Up-Regulation

Since protein ingestion is known to stimulate the secretion of glucagon-like peptide-1 (GLP-1), we hypothesised that enhancing GLP-1 secretion to harness its insulinotropic/beta cell-stimulating activity with whey protein pre-load may have beneficial glucose-lowering effects in type 2 diabetes.. In a randomised, open-label crossover clinical trial, we studied 15 individuals with well-controlled type 2 diabetes who were not taking any medications except for sulfonylurea or metformin. These participants consumed, on two separate days, 50 g whey in 250 ml water or placebo (250 ml water) followed by a standardised high-glycaemic-index breakfast in a hospital setting. Participants were randomised using a coin flip. The primary endpoints of the study were plasma concentrations of glucose, intact GLP-1 and insulin during the 30 min following meal ingestion.. In each group, 15 patients were analysed. The results showed that over the whole 180 min post-meal period, glucose levels were reduced by 28% after whey pre-load with a uniform reduction during both early and late phases. Insulin and C-peptide responses were both significantly higher (by 105% and 43%, respectively) with whey pre-load. Notably, the early insulin response was 96% higher after whey. Similarly, both total GLP-1 (tGLP-1) and intact GLP-1 (iGLP-1) levels were significantly higher (by 141% and 298%, respectively) with whey pre-load. Dipeptidyl peptidase 4 plasma activity did not display any significant difference after breakfast between the groups.. In summary, consumption of whey protein shortly before a high-glycaemic-index breakfast increased the early prandial and late insulin secretion, augmented tGLP-1 and iGLP-1 responses and reduced postprandial glycaemia in type 2 diabetic patients. Whey protein may therefore represent a novel approach for enhancing glucose-lowering strategies in type 2 diabetes. Trial registration ClinicalTrials.gov NCT01571622 Funding The Israeli Ministry of Health and Milk Council funded the research.

Topics: Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Male; Middle Aged; Milk Proteins; Whey Proteins

To identify the metabolic determinants of type 2 diabetes non-remission status after bariatric surgery at 12 and 24 months.. A total of 40 adults [mean ± sd body mass index 36 ± 3 kg/m(2) , age 48 ± 9 years, glycated haemoglobin (HbA1c) 9.7 ± 2%) undergoing bariatric surgery [Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG)] were enrolled in the present study, the Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. Type 2 diabetes remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl (i.e. <7 mmol/l) without antidiabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide values during a 120-min mixed-meal tolerance test. Body fat, incretins (glucagon-like polypeptide-1, gastric inhibitory peptide, ghrelin) and adipokines [adiponectin, leptin, tumour necrosis factor-α, high-sensitivity C-reactive protein (hs-CRP)] were also assessed.. At 24 months, 37 patients had available follow-up data (RYGB, n = 18; SG, n = 19). Bariatric surgery induced type 2 diabetes remission rates of 40 and 27% at 12 and 24 months, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity and β-cell function (C-peptide0-120 /glucose0-120 × Matsuda index) improved more in those with remission at 12 and 24 months than in those without remission. Incretin levels were unrelated to type 2 diabetes remission, but, compared with those without remission, hs-CRP decreased and adiponectin increased more in those with remission. Only baseline adiponectin level predicted lower HbA1c levels at 12 and 24 months, and elevated adiponectin correlated with enhanced β-cell function, lower triglyceride levels and fat loss.. Smaller rises in adiponectin level, a mediator of insulin action and adipose mass, characterize type 2 diabetes non-remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key to achieving higher type 2 diabetes remission rates after bariatric surgery.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastrectomy; Gastric Bypass; Glycated Hemoglobin; Humans; Incretins; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Remission Induction; Time Factors; Treatment Outcome; Weight Loss

Nopal is a plant used in traditional Mexican medicine to treat diabetes. However, there is insufficient scientific evidence to demonstrate whether nopal can regulate postprandial glucose. The purpose for conducting this study was to evaluate the glycemic index, insulinemic index, glucose-dependent insulinotropic peptide (GIP) index, and the glucagon-like peptide 1 (GLP-1) index, and the effect of nopal on patients with type 2 diabetes after consumption of a high-carbohydrate breakfast (HCB) or high-soy-protein breakfast (HSPB) on the postprandial response of glucose, insulin, GIP, GLP-1, and antioxidant activity. In study 1, the glycemic index, insulinemic index, GIP index, and GLP-1 index were calculated for seven healthy participants who consumed 50 g of available carbohydrates from glucose or dehydrated nopal. In study 2, 14 patients with type 2 diabetes consumed nopal in HCB or HSPB with or without 300 g steamed nopal. The glycemic index of nopal was 32.5±4, insulinemic index was 36.1±6, GIP index was 6.5±3.0, and GLP-1 index was 25.9±18. For those patients with type 2 diabetes who consumed the HCB+nopal, there was significantly lower area under the curve for glucose (287±30) than for those who consumed the HCB only (443±49), and lower incremental area under the curve for insulin (5,952±833 vs 7,313±1,090), and those patients with type 2 diabetes who consumed the HSPB avoided postprandial blood glucose peaks. Consumption of the HSPB+nopal significantly reduced the postprandial peaks of GIP concentration at 30 and 45 minutes and increased the antioxidant activity after 2 hours measured by the 2,2-diphenyl-1-picrilhidracyl method. These findings suggest that nopal could reduce postprandial blood glucose, serum insulin, and plasma GIP peaks, as well as increase antioxidant activity in healthy people and patients with type 2 diabetes.

Topics: Adult; Antioxidants; Breakfast; Diabetes Mellitus, Type 2; Female; Food, Preserved; Functional Food; Gastric Inhibitory Polypeptide; Glycemic Index; Humans; Hyperglycemia; Hyperinsulinism; Incretins; Male; Medicine, Traditional; Mexico; Middle Aged; Opuntia; Plant Components, Aerial; Plant Proteins, Dietary; Postprandial Period; Soybean Proteins

To show that albiglutide, a glucagon-like peptide-1 receptor agonist, is an effective and generally safe treatment to improve glycaemic control in patients with type 2 diabetes mellitus whose hyperglycaemia is inadequately controlled with pioglitazone (with or without metformin).. In this 3-year, randomized, double-blind, placebo-controlled study, 310 adult patients on a regimen of pioglitazone (with or without metformin) were randomly assigned to receive additional treatment with albiglutide [30 mg subcutaneous (s.c.) once weekly, n = 155] or matching placebo (n = 155). The primary efficacy endpoint was change from baseline to week 52 (intention-to-treat) in glycated haemoglobin (HbA1c).. The model-adjusted change from baseline in HbA1c at week 52 was significantly better with albiglutide than with placebo (-0.8%, 95% confidence interval -1.0, -0.6; p < 0.0001). Change from baseline fasting plasma glucose was -1.3 mmol/l in the albiglutide group and +0.4 mmol/l in the placebo group (p < 0.0001); a significantly higher percentage of patients reached the HbA1c goals with albiglutide (p < 0.0001), and the rate of hyperglycaemia rescue up to week 52 for albiglutide was 24.4 versus 47.7% for placebo (p < 0.0001). Albiglutide plus pioglitazone had no impact on weight, and severe hypoglycaemia was observed rarely (n = 2). With few exceptions, the results of safety assessments were similar between the groups, and most adverse events (AEs) were mild or moderate. The 52-week incidence rates for gastrointestinal AEs for albiglutide and placebo were: 31.3 and 29.8%, respectively (diarrhoea: 11.3 and 8.6%; nausea: 10.7 and 11.3%; vomiting: 4.0 and 4.0%).. Albiglutide 30 mg administered once weekly as an add-on to pioglitazone (with or without metformin) provided effective and durable glucose lowering and was generally well tolerated.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Metformin; Middle Aged; Pioglitazone; Thiazolidinediones; Treatment Outcome

This randomized, prospective study was conducted in 76 subjects to assess whether low-dose (0.5-2 mg/day) glimepiride, in combination therapy with sitagliptin, improves glycemic control in a dose-dependent manner in Japanese patients with type 2 diabetes. Eligible subjects had been treated with glimepiride at doses of 3-6 mg/day for at least 3 months and had a HbA1c level of ≥6.9%. Subjects were randomly assigned to three treatment groups of reduced doses of glimepiride (0.5 mg/day, 1 mg/day, or 2 mg/day) in addition to sitagliptin for 24 weeks. The primary efficacy analysis evaluated the change in HbA1c from baseline to week 24. Secondary efficacy endpoints included the changes in fasting plasma glucose, insulin secretion capacity, and β-cell function. Safety endpoints included hypoglycemia and any adverse event. Despite dose reduction of glimepiride, combination therapy with sitagliptin induced significant improvements in HbA1c levels (-0.8%, p < 0.001). Insulin secretion parameters (CPI, SUIT) also increased significantly. There were no significant differences between groups in changes from baseline HbA1c, insulin secretion capacity, and β-cell function (proinsulin/insulin) at 24 weeks of combination therapy. Multivariate analysis showed that baseline HbA1c was the only predictor for efficacy of combination therapy with sitagliptin and low-dose glimeripide. No changes in body weight were noted and no symptomatic hypoglycemia was documented. These findings indicate that combination therapy with sitagliptin and low-dose glimepiride (0.5 mg/day) is both effective for glycemic control and safe in Japanese patients with type 2 diabetes inadequately controlled with high-dose glimepiride.

Topics: Aged; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Japan; Kidney; Male; Middle Aged; Pyrazines; Severity of Illness Index; Sitagliptin Phosphate; Sulfonylurea Compounds; Triazoles

Treatment decisions for older patients with type 2 diabetes mellitus must balance glycemic control and adverse event risk. The objective of this study was to evaluate the long-term safety and tolerability of saxagliptin 5 mg as add-on therapy to common antihyperglycemic drugs in patients aged ≥ 65 years and <65 years.. Pooled adverse event data from three placebo-controlled trials of 76-206 weeks' duration in older (≥ 65 years) and younger (<65 years) patients receiving saxagliptin 5 mg or matching placebo added to metformin, glyburide, or a thiazolidinedione were analyzed. Measurements were calculated from day of first dose to specified event or last dose and included time at risk for adverse events, treatment-related adverse events, serious adverse events, adverse events leading to discontinuation, and events of special interest. Weighted incidence rates (number of events/total time) and incidence rate ratios (saxagliptin/placebo) with 95% confidence intervals were calculated (Mantel-Haenszel test).. A total of 205 older (mean age 69 years; saxagliptin, n=99; placebo, n=106) and 1,055 younger (mean age 52 years; saxagliptin, n=531; placebo, n=524) patients were assessed. Regardless of age category, the adverse event incidence rates were generally similar between treatments, with confidence intervals for incidence rate ratios bridging 1. Treatment-related adverse events occurred in 36 older patients receiving saxagliptin versus 32 receiving placebo (incidence rate 34.1 versus 27.1 per 100 person-years) and in 150 younger patients in both treatment groups (incidence rate 24.0 versus 27.8 per 100 person-years). With saxagliptin versus placebo, serious adverse events occurred in eight versus 14 older (incidence rate 5.7 versus 9.9 per 100 person-years) and 49 versus 44 younger patients (incidence rate 6.5 versus 6.6 per 100 person-years). There were two deaths (one patient ≥ 65 years) with saxagliptin and six (none aged ≥ 65 years) with placebo. Older patients rarely experienced symptomatic confirmed hypoglycemia (fingerstick glucose ≤ 50 mg/dL; saxagliptin, n=1; placebo, n=2).. Saxagliptin add-on therapy was generally well tolerated in older patients aged ≥ 65 years with type 2 diabetes mellitus, with a long-term safety profile similar to that of placebo.

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Dipeptides; Double-Blind Method; Female; Humans; Incretins; Male; Middle Aged; Placebos; Risk Factors; Treatment Outcome

Sitagliptin inhibits dipeptidyl peptidase-4, which inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. To assess its antidiabetic potency, we used meal tolerance tests (MTTs) to determine the very short-term effects of sitagliptin on plasma concentrations of insulin and glucagon.. On day 1, patients with newly diagnosed or uncontrolled type 2 diabetes mellitus started a calorie-restricted diet. On day 2, the first MTT was performed, before treatment with sitagliptin 50 mg/day started later the same day. On day 5, a second MTT was performed. Area under the concentration-time curves (AUCs) of relevant laboratory values were calculated [AUC from time zero to 2 h (AUC0-2h) and from time zero to 4 h (AUC0-4h)].. Fifteen patients were enrolled. AUCs for postprandial plasma glucose were decreased after 3 days of sitagliptin treatment [AUC0-2h 457 ± 115 mg/dL·h (25.4 ± 6.4 mmol/L·h) to 369 ± 108 mg/dL·h (20.5 ± 6.0 mmol/L·h); AUC0-4h 896 ± 248 mg/dL·h (49.7 ± 13.8 mmol/L·h) to 701 ± 246 mg/dL·h (38.9 ± 13.7 mmol/L·h); both p < 0.001]. AUC0-2h and AUC0-4h for postprandial plasma glucagon also decreased: 195 ± 57 to 180 ± 57 pg/mL·h (p < 0.05) and 376 ± 105 to 349 ± 105 pg/mL·h (p < 0.01), respectively. The AUC0-2h [median with quartile values (25%, 75%)] for active GLP-1 increased: 10.5 (8.5, 15.2) to 26.4 (16.7, 32.4) pmol/L·h (p = 0.03).. Very short-term (3-day) treatment with sitagliptin decreases postprandial plasma glucose significantly. This early reduction in glucose may result partly from suppression of excessive glucagon secretion, through a direct effect on active GLP-1. Improvement in postprandial plasma glucose, through suppression of glucagon secretion, is believed to be an advantage of sitagliptin for the treatment of patients with type 2 diabetes.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Food; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged; Postprandial Period; Sitagliptin Phosphate

To assess changes in circulating incretin levels and body fat compositions with initial combination therapy with α-glucosidase inhibitor and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes (T2D).. In this multicenter open-label 24-week trial, Japanese over-weight (BMI ≥ 25 kg/m(2)) patients with T2D not taking medication or taking metformin and/or sulfonylurea were randomly assigned to receive either 50mg of miglitol three times a day (M, n=14), 50mg of sitagliptin once a day (S, n=14), or a combination of both (M+S, n=13). Changes in plasma incretin levels during a meal tolerance test (MTT) and body fat composition with impedance method were evaluated.. During MTT, postprandial plasma glucose levels decreased more after M+S than after M or S, and postprandial serum insulin levels decreased significantly after M and M+S whereas they increased after S. After M, active gastric inhibitory polypeptide (aGIP) decreased significantly at 30 min despite a significant increase at 120 min. After S, aGIP levels increased significantly throughout the MTT. After M+S, aGIP increased significantly at 0 and 120 min despite of significant decrease at 30 min. M+S further enhanced postprandial active glucagon-like peptide-1 levels during MTT than S did. Total body fat mass decreased significantly after M and M+S. Visceral fat mass decreased significantly only after M+S. Serum adiponectin increased significantly only after M+S.. In over-weight patients with T2D, M+S may have a beneficial effect on adiposity with relation to these different effects on two incretins.

Topics: 1-Deoxynojirimycin; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Incretins; Intra-Abdominal Fat; Japan; Male; Middle Aged; Overweight; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles

Glutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying.. Ten healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline.. ID glutamine stimulated glucagon-like peptide 1 (GLP-1; healthy: P < 0.05; T2DM: P < 0.05), glucose-dependent insulinotropic polypeptide (GIP; P = 0.098; P < 0.05), glucagon (P < 0.01; P < 0.001), insulin (P = 0.05; P < 0.01), and phasic pyloric pressures (P < 0.05; P < 0.05), but did not lower blood glucose (P = 0.077; P = 0.5).. Glutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Duodenum; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glutamine; Healthy Volunteers; Humans; Incretins; Insulin; Insulin Secretion; Male

To assess safety and efficacy of saxagliptin in older patients with type 2 diabetes mellitus (T2DM).. This was a post hoc analysis of pooled data from older patients (≥65 years of age) from five 24-week phase III trials: three studies of saxagliptin versus placebo as an add-on therapy to metformin, glyburide, or a thiazolidinedione; and two studies of saxagliptin versus placebo as monotherapy in drug-naïve patients. Separate analyses were conducted on one study of initial combination therapy with saxagliptin plus metformin versus metformin monotherapy in drug-naïve patients. The safety analysis population for the five-study pool included 428 patients ≥ 65 years of age with baseline glycated hemoglobin (HbA(1c)) 7.0% to 10.5% who received saxagliptin 2.5 or 5 mg or placebo, and for the study of initial combination therapy included 69 patients ≥ 65 years of age with baseline HbA(1c) 8.0% to 12.0% who received saxagliptin 5 mg in combination with metformin or metformin monotherapy. The primary efficacy endpoint was change from baseline HbA(1c).. In the five-study pool, the differences in the adjusted mean change from baseline HbA(1c) among older patients receiving saxagliptin versus placebo were -0.60% (95% confidence interval [CI], -0.99% to -0.21%) for saxagliptin 2.5 mg and -0.55% (-0.97% to -0.14%) for saxagliptin 5 mg; in the initial combination study, the difference was -1.22% (-2.27% to -0.17%) among older patients receiving saxagliptin 5 mg plus metformin versus metformin monotherapy. The results were generally similar in older and younger patients. Saxagliptin was well tolerated; the incidence and types of adverse events were similar for saxagliptin and comparators. Hypoglycemia was reported in 3.0% to 9.4% of patients receiving saxagliptin (0%-8.0% for comparators) and was confirmed (finger stick glucose ≤ 50 mg/dL, with associated symptoms) in 0% to 0.7% (0%-0.7% for comparators); hypoglycemic episodes did not vary by age category and did not require medical intervention.. Saxagliptin was effective and well tolerated, with a low risk of hypoglycemia, when used as monotherapy, add-on therapy, or initial combination therapy with metformin in older patients with T2DM.

Topics: Adamantane; Aged; Aged, 80 and over; Analysis of Variance; Area Under Curve; Diabetes Mellitus, Type 2; Dipeptides; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Male; Metformin; Thiazolidinediones; Treatment Outcome

The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI × 10⁴ min⁻¹·pM⁻¹: 1.11 ± 0.44 vs. 0.62 ± 0.22, P < 0.015, in controls and 0.79 ± 0.34 vs. 0.40 ± 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 ± 1.36 vs. 1.13 ± 0.78 × 10⁶, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 ± 1.05 vs. 1.09 ± 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes.

Topics: Adult; Bariatric Surgery; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Duodenum; Enteral Nutrition; Female; Food; Glucose Intolerance; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Intubation, Gastrointestinal; Jejunum; Male; Middle Aged; Obesity

The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances β-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 × 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.

Topics: Adult; Aged; Chymotrypsin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Genotype; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Receptors, Glucagon; Signal Transduction

Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

Topics: Adult; Animals; Comorbidity; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Glucose; Hemodynamics; Humans; Incretins; Male; Middle Aged; Myocardium; Obesity; Oxygen Consumption; p38 Mitogen-Activated Protein Kinases; Physical Conditioning, Animal; Regional Blood Flow; Rest; Signal Transduction; Swine; Treatment Outcome

We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.

Topics: Acylation; Adolescent; Adult; Aged; Animals; Diabetes Mellitus, Type 2; Exenatide; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Haplorhini; Humans; Hyperglycemia; Incretins; Insulin; Liraglutide; Male; Mice; Middle Aged; Peptides; Rats; Receptors, Gastrointestinal Hormone; Receptors, Glucagon; Rodentia; Treatment Outcome; Venoms; Weight Loss; Young Adult

Metformin monotherapy is recommended as initial treatment of type 2 diabetes. The selection of optimal second-line therapy that is often necessary due to the progressive nature of the disease is still a subject of ongoing discussions.. The aim of the international EDGE (Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) study was to prospectively compare the efficacy and safety of vildagliptin vs other oral antidiabetic agents in patients with type 2 diabetes not adequately controlled on monotherapy in a real-life clinical setting. In this paper, we present the data of patients participating in the EDGE study in the Czech Republic.. Patients with type 2 diabetes not adequately controlled on monotherapy were enrolled into the study, and randomised into either the vildagliptin arm or control arm with another OAD at the discretion of the treating physician. Patients with the addition of other incretin-based medications were not enrolled into the study. The efficiency was evaluated as a proportion of patients reaching the combined endpoint of decreasing HbA1c> 3 mmol/mol without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects during the 12 months of treatment.. 654 patients were enrolled into the study in the Czech Republic. The mean age of the patients when enrolled into the study (vildagliptin group vs control group) was 59.5 ± 10.6 vs 63.7 ± 8.5 years, mean body mass index was 32.4 ± 5.7 vs 31.7 ± 6.5 kg/m2, mean HbA1c was 62 ± 12 vs 64 ± 11 mmol/mol. The probability of reaching the combined primary endpoint (calculated using a binary logistic regression model to calculate the odds ratios with 95% confidence intervals) was higher for vildagliptin regardless of baseline HbA1c or type of medication added in the control group. Primary endpoint was reached by 60.6 % of patients in the vildagliptin group vs 51.3 % of patients in the control group, odds ratio 1.46 (1.06, 1.99); p< 0.019. The proportion of patients reaching secondary endpoint (HbA1c< 54 mmol/mol without hypoglycemic event or weight gain 3 % with baseline glycated hemoglobin > 54 mmol/mol was higher for vildagliptin 45.7 % vs 31.4 % in the control arm, odds ratio 1.84 (1.26, 2.68), p< 0.001. The rate of adverse events was comparable in both groups.. In a real-life clinical set-ting, the percentage of patients reaching the combined endpoint of decreasing HbA1c> 3 mmol/mol, without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects was higher after the addition of vildagliptin as compared to other antidiabetic agents with comparable rate of side effects.

Topics: Adamantane; Adult; Aged; Cohort Studies; Czech Republic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Metformin; Middle Aged; Nitriles; Prospective Studies; Pyrrolidines; Vildagliptin; Weight Gain

Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin.. In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1-2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal.. Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0:30-4:30h) : -12.6 vs. -4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported.. Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide.

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Resistance; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Metformin; Middle Aged; Peptides

Postprandial glucagon-like peptide-1 (GLP-1) secretion and the 'incretin effect' have been reported to be deficient in Type 2 diabetes, but most studies have not controlled for variations in the rate of gastric emptying. We evaluated blood glucose, and plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) responses to intraduodenal glucose in Type 2 diabetes, and compared these with data from healthy controls.. Eight males with well-controlled Type 2 diabetes, managed by diet alone, were studied on four occasions in single-blind, randomized order. Blood glucose, and plasma insulin, GLP-1, and GIP were measured during 120-min intraduodenal glucose infusions at 1 kcal/min (G1), 2 kcal/min (G2) and 4 kcal/min (G4) or saline control.. Type 2 patients had higher basal (P < 0.0005) and incremental (P < 0.0005) blood glucose responses to G2 and G4, when compared with healthy controls. In both groups, the stimulation of insulin and GLP-1 by increasing glucose loads was not linear; responses to G1 and G2 were minimal, whereas responses to G4 were much greater (P < 0.005 for each) (incremental area under the GLP-1 curve 224 ± 65, 756 ± 331 and 2807 ± 473 pmol/l.min, respectively, in Type 2 patients and 373 ± 231, 505 ± 161 and 1742 ± 456 pmol/l.min, respectively, in healthy controls). The GLP-1 responses appeared comparable in the two groups. In both groups there was a load-dependent increase in plasma GIP with no difference between them.. In patients with well-controlled Type 2 diabetes, blood glucose, insulin and GLP-1 responses are critically dependent on the small intestinal glucose load, and GLP-1 responses are not deficient.

Topics: Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 2; Duodenum; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged; Postprandial Period; Single-Blind Method

To compare the effects of miglitol [an alpha-glucosidase inhibitor (AGI) absorbed in the intestine] and voglibose (an AGI not absorbed) on plasma glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels, 26 and 24 Japanese type 2 diabetic patients were randomly assigned to receive miglitol or voglibose, respectively. After 12-week administration of both drugs, during 2-h meal tolerance test, plasma glucose, serum insulin and total GIP were significantly decreased and active GLP-1 was significantly increased. Miglitol group showed a significantly lower total GIP level than voglibose group. Miglitol, but not voglibose, significantly reduced body weight (BW). In all participants, the relative change in BW was positively correlated with that of insulin significantly and of GIP with a weak tendency, but not of GLP-1. In conclusion, both drugs can enhance postprandial GLP-1 responses and reduce GIP responses. The significant BW reduction by miglitol might be attributable to its strong GIP-reducing efficacy.

Topics: 1-Deoxynojirimycin; Asian People; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Inositol; Male; Middle Aged; Obesity; Postprandial Period

G-protein coupled receptor agonists are currently under investigation for their potential utility in patients with type 2 diabetes mellitus (T2DM). The objective was to determine the pharmacokinetics, pharmacodynamics, safety and tolerability of GPR119 agonist, JNJ-38431055 in T2DM subjects.. This was a randomized, double-blind, placebo- and positive-controled, single-dose cross-over study and a randomized, double-blind, placebo-controled multiple-dose parallel design study. The study was conducted at 4 US research centres. Two different experiments involving 25 and 32 different subjects were performed in male and female subjects, aged 25-60 years, mean body mass index between 22 and 39.9 kg/m2 who had T2DM diagnosed 6 months to 10 years before screening. JNJ-38431055 (100 and 500 mg) or sitagliptin (100 mg) as a single-dose or JNJ-38431055 (500 mg) once daily for 14 consecutive days were tested. Effects on stimulated plasma glucose, insulin, C-peptide and incretin concentrations were pre-specified outcomes.. JNJ-38431055 was well tolerated and not associated with hypoglycaemia. Plasma systemic exposure of JNJ-38431055 increased as the dose increased, was approximately two-fold greater after multiple-dose administration, and attained steady-state after approximately 8 days. Compared with placebo, single-dose administration of oral JNJ-38431055 decreased glucose excursion during an oral glucose tolerance test, but multiple-dose administration did not alter 24-h weighted mean glucose. Multiple dosing of JNJ-38431055 increased post-meal total glucagon-like peptide 1 and gastric insulinotropic peptide concentrations compared to baseline.. These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with T2DM.

Topics: Administration, Oral; Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Male; Middle Aged; Pyrazines; Receptors, G-Protein-Coupled; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Individuals with normal glucose tolerance (NGT), whose 1-h postload plasma glucose is ≥155 mg/dL (NGT 1h-high), have an increased risk of type 2 diabetes. The purpose of this study was to characterize their metabolic phenotype.. A total of 305 nondiabetic offspring of type 2 diabetic patients was consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp.. Compared with individuals with a 1-h postload plasma glucose <155 mg/dL (NGT 1h-low), NGT 1h-high individuals exhibited lower insulin sensitivity after adjustment for age, sex, and BMI. Insulin secretion estimated from the OGTT did not differ between the two groups of individuals. By contrast, compared with NGT 1h-low individuals, the acute insulin response during an IVGTT and the disposition index were significantly reduced in NGT 1h-high individuals after adjustment for age, sex, and BMI. Incretin effect, estimated as the ratio between total insulin responses during OGTT and IVGTT, was higher in NGT 1h-high individuals compared with NGT 1h-low individuals.. NGT 1h-high individuals may represent an intermediate state of glucose intolerance between NGT and type 2 diabetes characterized by insulin resistance and reduced β-cell function, the two main pathophysiological defects responsible for the development of type 2 diabetes. Postload hyperglycemia is the result of an intrinsic β-cell defect rather than impaired incretin effect.

Topics: Adult; Blood Glucose; Child of Impaired Parents; Diabetes Mellitus, Type 2; Europe; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Time Factors; Up-Regulation; Young Adult

To compare duodenal-jejunal bypass (DJB) with standard medical care in nonobese patients with type 2 diabetes and evaluate surgically induced endocrine and metabolic changes.. Eighteen patients submitted to a DJB procedure met the following criteria: overweight, diabetes diagnosis less than 15 years, current insulin treatment, residual β-cell function, and absence of autoimmunity. Patients who refused surgical treatment received standard medical care (control group). At baseline, 3, 6, and 12 months after surgery, insulin sensitivity and production of glucagon-like peptide-1 and glucose-insulinotropic polypeptide were assessed during a meal tolerance test. Fasting adipocytokines and dipeptidyl-peptidase-4 concentrations were measured.. The mean age of the patients was 50 (5) years, time of diagnosis: 9 (2) years, time of insulin usage: 6 (5) months, fasting glucose: 9.9 (2.5) mmol/dL, and HbA1c (glycosylated hemoglobin) level: 8.9% (1.2%). Duodenal-jejunal bypass group showed greater reductions in fasting glucose (22% vs 6% in control group, P < 0.05) and daily insulin requirement (93% vs 15%, P < 0.01). Twelve patients from DJB group stopped using insulin and showed improvements in insulin sensitivity and β-cell function (P < 0.01), and reductions in glucose-insulinotropic polypeptide levels (P < 0.001), glucagon during the first 30 minutes after meal (P < 0.05), and leptin levels (P < 0.05). Dipeptidyl-peptidase-4 levels increased after surgery (P < 0.01), but glucagon-like peptide-1 levels did not change.. Duodenal-jejunal bypass improved insulin sensitivity and β-cell function and reduced glucose-insulinotropic polypeptide, leptin, and glucagon production. Hence, DJB resulted in better glycemic control and reduction in insulin requirement but DJB did not result in remission of diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Dipeptidyl Peptidase 4; Duodenum; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin Resistance; Jejunum; Middle Aged

In order to quantify the role of incretins in first- and second-phase insulin secretion (ISR) in type 2 diabetes mellitus (T2DM), a double-blind, randomized study with 12 T2DM subjects and 12 healthy subjects (HS) was conducted using the hyperglycemic clamp technique together with duodenal nutrition perfusion and intravenous infusion of the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). Intravenous glucose alone resulted in a significantly greater first- and second-phase ISR in HS compared with T2DM subjects. Duodenal nutrition perfusion augmented both first- and second-phase ISR but first-phase ISR more in T2DM subjects (approximately eight- vs. twofold). Glucose-related stimulation of ISR contributed only 20% to overall ISR. Infusion with exendin(9-39) significantly reduced first- and second-phase ISR in both HS and T2DM subjects. Thus, both GLP-1 and non-GLP-1 incretins contribute to the incretin effect. In conclusion, both phases of ISR are impaired in T2DM. In particular, the responsiveness to glucose in first-phase ISR is blunted. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretions are unaltered. The absolute incretin effect is reduced in T2DM; its relative importance, however, appears to be increased, highlighting its role as an important amplifier of first-phase ISR in T2DM.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Clamp Technique; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged; Peptide Fragments; Receptors, Glucagon

To assess the safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus (T2DM).. This randomized, single-blind, placebo-controlled, monotherapy study was carried out in two parts. In part A, 32 patients received AZD1656 (7, 20, 40 or 80 mg) twice daily or placebo for 8 days in hospital. In part B, another 20 patients received, as outpatients, individually titrated AZD1656 15-45 mg twice daily or placebo for 28 days. Safety, pharmacokinetics and pharmacodynamic variables were evaluated.. AZD1656 was generally well tolerated. Pharmacokinetics of AZD1656 were virtually dose- and time-independent. AZD1656 was rapidly absorbed and eliminated. An active metabolite was formed which had a longer half-life than AZD1656, but showed ∼15% of the area under the plasma concentration versus time curve from 0 to 24 h compared with that of AZD1656. Renal excretion of AZD1656 and the metabolite was low. In part A, fasting plasma glucose (FPG) was reduced by up to 21% and mean 24-h plasma glucose was reduced by up to 24% with AZD1656 versus placebo, depending on dose. No dose-related changes in serum insulin or C-peptide were observed with AZD1656 at the end of treatment. Results in part B confirmed the glucose-lowering effect of AZD1656 versus placebo.. AZD1656 was well tolerated with predictable pharmacokinetics in patients with T2DM. Dose-dependent reductions in plasma glucose were observed.

Topics: Adult; Azetidines; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucokinase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Peptide Fragments; Pyrazines; Single-Blind Method; Treatment Outcome

Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes.. Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m(2); glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR).. V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g. AUC(ISR oral), by 32.7%, P = 0.0006; AUC(ISR iv), by 33.1%, P = 0.01). The numerical incretin effect was not changed (IE(ISR), V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80).. DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

Topics: Adamantane; Administration, Oral; Adult; Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucose; Humans; Incretins; Injections, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged; Nitriles; Pyrrolidines; Up-Regulation; Vildagliptin

To determine whether short-term strict glycaemic control could restore incretin secretion in type 2 diabetic patients. The factors associated with incretin levels were also investigated.. A meal tolerance test (MTT) was performed in eighteen poorly controlled (pDM) and fifteen well controlled (wDM) diabetic patients. Fourteen patients in the pDM group underwent follow-up MTT after strict glycaemic control. The secretions of intact glucagon-like peptide-1 (iGLP-1) and total glucose-dependent insulinotropic polypeptide (tGIP) during MTT were calculated by total and incremental area under the curve (TAUC and IAUC) values.. Posttreatment HbA1c level was significantly improved in the pDM group (11.2±0.9 to 7.9±0.9%). However, the secretion of incretin hormones was not increased in the posttreatment pDM group (TAUCiGLP-1, 3612±587 to 2916±405 pmol/L min; TAUCtGIP, 9417±1099 to 8338±903 pmol/L min). IAUCiGLP-1 was negatively correlated (r=-0.446, P=0.011) and independently associated (β=-137.2, P=0.027) with insulin resistance assessed by homeostasis model assessment.. Incretin secretion is not restored by short-term strict glycaemic control. Decreased incretin secretion seems to develop early in the course of type 2 diabetes with increasing insulin resistance, but not to be influenced by glycaemic status.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Male; Middle Aged

The incretin glucagon-like peptide 1 (GLP-1) exerts insulinotropic activity in type 2 diabetic patients, whereas glucose-dependent insulinotropic polypeptide (GIP) no longer does. We studied whether GIP can alter the insulinotropic or glucagonostatic activity of GLP-1 in type 2 diabetic patients.. Twelve patients with type 2 diabetes (nine men and three women; 61 ± 10 years; BMI 30.0 ± 3.7 kg/m²; HbA(1c) 7.3 ± 1.5%) were studied. In randomized order, intravenous infusions of GLP-1(7-36)-amide (1.2 pmol · kg⁻¹ · min⁻¹), GIP (4 pmol · kg⁻¹ · min⁻¹), GLP-1 plus GIP, and placebo were administered over 360 min after an overnight fast (≥ 1 day wash-out period between experiments). Capillary blood glucose, plasma insulin, C-peptide, glucagon, GIP, GLP-1, and free fatty acids (FFA) were determined.. Exogenous GLP-1 alone reduced glycemia from 10.3 to 5.1 ± 0.2 mmol/L. Insulin secretion was stimulated (insulin, C-peptide, P < 0.0001), and glucagon was suppressed (P = 0.009). With GIP alone, glucose was lowered slightly (P = 0.0021); insulin and C-peptide were stimulated to a lesser degree than with GLP-1 (P < 0.001). Adding GIP to GLP-1 did not further enhance the insulinotropic activity of GLP-1 (insulin, P = 0.90; C-peptide, P = 0.85). Rather, the suppression of glucagon elicited by GLP-1 was antagonized by the addition of GIP (P = 0.008). FFA were suppressed by GLP-1 (P < 0.0001) and hardly affected by GIP (P = 0.07).. GIP is unable to further amplify the insulinotropic and glucose-lowering effects of GLP-1 in type 2 diabetes. Rather, the suppression of glucagon by GLP-1 is antagonized by GIP.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Drug Interactions; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Male; Middle Aged

Fasting and postprandial plasma glucose (FPG, PPG) control are both necessary to achieve glycosylated hemoglobin (HbA(1c)) regulation goals. Liraglutide, based on its glucagon-like peptide 1 (GLP-1)-mediated pharmacology and pharmacokinetics may reduce HbA(1c) through both FPG and PPG levels. The objective of the present study was to investigate the effect of once-daily liraglutide (0.6, 1.2, and 1.8 mg) at steady state on FPG, PPG, postprandial insulin, and gastric emptying.. Eighteen subjects with type 2 diabetes, aged 18-70 years, with a body mass index of 18.5-40 kg/m(2) and HbA(1c) of 7.0%-9.5% were included in this single-centre, randomized, placebo-controlled, double-blind, two-period, cross over trial. Patients were randomized into two groups (A or B). Group A received oncedaily liraglutide for 3 weeks, followed by a 3-4-week washout period and 3 weeks of oncedaily placebo. Group B was treated as for Group A, but treatment periods were reversed (ie, placebo followed by liraglutide). A meal test was performed at steady-state liraglutide/placebo doses of 0.6, 1.2, and 1.8 mg/day. Plasma glucose, insulin, and paracetamol (acetaminophen) concentrations (to assess gastric emptying) were measured pre- and postmeal.. PPG levels significantly decreased (P<0.001) after all three liraglutide doses when compared with placebo. This decrease was also apparent when corrected for baseline (incremental excursions), with the exception of average incremental increase calculated as area under the concentration curve (AUC) over the fasting value from time zero to 5 hours (iAUC (0-5 h)/5 hours) after liraglutide 0.6 mg, where there was a trend to decrease (P=0.082). In addition, FPG levels significantly decreased at all three liraglutide dose levels when compared to placebo (P<0.001). Fasting and postprandial insulin levels significantly increased with liraglutide versus placebo at all doses studied (P<0.001). A significant delay in gastric emptying during the first hour postmeal was observed at the two highest liraglutide doses versus placebo.. In addition to lowering FPG levels, liraglutide improves PPG levels (absolute and incremental) possibly by both stimulating postprandial insulin secretion and delaying gastric emptying.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Liraglutide; Male; Middle Aged; Postprandial Period; Young Adult

Omentin is a protein expressed and secreted from visceral but not subcutaneous adipose tissue, which increases insulin sensitivity in human adipocytes. However, its pathophysiologic role in humans remains largely unknown. The objective of this study is to assess plasma omentin-1 levels in patients with type 2 diabetes mellitus (T2DM) and matched control subjects and to investigate the effects of liraglutide on plasma omentin-1 levels in patients with T2DM.. Thirty T2DM patients with poor glycemic control after more than 3 months of treatment with one or two OHA(s) (T2DM), and 30 matched normal glycaemic controls (NGT) participated in the study. The T2DM group was given an injection of liraglutide once-daily for 16 weeks. Plasma omentin-1 levels were measured by enzyme-linked immunosorbent assay and the relationship between plasma omentin-1 levels and metabolic parameters was also analyzed.. Plasma omentin-1 levels were lower in T2DM than in the control (19.3 ± 4.0 μg/L vs. 26.4 ± 6.0 μg/L, P < 0.01). Plasma omentin-1 levels increased significantly in T2DM patients after treatment with liraglutide compared with pre-treatment (19.3 ± 4.0 μg/L vs. 21.2 ± 3. 9 μg/L, P < 0.01). In all diabetic patients, multiple regression analysis showed that FINS and HOMA-IR were independently associated with plasma omentin-1 levels.. In T2DM patients, plasma omentin-1 levels decreased, but significantly increased after the treatment with liraglutide and metformin. These data suggest that liraglutide may play a role in increasing omentin-1 levels in T2DM patients.

Topics: Adolescent; Adult; Aged; Cytokines; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; GPI-Linked Proteins; Humans; Incretins; Lectins; Liraglutide; Male; Middle Aged; Young Adult

We evaluated how a structured patient/physician self-monitoring of blood glucose (SMBG) intervention influenced the timing, frequency, and effectiveness of primary care physicians' treatment changes with type 2 diabetes mellitus (T2DM) patients over 12 months.. The Structured Testing Program (STeP) study was a cluster-randomized, multicenter trial with 483 poorly controlled, insulin-naive T2DM subjects. Primary care practices were randomized to the Active Control Group (ACG) or the Structured Testing Group (STG), the latter of which included quarterly review of structured SMBG results. STG patients used a paper tool that graphs seven-point glucose profiles over 3 consecutive days; physicians received a treatment algorithm based on SMBG patterns. Impact of structured SMBG on physician treatment modification recommendations (TMRs) and glycemic outcomes was examined.. More STG than ACG patients received a TMR at each study visit (P < 0.0001). Of patients who received at least one TMR, STG patients demonstrated a greater reduction in glycated hemoglobin A1c (HbA1c) than ACG patients (-1.2% vs. -0.8%, P < 0.03). Patients with a baseline HbA1c ≥8.5% who received a TMR at the Month 1 visit experienced greater reductions in HbA1c (P = 0.002) than patients without an initial TMR. More STG than ACG patients were started on incretins (P < 0.01) and on thiazolidinediones (P = 0.004). The number of visits with a TMR was unrelated to HbA1c change over time.. Patient-provided SMBG data contribute to glycemic improvement when blood glucose patterns are easy to detect, and well-trained physicians take timely action. Collaborative use of structured SMBG data leads to earlier, more frequent, and more effective TMRs for poorly controlled, non-insulin-treated T2DM subjects.

Topics: Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Linear Models; Male; Middle Aged; Physicians, Primary Care; Thiazolidinediones

We hypothesize that type 2 diabetic patients with different phenotypes may show different response to incretin-based therapies. Therefore, we tested whether the presence of metabolic syndrome (MS) influences glycemic response to these drugs. We prospectively followed 211 patients, treated with the GLP-1 analog exenatide (n = 102) or a DPP-4 inhibitor (n = 109) for at least 4 months. Treatment was decided on clinical grounds. We collected baseline data (age, sex, BMI, waist, systolic and diastolic blood pressure, lipid profile, data on diabetic complications and concomitant treatment) and HbA1c at subsequent visits. Patients were divided into groups according to the presence/absence of MS. Compared to patients on exenatide, patients on DPP-4 inhibitors were older and had lower BMI, waist, diastolic blood pressure, fasting plasma glucose, and HbA1c. At means of baseline values, HbA1c reduction was similar in patients treated with exenatide or DPP-4 inhibitors. Patients on exenatide showed significantly higher HbA1c reduction if they had MS (-1.55 ± 0.22%; n = 88) than if they had not (-0.34 ± 0.18%; P = 0.002). Conversely, patients on DPP-4 inhibitors showed significantly lower HbA1c reduction if they had MS (-0.60 ± 0.12%; n = 73) than if they had not (-1.50 ± 0.24%; P < 0.001). Type of MS definition (ATP-III, IDF or WHO) poorly influenced these trends. The interaction between type of therapy (exenatide vs. DPP-4 inhibitors) and MS remained significant after adjusting for age, baseline HbA1c, BMI, and concomitant medications. In conclusion, the presence of MS appears to modify the response to incretin-based therapies. Given the non-randomized nature of this study, these data need to be replicated.

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Metabolic Syndrome; Middle Aged; Nitriles; Peptides; Prognosis; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms; Vildagliptin

Glucagon-like peptide 1 (GLP-1) is a peptide produced in the endocrine L cells of the distal intestine. GLP-1(7-36)NH2 is a major molecular form that stimulates insulin release, reduces food intake, and has a potential to promote beta-cell regeneration. We have developed a device for intranasal application of GLP-1(7-36)NH2 and completed a double-blind clinical trial of intranasal administration of GLP-1(7-36)NH2 to 26 type II diabetic patients. Intranasal administration of GLP-1 increased its plasma level, stimulated postprandial insulin release, and suppressed glucagon release. Two-week intranasal administration of GLP-1 just before meals significantly decreased serum glycoalbumin level and significantly increased 1,5-AG (1,5-anhydro-D-glucitol) level. Hypoglycemia was not found through this study. Intranasal GLP-1 administration using the novel device and medication improved glycemic control in type 2 diabetic patients without any adverse effects.

Topics: Administration, Intranasal; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Delivery Systems; Equipment Design; Glucagon-Like Peptide 1; Humans; Incretins

To examine the effects of glibenclamide and repaglinide on glucose stimulated insulin release, incretins, oxidative stress and cell adhesion molecules in patients with type 2 diabetes suboptimally treated with metformin.. A randomized clinical trial was performed recruiting 27 subjects (HbA(1c) between 7.5 and 10.5%) free from cardiovascular and renal disease. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), total antioxidant status, F(2)-isoprostane, interleukin-6 and cell adhesion molecules were measured during an oral glucose load at baseline and after eight weeks of treatment. The areas under the curve were analysed at 45, 60 and 120 min (AUC(45), AUC(60), AUC(120)).. Significant improvements in glucose were observed with repaglinide (HBA(1c): -1.5%, fasting glucose: -2.8 mmol/L, 2-h glucose: -3.7 mmol/L, AUC(120): -18.9%) and glibenclamide (-1.0%, -2.2 mmol/L, -2.5 mmol/L, -17.5%). Repaglinide was also associated with an increase in the AUC(60) and AUC(120) for insulin (+56%, +61%) and C-peptide (+41%, +36%). GLP-1, GIP, IL-6, ICAM-1 and E-selectin levels did not change in either group. No association was observed between GLP-1, GIP-1 and plasma markers of oxidative stress.. Repaglinide is associated with improved postprandial glycaemic control via insulin and C-peptide release. We observed no direct effects of glibenclamide or repaglinide on plasma levels of GLP-1 or GIP. We observed no associations of GLP-1 and GIP with plasma markers of oxidative stress.

Topics: Adult; Aged; Analysis of Variance; Biomarkers; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; E-Selectin; F2-Isoprostanes; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Metformin; Middle Aged; Oxidative Stress; Piperidines; Postprandial Period; Time Factors; Treatment Outcome; Wales

Exaggerated and prolonged postprandial lipemia is potentially atherogenic and associated with type 2 diabetes. Limited data exist regarding the influence of dietary protein on postprandial lipemia in type 2 diabetes. We investigated, over 8-h, the acute effects of casein alone or in combination with carbohydrate on postprandial lipid and incretin responses to a fat-rich meal in type 2 diabetes.. Eleven type 2 diabetic subjects ingested four test meals in random order: an energy-free soup plus 80 g of fat (control-meal); control-meal plus 45 g carbohydrates (CHO-meal); control-meal plus 45 g of casein (PRO-meal); and PRO-meal plus 45 g carbohydrates (CHO+PRO-meal). Triglyceride and retinyl palmitate responses were measured in plasma and in a chylomicron-rich and chylomicron-poor fraction. We found no significant differences in triglyceride responses to PRO- and CHO+PRO-meal compared to the control-meal. However, the addition of casein to the CHO-meal reduced the raised triglyceride response in the chylomicron-rich fraction. Retinyl palmitate responses did not differ significantly between meals in the chylomicron-rich fraction, whereas the PRO-meal increased retinyl palmitate in the chylomicron-poor fraction. PRO- and PRO+CHO-meal increased insulin and glucagon compared to the control-meal. PRO+CHO-meal increased the glucose-dependent insulinotropic peptide response while no change in glucagon-like peptide-1 responses was detected.. The data presented suggest that casein per se did not modulate the postprandial triglyceride response in type 2 diabetes. When added to carbohydrate, casein suppressed the triglyceride response in the chylomicron-rich fraction, increased insulin and glucagon but did not affect the incretin responses.

Topics: Aged; Biomarkers; Blood Glucose; Caseins; Chylomicrons; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Diterpenes; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Postprandial Period; Retinyl Esters; Time Factors; Triglycerides; Vitamin A

This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood glucose (BG) using insulin (mean diurnal BG: 6.4+/-0.3 mmol/l; HbA(1)c: 6.6+/-0.3%). Nine matched healthy subjects acted as controls. In controls, area-under-curve (AUC) for amylin, C-peptide and proinsulin were higher with GLP-1 than saline (P<0.001). The AUC amylin/C-peptide ratio was similar on both days, while AUC proinsulin/C-peptide ratio was higher with GLP-1 (P=0.02). In the patients, amylin, C-peptide and proinsulin AUCs were unaltered by near-normoglycaemia per se. Proinsulin responses to GLP-1 were unchanged, but amylin and C-peptide AUCs increased (P<0.05) after insulin treatment, and AUC amylin/C-peptide ratios rose to control levels. Near-normoglycaemia tended to reduce AUC proinsulin/C-peptide ratio, which was significant (P=0.04) with GLP-1, but still higher than with saline (P=0.004). In conclusion, amylin, C-peptide and proinsulin responses to glucose were unaffected by four weeks of near-normoglycaemia, whereas GLP-1 increased amylin and C-peptide secretion and amylin/C-peptide ratio. Near-normoglycaemia reduced proinsulin/C-peptide ratio during stimulation with GLP-1, suggesting that strict glycaemic control might ameliorate some of the disturbances in beta-cell function characterizing T2DM.

Topics: Amyloid; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Male; Middle Aged; Proinsulin; Time Factors

Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes.. One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months.. Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide.. Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Female; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Peptides; Proinsulin; Resistin; Retinol-Binding Proteins, Plasma; Venoms; Young Adult

alpha-glucosidase inhibitors (alphaGIs) increase active glucagon-like peptide-1 (GLP-1) and reduce the total glucosedependent insulinotropic polypeptide (GIP) levels, but their ability to prevent diabetes remains uncertain. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, increase active GLP-1 and GIP levels and improve hyperglycemia in a glucose-dependent fashion. However, the effectiveness of their combination in subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) is uncertain. The present study evaluated the effect of miglitol, sitagliptin, and their combination on glucose, insulin and incretin levels in non-diabetic men. Miglitol and sitagliptin were administered according to four different intake schedules (C: no drug, M: miglitol; S: sitagliptin, M+S: miglitol and sitagliptin). The plasma glucose levels were significantly lower for M, S and M+S than for the control. The areas under the curve (AUCs) of the plasma active GLP-1 level in the M, S, and M+S groups were significantly greater than that in the control group. The AUC of the plasma active GLP-1 level was significantly greater for M+S group than for the M and S groups. The AUC of the plasma total GIP level was significantly smaller for M+S group than for the control and M and S groups. The results of our study suggest that miglitol, sitagliptin, or their combination contributes to the prevention of type 2 diabetes.

Topics: 1-Deoxynojirimycin; Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme Inhibitors; Food; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Kinetics; Male; Pyrazines; Sitagliptin Phosphate; Triazoles

Post-prandial hyperglycemia, hyperlipidemia, and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis. Improvement in post-prandial hyperglycemia on alpha-glucosidase inhibitors (alpha-GIs) is associated with a risk reduction of cardiovascular diseases, but the post-prandial effects of alpha-GIs on endothelial function and incretin secretion in type 2 diabetic patients with coronary artery disease (CAD) remain unclear.. The post-prandial effects of a single administration of miglitol and voglibose on endothelial function and changing levels of glucose, insulin, lipids, glucagon-like peptide (GLP)-1, and gastric inhibitory polypeptide (GIP) were compared after a standard meal loading in 11 diabetic patients with CAD, using a placebo-controlled cross-over design. The changing levels of glucose, insulin and triglycerides at 60 min were significantly lower in the miglitol group than in the voglibose and placebo groups (all P<0.01). GLP-1 levels were significantly higher at 120 min (P<0.05) and GIP levels were significantly lower at 30 min and 60 min (P<0.05) in the miglitol group compared to other treatments. The reactive hyperemia duration at 120 min was significantly maintained in the miglitol group compared to the other groups.. A single administration of miglitol significantly improved post-prandial glucose/lipid metabolism, incretin secretion, and endothelial dysfunction in diabetic patients with CAD, suggesting that miglitol may be a useful anti-atherogenic agent (UMIN000002264).

Topics: 1-Deoxynojirimycin; Aged; Coronary Artery Disease; Coronary Disease; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; Female; Glucose; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Inositol; Lipid Metabolism; Male; Middle Aged; Treatment Outcome

Continuously administered insulin is limited by the need for frequent blood glucose measurements, dose adjustments, and risk of hypoglycemia. Regimens based on glucagon-like peptide 1 (GLP-1) could represent a less complicated treatment alternative. This alternative might be advantageous in hyperglycemic patients hospitalized for acute critical illnesses, who benefit from near normoglycemic control.. In a prospective open randomized crossover trial, we investigated eight clinically stable type 2 diabetic patients during intravenous insulin or GLP-1 regimens to normalize blood glucose after a standardized breakfast.. The time to reach a plasma glucose below 115 mg/dl was significantly shorter during GLP-1 administration (252 +/- 51 vs. 321 +/- 43 min, P < 0.01). Maximum glycemia (312 +/- 51 vs. 254 +/- 48 mg/dl, P < 0.01) and glycemia after 2 h (271 +/- 51 vs. 168 +/- 48 mg/dl, P = 0.012) and after 4 h (155 +/- 51 vs. 116 +/- 27 mg/dl, P = 0.02) were significantly lower during GLP-1 administration.. GLP-1 infusion is superior to an established insulin infusion regimen with regard to effectiveness and practicability.

Topics: Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged

* Patients with Type 2 diabetes are likely to have or to develop renal impairment, which affects the pharmacokinetics of some antidiabetic treatments. * Whether dosing of the once-daily human glucagon-like peptide-1 analogue liraglutide should be modified in patients with renal impairment has not previously been studied.. * Renal dysfunction was not found to increase the exposure of liraglutide. * Hence, no dose adjustment is expected to be required in patients with Type 2 diabetes and renal impairment treated with liraglutide.. To investigate whether dose adjustment of the once-daily human glucagon-like peptide-1 analogue liraglutide is required in patients with varying stages of renal impairment.. A cohort of 30 subjects, of whom 24 had varying degrees of renal impairment and six had normal renal function, were given a single dose of liraglutide, 0.75 mg subcutaneously, and completed serial blood sampling for plasma liraglutide measurements for pharmacokinetic estimation.. No clear trend for change in pharmacokinetics was evident across groups with increasing renal dysfunction. While the between-group comparisons of the area under the liraglutide concentration-curve (AUC) did not demonstrate equivalence [estimated ratio AUC(severe)/AUC(healthy) 0.73, 90% confidence interval (CI) 0.57, 0.94; and AUC (continuous ambulatory peritoneal dialysis)(CAPD)/AUC(healthy) 0.74, 90% CI 0.56, 0.97], the regression analysis of log(AUC) for subjects with normal renal function and mild-to-severe renal impairment showed no significant effect of decreasing creatinine clearance on the pharmacokinetics of liraglutide. The expected AUC ratio between the two subjects with the lowest and highest creatinine clearance in the study was estimated to be 0.88 (95% CI 0.58, 1.34) (NS). Degree of renal impairment did not appear to be associated with an increased risk of adverse events.. This study indicated no safety concerns regarding use of liraglutide in patients with renal impairment. Renal dysfunction was not found to increase exposure of liraglutide, and patients with Type 2 diabetes and renal impairment should use standard treatment regimens of liraglutide. There is, however, currently limited experience with liraglutide in patients beyond mild-stage renal disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Area Under Curve; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptide 1; Humans; Incretins; Kidney; Liraglutide; Male; Middle Aged; New Zealand; Young Adult

To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled intravenous glucose tolerance test.. The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity.. Fourteen weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine-stimulated insulin secretion during hyperglycaemia.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Islets of Langerhans; Liraglutide; Male; Middle Aged; Receptors, Glucagon; Treatment Outcome

The aim of this study was to determine the effect of diabetic autonomic neuropathy (AN) on the incretin effect in patients with type 2 diabetes mellitus (DM2).. Forty patients with DM2 (20 with and 20 without AN) and 10 healthy controls were studied. The subjects underwent an oral glucose tolerance test (OGTT) and 7-14 days later an intravenous infusion of 25 g glucose. Blood samples were drawn for glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) determination during the tests. The incretin effect was calculated from the total integrated amount of insulin or C-peptide during OGTT (A) and intravenous glucose infusion (B) according to the formula (A-B)/Ax100.. Total insulin and C-peptide responses during OGTT were significantly higher than those after IV glucose infusion in the group of normal subjects, but not in the groups of diabetic patients. After the oral glucose load, GIP levels presented a significant increase in normal subjects and patients without AN, whereas GLP-1 levels increased only in normal subjects. Calculated either with the insulin or C-peptide responses, the incretin effect presented no significant difference between the two diabetic groups. However, using insulin responses, only the patients with AN had significantly lower incretin effect than controls, whereas when using C-peptide responses, both diabetic groups did.. The incretin effect was impaired in both groups of diabetic patients. Autonomic neuropathy may further impair the incretin effect in DM2 through interference with GIP secretion or hepatic insulin extraction.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Health; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male

Topics: Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Male; Middle Aged

To study the effects of three weight-maintenance diets with different macronutrient composition on carbohydrate, lipid metabolism, insulin and incretin levels in insulin-resistant subjects.. A prospective study was performed in eleven (7 W, 4 M) offspring of obese and type 2 diabetes patients. Subjects had a BMI > 25 Kg/m2, waist circumference (men/women) > 102/88, HBA1c < 6.5% and were regarded as insulin-resistant after an OGTT (Matsuda ISIm <4). They were randomly divided into three groups and underwent three dietary periods each of 28 days in a crossover design: a) diet high in saturated fat (SAT), b) diet rich in monounsaturated fat (MUFA; Mediterranean diet) and c) diet rich in carbohydrate (CHO).. Body weight and resting energy expenditure did not changed during the three dietary periods. Fasting serum glucose concentrations fell during MUFA-rich and CHO-rich diets compared with high-SAT diets (5.02 +/- 0.1, 5.03 +/- 0.1, 5.50 +/- 0.2 mmol/L, respectively. Anova < 0.05). The MUFA-rich diet improved insulin sensitivity, as indicated by lower homeostasis model analysis-insulin resistance (HOMA-ir), compared with CHO-rich and high-SAT diets (2.32 +/- 0.3, 2.52 +/- 0.4, 2.72 +/- 0.4, respectively, Anova < 0.01). After a MUFA-rich and high-SAT breakfasts (443 kcal) the postprandial integrated area under curve (AUC) of glucose and insulin were lowered compared with isocaloric CHO-rich breakfast (7.8 +/- 1.3, 5.84 +/- 1.2, 11.9 +/- 2.7 mmol . 180 min/L, Anova < 0.05; and 1004 +/- 147, 1253 +/- 140, 2667 +/- 329 pmol . 180 min/L, Anova <0.01, respectively); while the integrated glucagon-like peptide-1 response increased with MUFA and SAT breakfasts compared with isocaloric CHO-rich meals (4.22 +/- 0.7, 4.34 +/- 1.1, 1.85 +/- 1.1, respectively, Anova < 0.05). Fasting and postprandial HDL cholesterol concentrations rose with MUFA-rich diets, and the AUCs of triacylglycerol fell with the CHO-rich diet. Similarly fasting proinsulin (PI) concentration fell, while stimulated ratio PI/I was not changed by MUFA-rich diet.. Weight maintenance with a MUFA-rich diet improves HOMA-ir and fasting proinsulin levels in insulin-resistant subjects. Ingestion of a virgin olive oil-based breakfast decreased postprandial glucose and insulin concentrations, and increased HDL-C and GLP-1 concentrations as compared with CHO-rich diet.

Topics: Analysis of Variance; Area Under Curve; Blood Glucose; Calorimetry, Indirect; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Fats, Unsaturated; Fatty Acids; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Obesity; Postprandial Period; Prospective Studies

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to treat patients with type 2 diabetes since 2005 and have become popular because of the efficacy and durability in relation to glycaemic control in combination with weight loss in most patients. Today in 2022, seven GLP-1 RAs, including oral semaglutide are available for treatment of type 2 diabetes. Since the efficacy in relation to reduction of HbA1c and body weight as well as tolerability and dosing frequency vary between agents, the GLP-1 RAs cannot be considered equal. The short acting lixisenatide showed no cardiovascular benefits, while once daily liraglutide and the weekly agonists, subcutaneous semaglutide, dulaglutide, and efpeglenatide, all lowered the incidence of cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs reduce the progression of diabetic kidney disease. In the 2019 consensus report from European Association for the Study of Diabetes/American Diabetes Association, GLP-1 RAs with demonstrated cardio-renal benefits (liraglutide, semaglutide and dulaglutide) are recommended after metformin to patients with established cardiovascular diseases or multiple cardiovascular risk factors. European Society of Cardiology suggests starting with a sodium-glucose cotransprter-2 inhibitor or a GLP-1 RA in drug naïve patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (CVD) or high CV Risk. However, the results from cardiovascular outcome trials (CVOT) are very heterogeneous suggesting that some GLP-1RAs are more suitable to prevent CVD than others. The CVOTs provide a basis upon which individual treatment decisions for patients with T2D and CVD can be made.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide

Mechanisms of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor dual-agonist in glycemic control and/or weight loss.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

The epicardial adipose tissue, which is referred to as fats surrounding the myocardium, is an active organ able to induce cardiovascular problems in pathophysiologic conditions through several pathways, such as inflammation, fibrosis, fat infiltration, and electrophysiologic problems. So, control of its volume and thickness, especially in patients with diabetes, is highly important. Incretin-based pharmacologic agents are newly developed antidiabetics that could provide further cardiovascular benefits through control and modulating epicardial adiposity. They can reduce cardiovascular risks by rapidly reducing epicardial adipose tissues, improving cardiac efficiency. We are at the first steps of a long way, but current evidence demonstrates the sum of possible mechanisms. In this study, we evaluate epicardial adiposity in physiologic and pathologic states and the impact of incretin-based drugs.

Topics: Adiposity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Obesity; Pericardium

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Risk Assessment

The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), are prime therapeutic targets for the treatment of type 2 diabetes (T2D) and obesity. They are expressed in pancreatic beta cells where they potentiate insulin release in response to food intake. Despite GIP being the main incretin in healthy individuals, GLP-1R has been favored as a therapeutic target due to blunted GIPR responses in T2D patients and conflicting effects of GIPR agonists and antagonists in improving glucose tolerance and preventing weight gain. There is, however, a recently renewed interest in GIPR biology, following the realization that GIPR responses can be restored after an initial period of blood glucose normalization and the recent development of dual GLP-1R/GIPR agonists with superior capacity for controlling blood glucose levels and weight. The importance of GLP-1R trafficking and subcellular signaling in the control of receptor outputs is well established, but little is known about the pattern of spatiotemporal signaling from the GIPR in beta cells. Here, we have directly compared surface expression, trafficking, and signaling characteristics of both incretin receptors in pancreatic beta cells to identify potential differences that might underlie distinct pharmacological responses associated with each receptor. Our results indicate increased cell surface levels, internalization, degradation, and endosomal vs plasma membrane activity for the GLP-1R, while the GIPR is instead associated with increased plasma membrane recycling, reduced desensitization, and enhanced downstream signal amplification. These differences might have potential implications for the capacity of each incretin receptor to control beta cell function.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin-Secreting Cells; Receptors, Gastrointestinal Hormone

Amino acids powerfully release glucagon but their contribution to postprandial hyperglucagonemia in type 2 diabetes remains unclear. Exogenously applied GIP stimulates, while GLP-1 inhibits, glucagon secretion in humans. However, their role in mixed meals is unclear, which we therefore characterized.. In three experiments, participants with type 2 diabetes and obese controls randomly received different loads of sugars and/or proteins. In the first experiment, participants ingested the rapidly cleaved saccharose (SAC) or slowly cleaved isomaltulose (ISO) which is known to elicit opposite profiles of GIP and GLP-1 secretion. In the second one participants received test meals which contained saccharose or isomaltulose in combination with milk protein. The third set of participants underwent randomized oral protein tests with whey protein or casein. Incretins, glucagon, C-peptide, and insulin were profiled by specific immunological assays.. 50 g of the sugars alone suppressed glucagon in controls but slightly less in type 2 diabetes patients. Participants with type 2 diabetes showed excessive glucagon responses within 15 min and lasting over 3 h, while the obese controls showed small initial and delayed greater glucagon responses to mixed meals. The release of GIP was significantly faster and greater with SAC compared to ISO, while GLP-1 showed an inverse pattern. The glucagon responses to whey or casein were only moderately increased in type 2 diabetes patients without a left shift of the dose response curve.. The rapid hypersecretion of glucagon after mixed meals in type 2 diabetes patients compared to controls is unaffected by endogenous incretins. The defective suppression of glucagon by glucose combined with hypersecretion to protein is required for the exaggerated response.. NCT03806920, NCT02219295, NCT04564391.

Topics: Blood Glucose; Caseins; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Meals; Obesity; Sucrose; Sugars

Neurotensin (NT) is a gastro-intestinal hormone involved in several pathways that regulate energy and glucose homeostasis. NT was hypothesized to act in synergy with incretin hormones to potentiate its anti-diabetic effects. Additionally, circulating NT levels were shown to rise after bariatric surgery-induced weight loss. Knowledge of NT-secreting cells distribution along the small intestine and its variation according to diabetes status could provide insights on NT role in mediating type 2 diabetes (T2D) improvement after bariatric surgery. So, our aims were to characterize NT-expressing cell distribution along the human small intestine and to compare the relative density of NT-expressing cells in the small intestine of individuals with and without T2D undergoing bariatric surgery for obesity treatment. Autopsy-derived small intestine fragments (n = 30) were obtained at every 20 cm along the entire intestinal length. Additionally, jejunum biopsies (n = 29) were obtained during elective gastric bypass interventions from patients with (n = 10) or without T2D (n = 18). NT-expressing cells were identified by immunohistochemistry and quantified via computerized morphometric analysis. NT-expressing cell density increased along the human small intestine. NT-expressing cell density was significantly higher from 200 cm distal to the duodenojejunal flexure onward, as well as in subjects with T2D when compared to those without T2D. NT-expressing cell density increases along the human small gut, and a higher density is found in individuals with T2D. This finding suggests a potential role for NT in the mechanisms of disease and T2D improvement observed after bariatric surgery.

Topics: Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Incretins; Intestine, Small; Neurotensin

Premenopausal women are at a lower risk of type 2 diabetes (T2D) compared to men, but the underlying mechanism(s) remain elusive. The secretion of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), from the small intestine is a major determinant of glucose homeostasis and may be influenced by sex.. This study compared blood glucose and plasma insulin and incretin responses to intraduodenal glucose infusions in healthy young males and females.. In Study 1, 9 women and 20 men received an intraduodenal glucose infusion at 2 kcal/min for 60 minutes. In Study 2, 10 women and 26 men received an intraduodenal glucose at 3 kcal/min for 60 minutes. Venous blood was sampled every 15 minutes for measurements of blood glucose and plasma insulin, GLP-1 and GIP.. In response to intraduodenal glucose at 2 kcal/min, the incremental area under the curve between t = 0-60 minutes (iAUC0-60min) for blood glucose and plasma GIP did not differ between the 2 groups. However, iAUC0-60min for plasma GLP-1 (P = 0.016) and insulin (P = 0.011) were ∼2-fold higher in women than men. In response to intraduodenal glucose at 3 kcal/min, iAUC0-60min for blood glucose, plasma GIP, and insulin did not differ between women and men, but GLP-1 iAUC0-60min was 2.5-fold higher in women (P = 0.012).. Healthy young women exhibit comparable GIP but a markedly greater GLP-1 response to intraduodenal glucose than men. This disparity warrants further investigations to delineate the underlying mechanisms and may be of relevance to the reduced risk of diabetes in premenopausal women when compared to men.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Male

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes.. We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19.. Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines.. Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

Topics: Adipokines; Adiponectin; C-Peptide; Child; Complement Factor D; COVID-19; Cytokines; Diabetes Mellitus, Type 2; Ghrelin; Glucagon; Granulocyte Colony-Stimulating Factor; Humans; Incretins; Interleukin-12; Interleukin-17; Interleukin-6; Leptin; Pancreatic Hormones; SARS-CoV-2; Tumor Necrosis Factor-alpha

To date, the 21. A PubMed search of published data on the GLP1PP class of therapies was conducted. The gut-brain axis forms complex multi-directional interlinks that include autonomic nervous signaling, components of the gut microbiota (including metabolic by-products and gram-negative cell wall components [e.g. endotoxinaemia]), and incretin hormones that are secreted from the gut in response to the ingestion of nutrients. The development of dual-incretin agonist therapies includes combinations of the GLP1 peptide with Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon (Gcg), Cholecystokinin (CCK), Peptide YY (PYY), and Glucagon-Like Peptide 2 (GLP2). Triple incretin agonist therapies are also under development.. At the dawn of a new era in the therapeutic management of diabesity, the designer GLP1PP class holds great promise, with each novel combination building on a preexisting palimpsest of clinical data and insights. Future innovations of the GLP1PP class will likely enable medically induced weight loss and glycemic control in diabesity to rival or even out-perform those resulting from bariatric surgery.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins

Glucagon like peptide-1 receptor agonists (GLP-1RAs) belong to the class of incretin drugs. Incretin is a hormone secreted into blood by intestinal cells after food stimulation that induces insulin secretion. Liraglutide is a long-acting GLP-1RA that can reduce blood pressure, blood lipids, and inflammation. Previous studies showed that liraglutide can promote white fat browning and improve renal outcomes in patients with type 2 diabetes mellitus. However, no studies have linked white fat browning to kidney damage. The objective of this study was to investigate the effects of liraglutide-induced white fat browning on podocyte apoptosis in diabetic nephropathy. We also aimed to determine whether podocytes express glucagon like peptide-1 receptor (GLP-1R) and if liraglutide directly affects podocytes via GLP-1R. We assessed fat and renal function in db/db and wild-type mice and the effects of adipocyte conditioned medium on cultured podocytes. Liraglutide (400 mg/kg/d) was subcutaneously injected for 8 weeks. Liraglutide promoted white fat browning in vivo. During adipogenic differentiation of 3T3-L1 cells in vitro, liraglutide also upregulated expression of peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC1α) and uncoupling protein 1 (UCP1), which can induce white fat browning in vitro. Furthermore, we found that supernatant from 3T3-L1 cells stimulated by liraglutide reduced podocyte apoptosis. The inhibitory effect of liraglutide on apoptosis was eliminated by exogenous TNF-α. Finally, podocytes express GLP-1R. In vivo and in vitro studies showed that the apoptosis of podocytes in diabetic nephropathy may be related to the effect of liraglutide on promoting white lipid browning. Similarly, liraglutide may directly affect podocytes via GLP-1R.

Topics: Adipose Tissue, White; Animals; Apoptosis; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucagon-Like Peptide-1 Receptor; Incretins; Liraglutide; Mice; Podocytes

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin

Topics: Diabetes Mellitus, Type 2; Exercise; Humans; Incretins; Weight Loss

Incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) cause increased insulin secretion in non-pregnant adults, but their role in pregnancy, where there are additional metabolically-active hormones from the placenta, is less clear. The aim of the present study was to assess if fasting and post-load incretin concentrations were predictive of pregnancy insulin and glucose concentrations.. Pregnant women (n = 394) with one or more risk factors for gestational diabetes were recruited at 28 weeks for a 75 g oral glucose tolerance test (OGTT). Glucose, insulin, GLP-1 and GIP were measured in the fasting state and 120 min after glucose ingestion.. Fasting plasma GLP-1 concentrations were associated with plasma insulin (standardised β' 0.393 (0.289-0.498), p = 1.3 × 10. These results suggest that the relationship between insulin and incretins is preserved in pregnancy, but that other factors, such as placental hormones or counter-regulatory hormones, may be more important determinants of glycaemia and gestational diabetes aetiology.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Placenta; Pregnancy

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)-treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea-treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0-240 minutes) for total GLP-1 and GIP were compared between groups, using non-parametric statistical methods. Post-meal GLP-1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate-sensitive potassium channel-independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone.

Topics: Adult; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Infant, Newborn; Insulin

Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.

Topics: Adult; Diabetes Mellitus, Type 2; Humans; Incretins; Obesity; Sleep Apnea, Obstructive; Weight Loss

Pancreatic β-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress responses, especially those mediated by the protein kinase RNA-like ER kinase and activating transcription factor 4 (PERK-ATF4) pathway, have been implicated in promoting these β-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in β-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts β-cell function via a downregulation of cAMP signaling. We found that β-cell-specific transgenic expression of ATF4 led to early β-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than C/EBP homologous protein (CHOP), promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that β-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired β-cell function. Accordingly, pharmacological inhibition of the ATF4 pathway attenuated PDE4D expression in the islets and promoted incretin-simulated glucose tolerance and insulin secretion in db/db mice. Finally, we found that inhibiting PDE4 activity with selective pharmacological inhibitors improved β-cell function in both db/db mice and β-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes β-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting β-cell function during the progression of T2D.

Topics: Activating Transcription Factor 4; Animals; Apoptosis; Diabetes Mellitus, Type 2; eIF-2 Kinase; Endoplasmic Reticulum Stress; Glucose; Incretins; Insulin-Secreting Cells; Mice

Postmenopausal individuals with type 2 diabetes are susceptible to fractures due to the interaction of elevated blood glucose levels and a deficiency of the hormone estrogen. Despite continued concerns of fracture risks associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i), existing evidence in this high-risk population is lacking.. To assess the risk of fractures associated with SGLT2i vs incretin-based drugs of dipeptidyl-peptidase 4 inhibitors (DPP4i) and glucagon-like peptide 1 receptor agonists (GLP1RA), separately, in postmenopausal individuals with type 2 diabetes.. This active-comparator, new-user cohort study used nationwide claims data of Korea and took place from January 1, 2013, to December 31, 2020. Postmenopausal individuals (aged ≥45 years) with type 2 diabetes were included.. New users of SGLT2i or comparator drugs.. The primary outcome was overall fractures, comprising vertebral, hip, humerus, and distal radius fractures. Patients were followed up from the day after drug initiation until the earliest of outcome occurrence, drug discontinuation (90-day grace period) or switch, death, or end of the study period. After propensity score fine stratification, hazard ratios (HRs) with 95% CIs were estimated using weighted Cox models.. Among 37 530 (mean [SD] age, 60.6 [9.7] years) and 332 004 (mean [SD] age, 60.6 [9.9] years) new users of SGLT2i and DPP4i, respectively, a lower rate of incident overall fractures was presented with SGLT2i vs DPP4i (weighted HR, 0.78; 95% CI, 0.72-0.84). Among 111 835 (mean [SD] age, 61.4 [9.8] years) and 8177 (mean [SD] age, 61.1 [10.3] years) new users of SGLT2i and GLP1RA, respectively, no association with an increased risk of overall fractures was presented with SGLT2i vs GLP1RA (weighted HR, 0.92; 95% CI, 0.68-1.24). Results from several subgroup and sensitivity analyses presented consistent results from main analysis.. This population-based cohort study suggests that SGLT2i was not associated with an increased rate of incident fractures compared with DPP4i and GLP1RA, separately, among postmenopausal individuals with type 2 diabetes.

Topics: Aged; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fractures, Bone; Humans; Incretins; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors

Duodenal ablation improves glycaemic control and weight loss, so it has been applied using hydrothermal catheters in obese and type 2 diabetes patients, indicating similar mechanisms and therapeutic effects as bariatric surgeries. Endoscopic photodynamic therapy is an innovative procedure that easily accessible to endocrine or gastrointestinal organs, so it is critical for the sprayed photosensitizer (PS) to long-term interact with target tissues for enhancing its effects. Surfactant-like PS was more stable in a wide range of pH and 2.8-fold more retained in the duodenum at 1 h than hydrophilic PS due to its amphiphilic property. Endoscopic duodenal ablation using surfactant-like PS was performed in high fat diet induced rat models, demonstrating body weight loss, enhanced insulin sensitivity, and modulation of incretin hormones. Locoregional ablation of duodenum could affect the profiles of overall intestinal cells secreting meal-stimulated hormones and further the systemic glucose and lipid metabolism, regarding gut-brain axis. Our strategy suggests a potential for a treatment of minimally invasive bariatric and metabolic therapy if accompanied by detailed clinical trials.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Duodenum; Humans; Incretins; Obesity; Photosensitizing Agents; Rats; Surface-Active Agents

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Weight Loss

In youths with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on β cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high-incretin effect group demonstrated a longitudinal increase in β cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of β cell function and weight in youths with obesity.

Topics: Adolescent; Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Obesity

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Humans; Incretins; Insulin

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors might increase the risk of intestinal obstruction, but real-world evidence for this severe adverse event is lacking. Thus, the objective of this study was to determine whether GLP-1 RAs and DPP-4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new-user, active comparator cohorts (2013-2019). The first included 25,617 and 67,261 GLP-1 RA and SGLT-2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP-4 inhibitor and SGLT-2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP-1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT-2 inhibitors (1.9 vs. 1.1 per 1,000 person-years, respectively; HR: 1.69, 95% CI: 1.04-2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79-6.79). DPP-4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person-years; HR: 2.59, 95% CI: 1.52-4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47-20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP-1 RAs and DPP-4 inhibitors, respectively. In this large real-world study, GLP-1 RAs and DPP-4 inhibitors were associated with an increased risk of intestinal obstruction.

Topics: Aged; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incidence; Incretins; Intestinal Obstruction; Male; Middle Aged; Odds Ratio; Propensity Score; Proportional Hazards Models; Sodium-Glucose Transporter 2 Inhibitors; United Kingdom

Topics: Aged; Amylases; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Lipase; Male; Middle Aged

Topics: Diabetes Mellitus, Type 2; Humans; Incretins

Real-world data comparing the effectiveness of various glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in type 2 diabetes mellitus (T2DM) are limited. We investigated the clinical effectiveness of liraglutide and dulaglutide in Japanese T2DM in a real-world setting. This retrospective study included 179 patients with T2DM who were treated with GLP-1 RA for at least 12 months (liraglutide, n = 97; dulaglutide, n = 82). We used stabilized propensity score-based inverse probability of treatment weighting (IPTW) to reduce selection bias and confounding by observed covariates. Changes in glycated hemoglobin (HbA1c) at the end of the 12-month treatment were evaluated. After adjustment by stabilized propensity score-based IPTW, no significant differences were observed in patient characteristics between the liraglutide and dulaglutide groups. HbA1c was significantly lower at 12 months in both groups (liraglutide, 8.9 to 7.4%; dulaglutide, 8.7 to 7.5%). Multivariate linear regression analysis showed no differences in the extent of changes in HbA1c at 12 months between the two agents. High baseline HbA1c, the addition of GLP-1 RA treatment modality, and in-hospital initiation of GLP-1 RA treatment were identified as significant contributing factors to HbA1c reduction. The effects of liraglutide and dulaglutide on lowering HbA1c levels at 12 months were comparable in a real-world setting.

Topics: Aged; Biomarkers; Blood Glucose; Comparative Effectiveness Research; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Japan; Liraglutide; Male; Middle Aged; Recombinant Fusion Proteins; Retrospective Studies; Time Factors; Treatment Outcome

There is a closely relationship between the development and progression of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD) and obesity and diabetes. NAFLD fibrosis scores should be routinely used to rule out patients with advanced fibrosis. High scores may help identify patients at higher risk of all causes andliverrelated morbidity and mortality. The aim of this study was to investigate the association between exenatide and fibrosis scores. The effect of exenatide treatment on fibrosis scores was evaluated in type 2 diabetes mellitus (DM) patients with MAFLD. Evaluation was made of 50 patients with type 2 DM and MAFLD. The NFS, FIB4 and APRI scores were calculated before and after 6 months of treatment. After 6 months of exenatide treatment, the NFS and APRI scores were determined to have decreased significantly. Exenatide was observed to control blood glucose, reduce body weight and improve fibrosis scores in MAFLD patients with type 2 diabetes.

Topics: Adult; Biomarkers; Blood Glucose; Decision Support Techniques; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Incretins; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Predictive Value of Tests; Retrospective Studies; Time Factors; Treatment Outcome; Weight Loss

The insufficient activity of insulin and the hyperactivity of glucagon are responsible for glucose intolerance in patients with type 2 diabetes. Whereas sodium-glucose cotransporter-2 (SGLT2) inhibitors improve blood glucose levels in patients with type 2 diabetes, their effects on the secretion profiles of glucagon and incretins remain unclear. Therefore, to investigate the effects of the SGLT2 inhibitor luseogliflozin on metabolic and endocrine profiles, 19 outpatients with type 2 diabetes were administered luseogliflozin for 12 weeks. It is of note that all subjects were treated only with diet and exercise therapy, and we were able to investigate the effects of luseogliflozin separately from the effects of other antidiabetic agents. Body weight, body fat mass, fat-free mass, and muscle mass were significantly reduced after 12 weeks of luseogliflozin administration. Glycosylated hemoglobin significantly decreased from the baseline of 8.2% ± 0.8% to 7.3% ± 0.7% (p < 0.0001). The meal tolerance test demonstrated that luseogliflozin significantly recovered glucose tolerance, accompanied by improved insulin resistance and β-cell function, whereas glucagon secretion was unaffected. Furthermore, GLP-1 secretion was significantly increased after luseogliflozin administration. Thus, luseogliflozin improved metabolic and endocrine profiles accompanied by increased GLP-1 secretion in type 2 diabetic patients without any antidiabetic medication, but did not affect glucagon secretion.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins; Sorbitol

Incretins are crucial stimulators of insulin secretion following food intake. Data on incretin secretion and action during pregnancy are sparse.. The aim of the study was to investigate the incretin response during an oral glucose tolerance test (OGTT) in pregnant women with and without gestational diabetes mellitus (GDM).. We analyzed data from the ongoing observational PREG study (NCT04270578).. The study was conducted at the University Hospital Tübingen.. We examined 167 women (33 with GDM) during gestational week 27 ± 2.2.. Subjects underwent 5-point OGTT with a 75-g glucose load.. We assessed insulin secretion and levels of total glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), glicentin, and glucagon during OGTT. Linear regression was used to analyze the relation of GLP-1 and glucose with insulin secretion and the association of incretin levels on birth outcome.. Insulin secretion was significantly lower in women with GDM (P < 0.001). Postload GLP-1 and GIP were ~20% higher in women with GDM (all P < 0.05) independent of age, body mass index, and gestational age. GLP-1 increase was associated with insulin secretion only in GDM, but not in normal glucose tolerance. Postprandial GLP-1 levels were negatively associated with birth weight.. The more pronounced GLP-1 increase in women with GDM could be part of a compensatory mechanism counteracting GLP-1 resistance. Higher GLP-1 levels might be protective against fetal overgrowth.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Macrosomia; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Pregnancy

The glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone very well known for its incretin effect in the glucose-dependent stimulation of insulin secretion. However, GLP-1 is also produced in the brain, and it displays critical roles in neuroprotection by activating the GLP-1 receptor signaling pathways. GLP-1 enhances learning and memory in the hippocampus, promotes neurogenesis, decreases inflammation and apoptosis, modulates reward behavior, and reduces food intake. Its pharmacokinetics have been improved to enhance the peptide's half-life, enhancing exposure and time of action. The GLP-1 agonists are successfully in clinical use for the treatment of type-2 diabetes, obesity, and clinical evaluation for the treatment of neurodegenerative diseases.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Humans; Incretins; Peptide Fragments

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins

Interventions targeting diet and physical activity have demonstrated to be effective for improving glycaemic control in adults with type 2 diabetes. However, initiating and sustaining these changes remains a challenge. Ingestion of whey protein has shown to be effective for improving glycaemic control by increasing insulin and incretin secretion, and influencing appetite regulation; however, little is known about what influences uptake and adherence. We conducted a qualitative interview study to explore behavioural determinants of uptake and adherence to a commercially made whey protein supplementation. In total, 16/18 adults with type 2 diabetes who participated in an RCT took part in a semi-structured interview. Seven themes were generated from the data following thematic analyses. The most frequently reported determinant of uptake was the expectation that the supplement would improve health status (e.g., type 2 diabetes management), as a consequence of appetite suppression and weight loss. Determinants of adherence included palatability; the belief that the supplement was an appetite suppressant; and receiving positive reinforcement on the effects of the supplement. Frequency of consumption led to reduced adherence with some participants. Findings support that the whey protein supplement is a viable management option for adults with type 2 diabetes; however, uptake will be driven by conveying information on the positive effects of the supplement on appetite suppression and glycaemic control. Adherence will be determined by palatability, behavioural prompting, and positive reinforcement.

Topics: Adult; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Incretins; Qualitative Research; Whey Proteins

To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively.. Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36 (PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test.. Single or multiple dose GTS-21 (0.5-8.0 mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged.. α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzylidene Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Male; Mice; Mice, Knockout; Nicotinic Agonists; Pyridines; Sitagliptin Phosphate; Tyrosine

Patients with type 2 diabetes often exhibit impairments in both glucose-induced insulin secretion (GIIS) and incretin-induced insulin secretion (IIIS). These phenotypes are associated with altered glucose metabolism in pancreatic β-cells, although the molecular mechanisms remain unclear. Here, we used MIN6-K8 pancreatic β-cell lines as a model to examine the effect of O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation), a glucose-induced protein posttranslational modification, on insulin secretion. O-GlcNAcylation was enhanced in high-glucose-treated MIN6-K8 cells, and high levels of O-GlcNAcylation attenuated PKA-dependent phosphorylation, suggesting that the two protein modifications may compete with each other. Immunoprecipitation proteomic analysis identified six candidate proteins that were O-GlcNAcylated by high-glucose treatment, whereas the O-GlcNAcylations were removed by treatment with an incretin mimetic, exendin-4. Among these proteins, knockdown of myocyte enhancer factor 2D (Mef2d) enhanced insulin secretion, and high-glucose treatment increased the level of O-GlcNAcylation of Mef2d in MIN6-K8 cells. Furthermore, knockout of Mef2d promoted GIIS in MIN6-K8 cells, whereas adenovirus-mediated rescue of Mef2d decreased GIIS in the knockout cells. These results suggest that Mef2d negatively regulates insulin secretion through O-GlcNAcylation.

Topics: Acetylglucosamine; Diabetes Mellitus, Type 2; Glucose; Humans; Incretins; Insulin Secretion; MEF2 Transcription Factors; Protein Processing, Post-Translational; Proteomics

Background Evidence is limited in comparing treatment modification by substitution or add-on of glucose-lowering medications in patients with type 2 diabetes. This observational study aims to compare switching versus add-on of incretin-based drugs among patients with type 2 diabetes on background sodium-glucose cotransporter-2 inhibitors (SGLT2i). Methods and Results This population-based, retrospective cohort study was conducted using the IQVIA Medical Research Data, including adults with type 2 diabetes on background SGLT2i from 2005 to 2020. New users of incretin-based drugs were allocated into the "Switch" group if they had discontinued SGLT2i treatment, or the "Add-on" group if their background SGLT2i was continued. Baseline characteristics of patients were balanced between groups. Study outcomes were all-cause mortality, cardiovascular diseases, kidney diseases, hypoglycemia, and ketoacidosis. Patients were observed from the index date of initiating incretin-based drugs until the earliest of an outcome event, death, or data cut-off date. Changes in anthropometric and metabolic parameters were also compared between groups from baseline to 12-month follow-up. A total of 2888 patients were included, classified into "Switch" (n=1461) or "Add-on" group (n=1427). Median follow-up was 18 months with 5183 person-years. Overall, no significant differences in the risks of study outcomes were observed between groups; however, patients in the "Add-on" group achieved significantly greater reductions in glycated hemoglobin, weight, percentage weight loss, and systolic blood pressure than their "Switch" counterparts. Conclusions Initiating incretin-based drugs as add-on among patients with type 2 diabetes on background SGLT2i was associated with risks of clinical end points comparable to switching treatments, in addition to better glycemic and weight control observed with the combination approach.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucose; Humans; Hypoglycemic Agents; Incretins; Retrospective Studies; Sodium; Sodium-Glucose Transporter 2 Inhibitors

SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Gastrointestinal Hormone

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are increasingly used in treating type 2 diabetes and obesity. Exendin-4 (Ex-4), a long acting GLP-1ra, was previously reported to decrease oxidative stress in hepatocytes, adipocytes and skeletal muscle cells in obese nondiabetic fa/fa Zucker rats (ZFR), thereby improving insulin resistance.. We aimed first to identify Ex-4-induced changes in the transcriptome of skeletal muscle cells in ZFR.. Ontology analysis of differentially expressed genes (DEGs) in ZFR versus lean animals (LR) showed that the extracellular matrix (ECM) is the first most affected cellular compartment, followed by myofibrils and endoplasmic reticulum (ER). Interestingly, among 15 genes regulated in ZFR versus LR, 14 of them were inversely regulated by Ex-4, as further confirmed by RT-qPCR. Picro-Sirius red histological staining showed that decreased ECM fiber area in ZFR is partially restored by Ex-4. Ontology analysis of the myofibril compartment revealed that decreased muscle contractile function in ZFR is partially restored by Ex-4, as confirmed by Phalloidin histological staining that showed a partial restoration by Ex-4 of altered contractile apparatus in ZFR. Ontology analysis of ER DEGs in ZFR versus LR showed that some of them are related to the AMP-activated protein kinase (AMPK) signaling pathway. Phosphorylated AMPK levels were strongly increased in Ex-4-treated ZFR.. Altogether, our results suggest that GLP-1ra strongly restructure ECM and reinforce contractile capabilities in ZFR, while optimizing the cellular metabolism through AMPK.

Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Exenatide; Incretins; Insulin; Muscle, Skeletal; Obesity; Rats; Rats, Zucker; Transcriptome

There is some evidence that glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have chemopreventive effects on prostate cancer cells but real-world evidence for this possible effect is lacking. Thus, the objective of this study was to estimate whether use of GLP-1 receptor agonists and DPP-4 inhibitors, separately, is associated with a decreased risk of prostate cancer among patients with type 2 diabetes.. We assembled two new-user, active-comparator cohorts using the UK Clinical Practice Research Datalink (2007 to 2019). The first cohort included 5,063 initiators of GLP-1 receptor agonists and 112,955 of sulfonylureas. The second cohort included 53,529 initiators of DPP-4 inhibitors and 114,417 of sulfonylureas. We fit Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer. We weighted the models using propensity score fine stratification, which considered over 50 potential confounders.. GLP-1 receptor agonists were associated with a decreased risk of prostate cancer when compared with sulfonylureas (incidence rates = 156.4 vs. 232.0 per 100,000 person-years, respectively; HR = 0.65; 95% CI = 0.43, 0.99). DPP-4 inhibitors were also associated with a decreased risk of prostate cancer when compared with sulfonylureas (incidence rates = 316.2 vs. 350.5 events per 100,000 person-years, respectively; HR = 0.90; 95% CI = 0.81, 1.00).. The results of this study are consistent with the hypothesis that the use of GLP-1 receptor agonists and DPP-4 inhibitors, separately, may decrease the risk of prostate cancer when compared with the use of sulfonylureas.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incidence; Incretins; Male; Prostatic Neoplasms; Sulfonylurea Compounds

Among the various treatments, GLP-1 receptor agonists (incretin mimics) such as liraglutide and exenatide have been well received in treating type 2 diabetes mellitus (T2DM) and obesity. In this study, an exenatide analogue, in which methionine at position 14 substituted with leucine, was ligated to human αB-crystallin (αB-Cry) and then expressed in the bacterial host cells. In the next step, the exenatide analogue was effectively released from the hybrid protein (αB-Ex) and subsequently purified using gel filtration chromatography. The HPLC and electrospray ionization mass spectrometry (ESI-MS) analyses respectively suggested a high purity (more than 97%) and an accurate molecular mass for the exenatide analogue (4168.22 Da and 835.01, z = 5). Also, the molecular mass of the αB-Ex hybrid protein based on the MALDI-TOF analysis was 24,702.162 Da. The secondary structure assessment by the three spectroscopic methods revealed that exenatide analogue and αB-Ex hybrid protein have an α-helix and a β-sheet rich structure, respectively. Also, according to the results of the DLS analysis, the αB-Ex hybrid protein indicated a high tendency to form large oligomeric structures. The NMR assessment suggested that the hybrid protein exists in its folding state. Both exenatide analogue and the αB-Ex hybrid protein revealed a crucial ability to reduce the blood sugar levels in healthy and diabetic mice. They were also capable of inducing insulin secretion to the bloodstream. Overall, our study introduces the αB-Ex hybrid protein as a novel incretin mimic, exerting its biological activity for a longer period of time. It might also be considered a potential drug candidate in the treatment of T2DM.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Incretins; Liraglutide; Mice

Topics: Appetite; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity; Overweight; Receptors, Gastrointestinal Hormone

Nowadays, a small number of incretin mimics are used to treat type 2 diabetes mellitus (T2DM) due to their longer half-life. The present study aimed to introduce a novel method for producing the liraglutide precursor peptide (LPP) and developing a potentially new incretin mimic. Here, human αB-crystallin (αB-Cry) was ligated to the LPP at the gene level, and the gene construct was expressed in Escherichia coli with a relatively good efficiency. The hybrid protein (αB-lir) was then purified by a precipitation method followed by anion exchange chromatography. After that, the peptide was released from the carrier protein by a chemical cleavage method yielding about 70%. The LPP was then purified by gel filtration chromatography, and HPLC estimated its purity to be about 98%. Also, the molecular mass of the purified peptide was finally confirmed by mass spectroscopy analysis. Assessment of the secondary structures suggested a dominant α-helical structure for the LPP and a β-sheet rich structure for the hybrid protein. The subcutaneous injection of the LPP and the αB-lir hybrid protein significantly reduced the blood sugar levels in healthy and diabetic mice and stimulated insulin secretion. Also, the hybrid protein exerts its bioactivities more effectively than the LPP over a relatively longer period of time. The results of this study suggested a novel method for the easy and cost-effective production of the LPP and introduced a new long-acting incretin mimic that can be potentially used for the treatment of T2DM patients.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Humans; Incretins; Liraglutide; Mice; Peptides

Diabetes mellitus has become a widespread disease worldwide. In recent years, there has been a rapid development of therapeutic options in the field of diabetology. Many new drugs and therapeutic strategies are now available or will be available in the near future, which have the potential to significantly improve the care of patients even if they do not have diabetes. In this article, we would like to present the latest therapeutic options and possible further applications. The article focuses, among other things, on the new findings of SGLT-2-inhibitors in cardiac and chronic renal failure and the further development of incretin-based drugs toward dual GIP/GLP-1-receptor agonists. Once-weekly insulin and the selective mineralocorticoid receptor antagonist finerenone will also be presented.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Sodium-Glucose Transporter 2 Inhibitors

Cushing’s disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM−) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM− (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Insulin; Insulin Resistance; Meals; Pituitary ACTH Hypersecretion; Somatostatin

Our study aimed to evaluate the exposure-response relationship between incretin-based medications and the risk of major adverse cardiovascular events (MACE) using cardiovascular outcome trials (CVOTs). Eleven CVOTs with incretin-based medications were included. The median follow-up time, percentage of time exposure, and hazard ratio (HR) of MACE were obtained from each CVOT. The pharmacokinetic parameters of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitor (DPP-4) were obtained from published studies. Regression analysis was performed to assess the relationship between drug exposure and MACE HR. Cutoff values were determined from the ROC curves. The linear regression results indicated that log C

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins

Polymorphisms in the gene encoding the glucagon-like peptide-1 receptor (GLP1R) are associated with type 2 diabetes but their effects on incretin levels remain unclear.. We evaluated the physiologic and hormonal effects of GLP1R genotypes before and after interventions that influence glucose physiology.. Pharmacogenetic study conducted at 3 academic centers in Boston, Massachusetts.. A total of 868 antidiabetic drug-naïve participants with type 2 diabetes or at risk for developing diabetes.. We analyzed 5 variants within GLP1R (rs761387, rs10305423, rs10305441, rs742762, and rs10305492) and recorded biochemical data during a 5-mg glipizide challenge and a 75-g oral glucose tolerance test (OGTT) following 4 doses of metformin 500 mg over 2 days.. We used an additive mixed-effects model to evaluate the association of these variants with glucose, insulin, and incretin levels over multiple timepoints during the OGTT.. During the OGTT, the G-risk allele at rs761387 was associated with higher total GLP-1 (2.61 pmol/L; 95% CI, 1.0.72-4.50), active GLP-1 (2.61 pmol/L; 95% CI, 0.04-5.18), and a trend toward higher glucose (3.63; 95% CI, -0.16 to 7.42 mg/dL) per allele but was not associated with insulin. During the glipizide challenge, the G allele was associated with higher insulin levels per allele (2.01 IU/mL; 95% CI, 0.26-3.76). The other variants were not associated with any of the outcomes tested.. GLP1R variation is associated with differences in GLP-1 levels following an OGTT load despite no differences in insulin levels, highlighting altered incretin signaling as a potential mechanism by which GLP1R variation affects T2D risk.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glipizide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Incretins; Insulin

Type 2 diabetes mellitus (T2DM) is a disease of global impact that has led to an increase in comorbidities and mortality in several countries. Immunoexpression of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (3-36) (PYY3-36) can be used as a scorer in the gastrointestinal tract to analyze L-cell activity in response to T2DM treatment. This study aimed to investigate the presence, location, and secretion of L cells in the small intestine of patients undergoing the form of bariatric surgery denominated adaptive gastroenteromentectomy with partial bipartition.. Immunohistochemical assays, quantitative real-time polymerase chain reaction (qPCR), and Western blot analysis were performed on samples of intestinal mucosa from patients with T2DM in both the preoperative and postoperative periods.. All results were consistent and indicated basal expression and secretion of GLP-1 and PYY3-36 incretins by L cells. A greater density of cells was demonstrated in the most distal portions of the small intestine. No significant difference was found between GLP-1 and PYY3-36 expression levels in the preoperative and postoperative periods because of prolonged fasting during which the samples were collected.. The greater number of L cells in activity implies better peptide signaling, response, and functioning of the neuroendocrine system.

Topics: Animals; Diabetes Mellitus, Type 2; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; L Cells; Mice; Mucous Membrane

To determine whether the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs), separately, is associated with an increased risk of acute liver injury compared with the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors.. We used the U.K. Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and the Office for National Statistics databases to assemble two new-user, active-comparator cohorts. The first included 106,310 initiators of DPP-4 inhibitors and 27,277 initiators of SGLT-2 inhibitors, while the second included 9,470 initiators of GLP-1 RAs and 26,936 initiators of SGLT-2 inhibitors. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate hazard ratios (HRs) and 95% CIs of acute liver injury.. Compared with SGLT-2 inhibitors, DPP-4 inhibitors were associated with a 53% increased risk of acute liver injury (HR 1.53, 95% CI 1.02-2.30). In contrast, GLP-1 RAs were not associated with an overall increased risk of acute liver injury (HR 1.11, 95% CI 0.57-2.16). However, an increased risk was observed among female users of both DPP-4 inhibitors (HR 3.22, 95% CI 1.67-6.21) and GLP-1 RAs (HR 3.23, 95% CI 1.44-7.25).. In this population-based study, DPP-4 inhibitors were associated with an increased risk of acute liver injury compared with SGLT-2 inhibitors in patients with type 2 diabetes. In contrast, an increased risk of acute liver injury was observed only among female GLP-1 RA users.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Liver; Sodium; Sodium-Glucose Transporter 2 Inhibitors

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Analogs of the incretin hormones Gip and Glp-1 are used to treat type 2 diabetes and obesity. Findings in experimental models suggest that manipulating several hormones simultaneously may be more effective. To identify small molecules that increase the number of incretin-expressing cells, we established a high-throughput in vivo chemical screen by using the gip promoter to drive the expression of luciferase in zebrafish. All hits increased the numbers of neurogenin 3-expressing enteroendocrine progenitors, Gip-expressing K-cells, and Glp-1-expressing L-cells. One of the hits, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor, additionally decreased glucose levels in both larval and juvenile fish. Knock-down experiments indicated that nfatc4, a downstream mediator of DYRKs, regulates incretin

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Discovery; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Incretins; Mice; Tyrosine; Zebrafish

Diabetes mellitus is a major global health concern in the current scenario which is chiefly characterized by the rise in blood sugar levels or hyperglycemia. In the context, DPP4 enzyme plays a critical role in glucose homeostasis. DPP4 targets and inactivates incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) as physiological substrates, which are essential to regulate the amount of insulin that is secreted after eating. Since the inactivation of incretins occurs, the hyperglycemic conditions continue to rise, and result in adverse physiological conditions linked with diabetes mellitus. Hence, inhibition of DPP4 has been the center of focus in the present antidiabetic studies. Although few DPP4 inhibitor drugs, such as alogliptin, saxagliptin, linagliptin, and sitagliptin, are available, their adverse effects on human metabolism are undeniable. Therefore, it becomes essential for the phytochemical intervention of the disease using computational methods prior to performing in vitro and in vivo studies. In this regard, we used an in-silico approach involving molecular docking, molecular dynamics simulations, and binding free energy calculations to investigate the inhibitory potential of

Topics: Computers; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Molecular Docking Simulation; Molecular Dynamics Simulation; Ocimum sanctum

Worldwide, metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. MAFLD is associated with insulin resistance, type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Early diagnosis and management are vital to improving hepatic and cardiometabolic outcomes. Dietary change, weight loss, and structured exercise are the main treatment approaches for fatty liver disease. Since 2010, several investigational drug treatments failed to achieve regulatory approval due to mixed and unsatisfactory results. Although glucagon-like peptide 1 receptor agonists (GLP1-RAs) showed initial promise as therapeutic agents, metabolic liver damage can recur after monotherapy cessation. Dual incretin receptor agonists target the receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). Importantly, on May 13, 2022, the US Food and Drug Administration (FDA) approved tirzepatide as the first dual GLP-1 and GIP receptor agonist for the treatment of T2DM. Dual incretin receptor agonists induce weight loss and enhance hepatic lipid metabolism and systemic insulin sensitivity. Insulin resistance and hepatic steatosis are the main contributors to the development of MAFLD. Treatment with dual incretin analogs reduces hepatic steatosis, lobular inflammation, liver cell damage, fibrosis, and total liver triglyceride levels. The availability of dual incretin receptor agonists for patients with MAFLD may result in weight control, normalizing insulin sensitivity, and reducing or even reversing metabolic dysfunction and liver damage. This Editorial aims to provide an update and discuss how treatment with dual incretin receptor agonists may maintain normal glucose levels and weight and control MAFLD.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin Resistance; United States; Weight Loss

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Incretins; Obesity; Renal Insufficiency, Chronic

Impaired secretion of glucagon-like peptide-1 (GLP-1) among Caucasians contributes to reduced incretin effect in type 2 diabetes mellitus (T2DM) patients. However, studies emanating from East Asia suggested preserved GLP-1 levels in pre-diabetes (pre-DM) and T2DM. We aimed to resolve these conflicting findings by investigating GLP-1 levels during oral glucose tolerance test (OGTT) among Malay, Chinese, and Indian ethnicities with normal glucose tolerance (NGT), pre-DM, and T2DM. The association between total GLP-1 levels, insulin resistance, and insulin sensitivity, and GLP-1 predictors were also analyzed.. A total of 174 subjects were divided into NGT (n=58), pre-DM (n=54), and T2DM (n=62). Plasma total GLP-1 concentrations were measured at 0, 30, and 120 min during a 75-g OGTT. Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of insulin sensitivity (HOMA-IS), and triglyceride-glucose index (TyG) were calculated.. Total GLP-1 levels at fasting and 30 min were significantly higher in T2DM compared with pre-DM and NGT (27.18 ± 11.56 pmol/L vs. 21.99 ± 10.16 pmol/L vs. 16.24 ± 7.79 pmol/L, p=0.001; and 50.22 ± 18.03 pmol/L vs. 41.05 ± 17.68 pmol/L vs. 31.44 ± 22.59 pmol/L, p<0.001; respectively). Ethnicity was a significant determinant of AUC. This is the first study that showed GLP-1 responses are augmented as IR states increase. Fasting and post-OGTT GLP-1 levels are raised in T2DM and pre-DM compared to that in NGT. This raises a possibility of an adaptive compensatory response that has not been reported before. Among the three ethnic groups, the Indians has the highest IR and GLP-1 levels supporting the notion of an adaptive compensatory secretion of GLP-1.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Ethnicity; Fasting; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Prediabetic State; Triglycerides

Enteroendocrine L cells can be found in the entire gastrointestinal tract and their incretins act on glycemic control and metabolic homeostasis. Patients with severe obesity and type 2 diabetes mellitus may have lower density of L cells in the proximal intestine.. This study aimed to analyze the density of L cells in the segments of the small intestine in the late postoperative of Roux-en-Y gastric bypass in diabetic patients with standardization of 60 cm in both loops, alimentary and biliopancreatic.. Immunohistochemistry analysis assays were made from intestinal biopsies in three segments: gastrointestinal anastomosis (GIA= Point A), enteroenteral anastomosis (EEA= Point B= 60 cm distal to the GIA) and 60 cm distal to the enteroenteral anastomosis (Point C).. A higher density of L cells immunostaining the glucagon-1 peptide was observed in the distal portion (Point C) when compared to the more proximal portions (Points A and B).. The concentration of L cells is higher 60 cm distal to enteroenteral anastomosis when comparing to proximal segments and may explain the difference in intestinal lumen sensitization and enterohormonal response after Roux-en-Y gastric bypass.

Topics: Anastomosis, Roux-en-Y; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Gastric Bypass; Glucagon; Humans; Incretins; Obesity, Morbid; Treatment Outcome

Incretin impairment refers to L-cell-derived glucagon-like peptide-1 (GLP-1) deficiency, commonly observed in patients with type 2 diabetes mellitus (T2DM). Promoting the enteroendocrine L-cell population to elevate GLP-1 secretory capacity represents a potential therapeutic strategy for T2DM. It has been established that ginsenoside compound K (CK) could stimulate GLP-1 secretion; however, the underlying mechanisms remain elusive.. CK was intragastrically administered to male db/db mice for 4 weeks that subsequently underwent oral glucose tolerance testing. Serum samples were collected to measure the GLP-1 secretion, insulin level, inflammatory factors, and bile acid (BA) profiles. Ileum epithelial injury was detected by Hematoxylin and Eosin (H&E) and Masson staining. Gene markers associated with L-cell differentiation were evaluated by RT-PCR, and L-cells were labeled by Gcg via immunofluorescence assays. TGR5 and YAP expression was analyzed by immunoblotting and immunofluorescence assays.. Compound K attenuated hyperglycemia and inflammation in db/db mice and upregulated TGR5 expression by increasing lithocholic acid (LCA) and deoxycholic acid (DCA) levels in response to ileum epithelium injury. Meanwhile, fibrosis was alleviated, and the crypt architecture was restored, with increased L-cell abundance and serum GLP-1 levels. The upregulation in genes associated with L-cell differentiation promoted transformation into L-cells. Further mechanistic analyses showed that the effects of CK on the L-cell population required YAP activation, which triggered actin cytoskeleton dynamics.. Our results indicate that TGR5 could modulate the abundance of L-cells to enhance GLP-1 release through YAP-driven intestinal regeneration in db/db mice. Accordingly, CK has huge prospects for application to alleviate incretin impairment in T2DM.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Incretins; L Cells; Male; Mice; Mice, Inbred Strains

Recent studies show that incretin hormone analogues effectively control blood glucose while producing major weight losses and reducing the risk of all-cause mortality, myocardial infarction, stroke and kidney function impairment. Furthermore, the risk of dementia and cognitive impairment is reduced. A monomolecular coagonist (tirzepatide) of receptors for both incretin hormones (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) produced HbA1c values below 5.7% in 50% of the treated patients and weight losses exceeding 20% in obese individuals. These new agents will radically change our approach to the treatment of T2DM and obesity alike.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Metabolic Diseases; Obesity; Weight Loss

To evaluate the change in circulating serum irisin and interleukin-6 (IL-6), in patients with type 2 diabetes mellitus (T2DM) after 6 and 12 months of GLP-1 treatment.. Eighty-five patients with T2DM inadequately controlled with insulin or other hypoglycaemic drugs were added to dulaglutide (N° = 44) and liraglutide (N° = 41) treatment. After 6 months of GLP-1 analogues a significant decrease in BMI (p < 0.001), waist circumference (WC) (p < 0.001), fasting blood glucose (p < 0.001), HbA1c (p < 0.001), total cholesterol (p < 0.001), LDL-cholesterol (p = 0.003), triglycerides (p = 0.017), IL-6 (p = 0.045) and a significant increase in serum irisin (p < 0.001) were observed compared to baseline. After 12 months of treatment no significant differences were found compared to the levels at 6 months. The change in irisin from baseline (Δ_irisin) was significantly related to the changes in total-cholesterol (Δ_total-cholesterol) (r = -0.293; p = 0.020), while the change in IL-6 (Δ_IL-6) was significantly related to the changes in WC (Δ_WC) (r = 0.347; p = 0.006).. Additive treatment with GLP1-analogues results in an increase in serum circulating irisin levels and a decrease in IL-6. The post-treatment change in irisin was correlated with a decrease in total cholesterol, while the change in IL-6 was correlated with a decrease in WC.

Topics: Aged; Biomarkers; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Fibronectins; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Inflammation Mediators; Insulin; Interleukin-6; Liraglutide; Male; Middle Aged; Recombinant Fusion Proteins; Time Factors; Treatment Outcome; Waist Circumference

Topics: Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Obesity; Peptides

Cardiovascular disease (CVD) remains the leading cause of death in patients with type 2 diabetes (T2D). Older age, prior heart failure (HF) and CV events, peripheral artery disease, and kidney complications can identify a subgroup of patients with T2D at high risk of mortality who are likely to achieve the greatest benefit from newer glucose-lowering agents. Both glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors can reduce CV risk in patients with T2D, and both are recommended by the American Diabetes Association to reduce the risk of major cardiovascular events (MACE). The magnitude of the benefits of GLP-1RA and SGLT-2 inhibitors on MACE are similar, ranging from 12 to 14% reduction of risk, but only GLP-1RA may reduce the risk of stroke. The most striking difference between the two classes of drugs relates to the amelioration on hospitalization for HF, as the benefit of SGLT-2 inhibitors surpass by threefold that obtained with GLP-1RA. Despite this, GLP-1RA also exert a significant benefit on HF which suggest their use when SGLT-2 inhibitors are contraindicated or not tolerated. The difference between the two classes is less impressive for the kidney outcome. Overall, the results of CVOTs published so far seems to suggest that the gap between the cardiorenal benefits of SGLT-2 and GLP-1RA is narrowing.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Hospitalization; Humans; Incretins; Kidney Diseases; Protective Factors; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

We aimed to compare cardiovascular outcomes of patients with type 2 diabetes (T2D) who initiated GLP-1 receptor agonists (GLP-1RA) or basal insulin (BI) under routine care.. We accessed the administrative claims database of the Veneto Region (Italy) to identify new users of GLP-1RA or BI in 2014-2018. Propensity score matching (PSM) was implemented to obtain two cohorts of patients with superimposable characteristics. The primary endpoint was the 3-point major adverse cardiovascular events (3P-MACE). Secondary endpoints included 3P-MACE components, hospitalization for heart failure, revascularizations, and adverse events.. From a background population of 5,242,201 citizens, 330,193 were identified as having diabetes. PSM produced two very well matched cohorts of 4063 patients each, who initiated GLP-1RA or BI after an average of 2.5 other diabetes drug classes. Patients were 63-year-old and only 15% had a baseline history of cardiovascular disease. During a median follow-up of 24 months in the intention-to-treat analysis, 3P-MACE occurred less frequently in the GLP-1RA cohort (HR versus BI 0.59; 95% CI 0.50-0.71; p < 0.001). All secondary cardiovascular endpoints were also significantly in favor of GLP-1RA. Results were confirmed in the as-treated approach and in several stratified analyses. According to the E-value, confounding by unmeasured variables were unlikely to entirely explain between-group differences in cardiovascular outcomes.. Patients with T2D who initiated a GLP-1RA experienced far better cardiovascular outcomes than did matched patients who initiated a BI in the same healthcare system. These finding supports prioritization of GLP-1RA as the first injectable regimen for the management of T2D.

Topics: Administrative Claims, Healthcare; Aged; Aged, 80 and over; Cardiovascular Diseases; Comparative Effectiveness Research; Databases, Factual; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Italy; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Time Factors; Treatment Outcome

The present study aimed to investigate changes in glucose metabolism and incretin hormone response following longer intestinal bypass reconstruction after distal gastrectomy (DG) in low BMI patients with gastric cancer and type 2 diabetes. A total of 20 patients were prospectively recruited and underwent either conventional Billroth I (BI), Billroth II with long-biliopancreatic limb (BII), or Roux-en-Y anastomosis with long-Roux limb (RY) after DG. A 75g-oral glucose tolerance test (OGTT) was given preoperatively; and at 5 days, 3 months, and 6 months postoperatively. Serum glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were serially measured. At 6 months after surgery, complete diabetes remission was achieved in 57.1% of the BII group but in no patients in the other two groups (p = 0.018). BII group showed a significant reduction in glucose concentration during OGTT at 6 months in contrast to the other 2 groups. In the BII group, a significant increase in GLP-1 secretion was observed after surgery but not maintained at 6 months, while postoperative hyperglucagonemia was alleviated along with a reduction in GIP. BII gastrojejunostomy with long biliopancreatic limb achieved better diabetes control with favorable incretin response after DG compared to BI or RY reconstruction.

Topics: Aged; Anastomosis, Roux-en-Y; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastrectomy; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Postoperative Period; Prospective Studies; Stomach Neoplasms; Treatment Outcome

Incretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Lipids; Metabolic Syndrome; Receptors, Gastrointestinal Hormone; Treatment Outcome

Topics: Adrenergic beta-Antagonists; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Cats; COVID-19; COVID-19 Serotherapy; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dogs; Drug Combinations; Gastric Inhibitory Polypeptide; Heart Sounds; History, 20th Century; Humans; Hypertension; Immunization, Passive; Incretins; Insulin Glargine; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; SARS-CoV-2; Thiazides; Valsartan

We aimed to investigate insulin-, mTOR- and SGK1-dependent signaling basal states in morbidly obese patients' fat. We analyzed the correlation between the signaling activity, carbohydrate metabolism, and incretin profiles of patients.. The omental and subcutaneous fat was obtained in patients with obesity. The omental study included 16 patients with normal glucose tolerance (NGT) and 17 patients with type 2 diabetes mellitus (T2DM); the subcutaneous study included 9 NGT patients and 12 T2DM patients. Insulin resistance was evaluated using the hyperinsulinemic euglycemic clamp test and HOMA-IR index. The oral glucose tolerance test (OGTT) for NGT patients and mixed meal tolerance test (MMTT) for T2DM patients were performed. The levels of incretins (GLP-1, GIP, oxyntomodulin) and glucagon were measured during the tests. Signaling was analyzed by Western blotting in adipose tissue biopsies.. We have shown equal levels of basal phosphorylation of insulin- and mTOR-dependent signaling in omental fat depot in NGT and T2DM obese patients. Nevertheless, pNDRG1-T346 was decreased in omental fat of T2DM patients. Correlation analysis has shown an inverse correlation of pNDRG1-T346 in omental fat and diabetic phenotype (HbA1c, impaired incretin profile (AUC GLP-1, glucagon)). Moreover, pNDRG1-T346 in subcutaneous fat correlated with impaired incretin levels among obese patients (inverse correlation with AUC glucagon and AUC GIP).. According to results of the present study, we hypothesize that phosphorylation of pNDRG1-T346 can be related to impairment in incretin hormone processing. pNDRG1-T346 in adipose tissue may serve as a marker of diabetes-associated impairments of the systemic incretin profile and insulin sensitivity.

Topics: Adipose Tissue; Adult; Biomarkers; Biopsy; Case-Control Studies; Cell Cycle Proteins; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Incretins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Male; Metabolome; Middle Aged; Obesity, Morbid; Phosphorylation

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are innovative drugs that effectively reduce glycemic levels and overweight in patients with type 2 diabetes mellitus (T2DM). However, the criteria for predicting the hypoglycemic effect of this group of drugs have not been practically defined.. To assess the factors contributing to the achievement the glycemia normalization in patients with diabetes mellitus and obesity by adding to antihyperglycemic therapy (AT) a drug from the GLP-1 RA group liraglutide 3.0 mg per day.. A single-center, prospective, non-randomized study was provided. The objects of the study were patients with T2DM and obesity (n=22). Liraglutide 3.0 mg per day was added to the current AT of patients. Initially, the parameters of carbohydrate metabolism, hormones of the incretin system on an empty stomach and during the mixed-meal test, insulin resistance using the euglycemic hyperinsulinemic clamp test, and body composition were studied. After 9 months of therapy, all studies were repeated and a search for possible predictors of the carbohydrate metabolism normalization was made.. The body mass index of patients decreased from 42.4 [37.7; 45.0] to 35.9 [33.0; 40.9] kg/m2. Fasting blood glucose and glycated hemoglobin levels decreased from 9.02 [7.40; 11.37] mmol/L and 7.85 [7.43; 8.65]% up to 5.90 [5.12; 6.18] mmol/L and 6.40 [5.90; 6.60]%, respectively. 14 (63.6%) patients reached normoglycemia. Insulin resistance according to the clamp test did not change over the study. Basal concentrations of oxyntomodulin, glycentin and the area under the GLP-1, oxyntomodulin, glycentin curve significantly decreased 9 months after liraglutide administration. The prognostic marker of the achievement of normoglycemia during therapy with liraglutide 3.0 mg/day is the level of endogenous GLP-15.5 pmol/L before the appointment of arGPP-1 therapy.. The concentration of endogenous GLP-1 before the appointment of liraglutide therapy at a dose of 3.0 mg per day can be used for prediction the drug hypoglycemic effect and achieving normoglycemia possibility.. Актуальность. Агонисты рецепторов глюкагоноподобного пептида-1 (арГПП-1) являются инновационными препаратами, эффективно снижающими уровень гликемии и избыточный вес у пациентов с сахарным диабетом 2-го типа (СД 2). Однако практически не определены критерии, позволяющие прогнозировать сахароснижающий эффект этой группы препаратов. Цель. Оценить факторы, способствующие достижению нормализации гликемии у пациентов с СД 2 и ожирением при добавлении к сахароснижающей терапии (СТ) препарата из группы арГПП-1 лираглутида 3,0 мг/сут. Материалы и методы. Проведено одноцентровое проспективное нерандомизированное исследование. Объектами исследования выступили пациенты с СД 2 и ожирением (n=22). К текущей СТ пациентов был добавлен лираглутид 3,0 мг/сут. Исходно исследованы показатели углеводного обмена, гормонов инкретиновой системы натощак и в течение теста со смешанной пищей, инсулинорезистентности с помощью эугликемического гиперинсулинемического клэмп-теста, композитного состава тела. Через 9 мес терапии повторены все исследования и проведен поиск возможных предикторов нормализации углеводного обмена. Результаты. Индекс массы тела пациентов снизился с 42,4 [37,7; 45,0] до 35,9 [33,0; 40,9] кг/м2. Уровни глюкозы крови натощак и гликированного гемоглобина снизились с 9,02 [7,40; 11,37] ммоль/л и 7,85 [7,43; 8,65]% до 5,90 [5,12; 6,18] ммоль/л и 6,40 [5,90; 6,60]% соответственно. Нормогликемии достигли 14 (63,6%) пациентов. Инсулинорезистентность, согласно клэмп-тесту, не изменилась на протяжении 9 мес исследования. Базальные концентрации оксинтомодулина, глицентина и площади под кривой ГПП-1, оксинтомодулина, глицентина значимо снизились через 9 мес после назначения лираглутида. Прогностическим маркером достижения нормогликемии при терапии лираглутидом 3,0 мг/сут является уровень эндогенного ГПП-15,5 пмоль/л до назначения терапии арГПП-1. Заключение. Концентрация эндогенного ГПП-1 до назначения терапии лираглутидом в дозе 3,0 мг/сут может быть использована для прогнозирования сахароснижающего эффекта препарата и возможности достижения нормогликемии.

Topics: Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Obesity; Oxyntomodulin; Prognosis; Prospective Studies

To develop an oral delivery system of glucagon-like peptide 1 (GLP-1) (28-36) for treating type-2 diabetes, B.S-GLP-1(28-36), a recombinant Bacillus subtilis spores transformed with a plasmid vector encoding five consecutive GLP-1 (28-36) nonapeptides with an enterokinase site was constructed.. GLP-1(28-36) nonapeptide was successfully expressed on the surface of B. subtilis spores and validated by Western blot and immunofluorescence. The therapeutic effect of oral administration of B.S-GLP-1(28-36) spores was evaluated in type 2 diabetic model mice. The efficacy of recombinant spores was examined for a period of 13 weeks after oral administration in diabetic mice. At the end of the sixth week, diabetic mice with oral administration of BS-GLP-1(28-36) spores showed decreased blood glucose levels from 2·4 × 10. The results of pathological observation showed that the recombinant spores also had a certain protective effect on the liver and islets of mice, and the content of GLP-1(28-36) in the pancreas of the experimental group was increased.. The results of this study revealed that GLP-1(28-36) nonapeptides can reduce blood glucose and play an important role in the treatment of type 2 diabetes.

Topics: Administration, Oral; Animals; Bacillus subtilis; Blood Glucose; Cell Surface Display Techniques; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Incretins; Insulin; Male; Mice; Recombinant Proteins; Spores, Bacterial; Treatment Outcome

Topics: Animals; Carbohydrates; Diabetes Mellitus, Type 2; Humans; Incretins; Mice; Parasympathetic Nervous System; Weight Gain

The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects.. We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the β-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data.. a) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion.. We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin Secretion; Insulin-Secreting Cells; Models, Theoretical

This article is about new prospects for incretin-related drugs in the treatment of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Development; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Studies evaluating endocrine and exocrine functions in fibrocalculous pancreatic diabetes (FCPD) are scarce.. Insulin, C-peptide, glucagon, incretin hormones (glucagon-like peptide 1 [GLP-1] and gastric inhibitory peptide [GIP]), and dipeptidyl peptidase IV (DPP-IV) were estimated in patients with FCPD (n = 20), type 2 diabetes mellitus (T2DM) (n = 20), and controls (n = 20) in fasting and 60 minutes after 75 g glucose.. Fasting and post-glucose C-peptide and insulin in FCPD were lower than that of T2DM and controls. Plasma glucagon decreased after glucose load in controls (3.72, 2.29), but increased in T2DM (4.01, 5.73), and remained unchanged in FCPD (3.44, 3.44). Active GLP-1 (pmol/L) after glucose load increased in FCPD (6.14 to 9.72, P = <.001), in T2DM (2.87 to 4.62, P < .001), and in controls (3.91 to 6.13, P < .001). Median active GLP-1 in FCPD, both in fasting and post-glucose state (6.14, 9.72), was twice that of T2DM (2.87, 4.62) and 1.5 times that of controls (3.91, 6.13) (P < .001 for all). Post-glucose GIP (pmol/L) increased in all: FCPD (15.83 to 94.14), T2DM (21.85 to 88.29), and control (13.00 to 74.65) (P < .001 for all). GIP was not different between groups. DPP-IV concentration (ng/mL) increased in controls (1578.54, 3012.00) and FCPD (1609.95, 1995.42), but not in T2DM (1204.50, 1939.50) (P = .131). DPP-IV between the three groups was not different. Fecal elastase was low in FCPD compared with T2DM controls.. In FCPD, basal C-peptide and glucagon are low, and glucagon does not increase after glucose load. GLP-1, but not GIP, in FCPD increases 1.5 to 2 times as compared with T2DM and controls (fasting and post glucose) without differences in DPP-IV.. 背景: 评价纤维结石性胰腺糖尿病(FCPD)内分泌和外分泌功能的研究很少。 方法: 测定FCPD组(n=20)、2型糖尿病(T2 DM)组(n=20)和对照组(n=20)空腹和75g葡萄糖后60min的胰岛素、C肽、胰高血糖素、肠泌素(胰高血糖素样肽1[GLP-1]和胃抑制肽[GIP])、二肽基肽酶IV(DPP-IV)水平。 结果: FCPD组空腹和糖负荷后C肽、胰岛素水平均低于T2 DM组和对照组。对照组糖负荷后胰高血糖素(pmol/L)降低(3.72; 2.29); T2 DM组升高(4.01; 5.73); FCPD组(3.44; 3.44)无明显变化。FCPD组(6.14~9.72; P=<0.001)、T2 DM组(2.87~4.62; P<0.001)和对照组(3.91~6.13; P<0.001)糖负荷后活性GLP-1(pmol/L)升高。FCPD组空腹和糖负荷后GLP-1(pmol/L)活性中位数(6.14; 9.72)是T2 DM组(2.87; 4.62)的两倍; 是对照组(3.91; 6.13)的1.5倍(P<0.001)。糖负荷后GIP(pmol/L)在所有组别中都升高:FCPD(15.83~94.14)、T2DM(21.85~88.29)、对照组(13.00~74.65), P<0.01。不同组间GIP差异无统计学意义。对照组(1578.54,3012.00)和FCPD组(1609.95,1995.42)的DPP-IV浓度(ng/mL)升高; 而T2 DM组(1204.50,1939.50)的DPP-IV浓度无明显变化(P=0.131)。DPP-IV于三组间差异无统计学意义。FCPD组中粪弹性蛋白酶低于T2 DM组对照组。 结论: FCPD患者糖负荷后基础C肽和胰高血糖素降低; 在糖负荷后胰高血糖素不升高。FCPD的GLP-1; 而不是GIP; 与T2 DM和对照组(空腹和糖负荷后)相比升高了1.5-2倍; 而DPP-IV没有差异.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; C-Peptide; Calcinosis; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Fibrosis; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Pancreatitis, Chronic; Time Factors; Young Adult

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Immune Checkpoint Inhibitors; Incretins

Highlights In Chinese patients with type 2 diabetes (T2D) and body mass index (BMI) <25 kg/m

Topics: Adult; Biomarkers; Blood Glucose; Body Mass Index; China; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycemic Control; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Male; Middle Aged; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Time Factors; Treatment Outcome; Weight Loss

The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders.. Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague-Dawley rats (n = 7) were injected only with a vehicle.. The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment.. Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.

Topics: Albuminuria; Animals; Autophagy; Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Incretins; Kidney; Liraglutide; Male; Rats, Inbred Strains; Signal Transduction

Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI.. We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs.. MAFLD (defined by HSI > 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI < 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was > threefold higher among subjects with HSI > 36 than among those with HSI < 30. Notably, HSI declined significantly ~ 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide.. About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Fatty Liver; Female; Follow-Up Studies; Gliclazide; Humans; Hypoglycemic Agents; Incretins; Italy; Male; Middle Aged; Prevalence; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome; Ultrasonography; Young Adult

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Kidney; Pharmaceutical Preparations