incretins and Diabetes-Mellitus

The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet β cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight. Here, we discuss the foundational science that led to the development of monomeric multi-incretin receptor agonists, culminating in the development of tirzepatide. We also look to the future of this field and comment on how the concept of multi-receptor agonists will continue to progress for the treatment of metabolic disease.

Topics: Body Weight; Diabetes Mellitus; Humans; Hyperglycemia; Incretins; Receptors, G-Protein-Coupled; Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin

Topics: Albuminuria; Diabetes Mellitus; Diabetic Retinopathy; Humans; Incretins; Kidney Diseases; Male; Peripheral Nervous System Diseases; Retinal Diseases; Vascular Diseases

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

Diabetic kidney disease (DKD) is one of the most common causes of end-stage renal disease worldwide. The treatment of DKD is strongly associated with clinical outcomes in patients with diabetes mellitus. Traditional therapeutic strategies focus on the control of major risk factors, such as blood glucose, blood lipids, and blood pressure. Renin-angiotensin-aldosterone system inhibitors have been the main therapeutic measures in the past, but the emergence of sodium-glucose cotransporter 2 inhibitors, incretin mimetics, and endothelin-1 receptor antagonists has provided more options for the management of DKD. Simultaneously, with advances in research on the pathogenesis of DKD, some new therapies targeting renal inflammation, fibrosis, and oxidative stress have gradually entered clinical application. In addition, some recently discovered therapeutic targets and signaling pathways, mainly in preclinical and early clinical trial stages, are expected to provide benefits for patients with DKD in the future. This review summarizes the traditional treatments and emerging management options for DKD, demonstrating recent advances in the therapeutic strategies for DKD.

Topics: Blood Glucose; Diabetes Mellitus; Diabetic Nephropathies; Humans; Incretins; Receptor, Endothelin A; Sodium

Adipokines are a family of hormones and cytokines with both pro- and anti-inflammatory effects released into the circulation to exert their hormonal effects. Adipokines are closely involved in most metabolic pathways and play an important modulatory role in lipid and carbohydrate homeostasis as they are involved in the pathophysiology of most metabolic disorders. Incretin-based therapy is a newly introduced class of antidiabetic drugs that restores euglycemia through several cellular processes; however, its effect on adipokines expression/secretion is not fully understood. In this review, we propose that incretin-based therapy may function through adipokine modulation that may result in pharmacologic properties beyond their direct antidiabetic effects, resulting in better management of diabetes and diabetes-related complications.

Topics: Adipokines; Adiponectin; Animals; Biomarkers; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome

Diabetes mellitus (DM) is a risk factor for cancer in many organs and associated with an increased risk of cholangiocarcinoma (CCA). The molecular linkage between these diseases has been demonstrated in preclinical studies, which have highlighted the role of hyperinsulinemia and hyperglycemia in the carcinogenesis and progression of CCA. Recent studies on the emerging role of antidiabetic medication in the development and progression of CCA showed a subclass of antidiabetic drug with a therapeutic effect on CCA. Although associations between CCA, insulin analogues and sulfonylureas are unclear, incretin-based therapy is likely associated with an increased risk for CCA, and may lead to CCA progression, as demonstrated by in vitro and in vivo experiments. In contrast, biguanides, especially metformin, exert an opposite effect, associated with a reduced risk of CCA and inhibited in vitro and in vivo CCA progression. The association between incretin-based therapy and the risk of CCA needs further clarification, as metformin is being studied in an ongoing clinical trial. Understanding the association between DM and CCA is critical for preventing the development of CCA in patients with DM, and for establishing the appropriateness of antidiabetic medication to treat CCA. Determining how metformin affects CCA can lead to repurposing this safe and well-known drug for improving CCA treatment, regardless of the diabetes status of patients.

Topics: Blood Glucose; Case-Control Studies; Cholangiocarcinoma; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Sulfonylurea Compounds

Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis. The impaired incretin effects observed in the pathophysiologic abnormality of type 2 diabetes have triggered the pharmacological development of incretin-based therapy through the activation of glucagon-like peptide-1 (GLP-1) receptor, including GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP4) inhibitors. In the light of the mechanisms involved in the stimulation of GLP-1 secretion, it is a fundamental question to explore whether glucose and lipid homeostasis can be manipulated by the digestive system in response to nutrient ingestion and taste perception along the gastrointestinal tract. While glucose is a potent stimulant of GLP-1 secretion, emerging evidence highlights the importance of bitter tastants in the enteroendocrine secretion of gut hormones through activation of bitter taste receptors. This review summarizes bitter chemosensation in the intestines for GLP-1 secretion and metabolic regulation based on recent advances in biological research of bitter taste receptors and preclinical and clinical investigation of bitter medicinal plants, including bitter melon, hops strobile, and berberine-containing herbs (e.g. coptis rhizome and barberry root). Multiple mechanisms of action of relevant bitter phytochemicals are discussed with the consideration of pharmacokinetic studies. Current evidence suggests that specific agonists targeting bitter taste receptors, such as human TAS2R1 and TAS2R38, may provide both metabolic benefits and anti-inflammatory effects with the modulation of the enteroendocrine hormone secretion and bile acid turnover in metabolic syndrome individuals or diabetic patients with dyslipidemia-related comorbidities.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus; Dyslipidemias; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Intestines; Lipids; Receptors, G-Protein-Coupled; Secretory Pathway; Signal Transduction; Taste

An increasing number of studies have investigated associations of antidiabetes medications with cancer risk. Antidiabetes medications are classified by their mechanisms of action on tissues and organs. They potentially act as both causative and confounding factors in the temporal association of diabetes and cancer.. To present the current evidence regarding both the carcinogenic and anti-carcinogenic effects of antidiabetes medications on cancer in humans.. A review of the scientific literature.. The most conclusive evidence shown of an association of antidiabetes medication with a specific cancer was for that of the thiazolidinedione pioglitazone with bladder cancer. Currently, there is inconclusive evidence regarding a possible association of incretin therapies, drugs of the dipeptidyl peptidase-4 inhibitor class, with the risk of pancreatic cancer. Insulin, sulfonylureas, metformin and sodium-glucose co-transporter-2 inhibitors appear not to be associated with increased risk of any cancer. Sparse evidence suggests possible protective effects against cancer incidence of metformin, sulfonylureas, thiazolidinediones, incretin-based drugs and sodium-glucose co-transporter-2 inhibitors.. The conflicting evidence regarding associations of antidiabetes medications with cancer risk is apparently attributable to both methodological issues and to the complexity of the subject. More recent and better-designed studies have weakened the evidence for links between antidiabetes medications and cancer risk.

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Neoplasms; Pancreatic Neoplasms; Protective Factors; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones; Urinary Bladder Neoplasms

Type 2 diabetes mellitus (T2DM) portends high risk of atherosclerotic cardiovascular (CV) events and of CV mortality; moreover, this group of patients has a very high probability of developing heart failure (HF). In this review, we discuss new advances in pharmacological treatment both in CV prevention and in HF management with a special focus on T2DM patients. A large number of randomized clinical trials and meta-analyses provided strong evidence about therapeutic strategies acting on glucose metabolism, such as GLP-1 RA and SGLT2i and about lipid-lowering treatment, such as PCSK9i and icosapent ethyl. Moreover, SGLT2i demonstrated strong evidence of benefit particularly in HF management both in diabetic and non-diabetic patients. The pathophysiological bases of multiple mechanisms of benefit of this class of drug explain the unexpected and remarkable results demonstrated both by prevention trials and by trials dedicated only to HF (like DAPA-HF). These, new drugs in the CV therapeutic armamentarium are establishing a new comprehensive approach from prevention to therapy of HF, giving more emphasis on HF classification in four stages (A→D). New therapies, which are on the horizon, promise to further reduce CV mortality and morbidity in HF patients irrespective of diabetic status.

Topics: Anticholesteremic Agents; Cardiology; Cardiovascular Diseases; Cooperative Behavior; Diabetes Mellitus; Endocrinology; Glucagon-Like Peptide-1 Receptor; Heart Disease Risk Factors; Heart Failure; Humans; Incretins; Interdisciplinary Communication; Patient Care Team; PCSK9 Inhibitors; Risk Assessment; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Patients with diabetes mellitus have been reported to be at a high risk of complications from SARS-CoV2 virus infection (COVID-19). In type 2 diabetes, there is a change in immune system cells, which shift from an anti-inflammatory to a predominantly pro-inflammatory pattern. This altered immune profile may induce important clinical consequences, including increased susceptibility to lung infections; and enhanced local inflammatory response. Furthermore, dipeptidyl peptidase 4 (DPP4) enzyme is highly expressed in the lung, and that it may have additional actions besides its effects on glucose metabolism, which might exert profound pro-inflammatory effects. We briefly review the impact on the inflammatory system of DPP4 for its possible detrimental effect on COVID-19 syndrome, and of DPP4 inhibitors (gliptins), currently used as glucose lowering agents, which may have the potential to exert positive pleiotropic effect on inflammatory diseases, in addition to their effects on glucose metabolism. Thanks to these ancillary effects, gliptins could potentially be "repurposed" as salutary drugs against COVID-19 syndrome, even in non-diabetic subjects. Clinical studies should be designed to investigate this possibility.

Topics: Animals; Betacoronavirus; Coronavirus Infections; COVID-19; Diabetes Mellitus; Dipeptidyl Peptidase 4; Humans; Incretins; Inflammation; Pandemics; Pneumonia, Viral; Prognosis; SARS-CoV-2

New era antidiabetic drugs are characterized by cardiovascular safety, including specific outcome benefits observed in randomized clinical trials (RCTs). It has been postulated that the favorable effects of new antidiabetic agents are related both to better control of blood pressure (BP) levels and to activation of multiple anti-atherosclerotic properties. In this review, we aimed to assess whether antidiabetic drugs have a pressor effect in glucose control and outcome-oriented RCTs, and to summarize the activated pathophysiological mechanisms relevant to BP control following the use of different antidiabetic drug classes. We also tried to determine which, if any, are the BP-lowering effects of more intense vs less intense glucose-lowering strategy irrespectively of trial antidiabetic regimen. To provide more robust results and evidence-based argumentation, a meta-analysis of placebo-controlled antidiabetic drug RCTs was undertaken to estimate the ongoing BP reduction for all considered and each separate drug class alone. This quantitative synthesis might be helpful for the clinician 1) to select or avoid the use of some classes of antidiabetic agents with a potential favorable or adverse pressor effect, respectively 2) to organize the overall drug regimen in patients with diabetes mellitus and minimize side effects because of concomitant use of drugs with established pressor effect (i.e. antihypertensive agents). This review was also organized to indicate whether BP change associated with different antidiabetic treatments may explain the specific macrovascular outcome benefits. Between all antidiabetic drugs including exogenous insulin, only sodium-glucose cotransporter 2 inhibitors produce a clinically important BP-lowering effect, but this BP reduction alone cannot explain the observed cardiovascular benefit.

Topics: Biomarkers; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Diabetes mellitus (DM) is one of the most common diseases worldwide. Its adverse effects on several body organs, have made treatment of DM a priority. One of the most serious complications of DM is diabetic nephropathy (DN).. The aim of this review is to critically discuss available data on the pharmacological management of DN.. A comprehensive review of the literature was performed to identify studies assessing the impact of several drug classes on DN.. Several studies have been conducted in order to find a novel and effective treatment of DN. So far, the cornerstone therapy of DN consists of renin-angiotensin system (RAS) inhibitors, agents that decrease the synthesis of intrarenal angiotensin II or block its receptors. Their antiproteinuric and antihypertensive effects can not only decelerate the progress of DN but prevent its onset as well. Novel antidiabetic drugs, such as sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide- 1 receptor agonists (GLP-1 RA), are promising agents in the therapy of DN, due to their positive effect on renal and cardiovascular adverse events. From lipid-lowering agents, atorvastatin improves DN up to stage 3 and substantially reduces CVD.. RAS inhibitors, SGLT-2i and GLP-1 agonists were found to be beneficial for the treatment of DN. Larger renal trials are needed in order to incorporate these drugs into the first line treatment of DN.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus; Diabetic Nephropathies; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Kidney; Renin-Angiotensin System; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Incretin contains two peptides named glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Drug therapy using incretin has become a new strategy for diabetic treatments due to its significant effects on improving insulin receptors and promoting insulinotropic secretion. Considering the fact that diabetes millitus is a key risk factor for almost all age-related diseases, the extensive protective roles of incretin in chronic diseases have received great attention. Based on the evidence from animal experiments, where incretin can protect against the pathophysiological processes of neurodegenerative diseases, clinical trials for the treatments of Alzheimer's disease (AD) and Parkinson's disease (PD) patients are currently ongoing. Moreover, the protective effect of incretin on heart has been observed in cardiac myocytes, smooth muscle cells and endothelial cells of vessels. Meanwhile, incretin can also inhibit the proliferation of aortic vascular smooth muscle cells, which can induce atherosclerogenesis. Incretin is also beneficial for diabetic microvascular complications, including nephropathy, retinopathy and gastric ulcer, as well as the hepatic-related diseases such as NAFLD and NASH. Besides, the anti-tumor properties of incretin have been proven in diverse cancers including ovarian cancer, pancreas cancer, prostate cancer and breast cancer.

Topics: Aging; Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Incretins; Liver Diseases; Neoplasms; Neurodegenerative Diseases; Stomach Ulcer

Epidemiological evidence supports a reduced prevalence of Thoracic Aortic Aneurysm (TAA) and Abdominal Aortic Aneurysm (AAA) in patients with Diabetes (DM). The mechanisms underlying this negative association are unknown. Some studies support that hyperglycemia has effects on the Extracellular Matrix (ECM), resulting in collagen cross-links and altered proteolytic activity, which ultimately counteracts aneurysm formation. However, recent experimental research indicates that incretin- based anti-diabetic therapy and Glucagon-Like Peptide-1 (GLP-1) may reduce the formation of TAA. GLP-1 is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signaling exerts numerous pleiotropic effects on various tissues, including protective effects on the myocardium and vascular endothelium. Recent studies also report protective effects of GLP-1 based therapy on the formation of aneurysms in animal models and direct effects of GLP-1 signaling on the molecular mechanisms suggested to influence TAA formation, including inflammation, proteolytic activity and collagen composition. In this narrative review, we present the available evidence for effects of GLP-1 on experimental aneurysm development and discuss the potential role of GLP-1 in aneurysm formation based on available data from pre-clinical and clinical studies.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Risk Factors; Signal Transduction; Treatment Outcome; Vascular Remodeling

The cardiovascular (CV) safety in terms of heart failure among different classes of treatment remains largely unknown. We sought to assess the comparative effect of these agents on heart failure outcomes.. This study was registered in the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials were searched. For the primary outcomes reported previously, studies between Jan 1, 1980 and June 30, 2016 were screened, and subsequently updated till Jan 24, 2019. We performed network meta-analysis to obtain estimates for the outcomes of heart failure, in particular by rankograms for ranking of heart failure risk as well as by pairwise comparisons among all classes of anti-diabetic medications.. A total of 91 trials were included, among which were 171,253 participants and 4163 reported cases of heart failure events. As for rankograms, the surface under the cumulative ranking curves (SUCRA) of sodium-glucose co-transporters 2 and thiazolidinediones were 93.4% and 4.3%, respectively, signifying the lowest and highest risk of heart failure, respectively. As for pairwise comparisons in the network, sodium-glucose co-transporters 2 were significantly superior to insulin (OR: 0.75, 95% CI 0.62-0.91), dipeptidyl peptidase 4 inhibitors (OR: 0.68, 95% CI 0.59-0.78), glucagon-like peptide-1 receptor agonists (OR: 0.65, 95% CI 0.54-0.78), and thiazolidinediones (OR: 0.46, 95% CI 0.27-0.77) in terms of heart failure risk. Furthermore, in an exploratory analysis among subjects with underlying heart failure or at risk of heart failure, the superiority of sodium-glucose co-transporters 2 was still significant.. In terms of heart failure risk, sodium-glucose co-transporters 2 were the most favorable option among all classes of anti-diabetic medications.

Topics: Cardiovascular Diseases; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Protective Agents; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Incretins are metabolic hormones released after a meal that increase insulin secretion from pancreatic

Topics: Animals; Biological Products; Diabetes Mellitus; Humans; Hypoglycemic Agents; Incretins; Phytotherapy; Plants, Medicinal

Hypoglycaemia is common in both type 1 and type 2 diabetes and has both acute and long-term consequences. Therefore, a key to proper glucose-lowering therapy in diabetes is to avoid or prevent hypoglycaemia. Incretin therapy (DPP-4 inhibitors and GLP-1 receptor agonists) offers an advantage in this respect, because it reduces glucose with a low risk of hypoglycaemia, both in monotherapy and in combination with other therapies. The reason for this low risk of hypoglycaemia is the glucose dependency of action of incretin therapy and the sustainment of glucose counter-regulatory hormone responses to hypoglycaemia, in particular the glucagon response. Incretin therapy is also associated with a low risk of hypoglycaemia in patient groups which are especially vulnerable and susceptible for hypoglycaemia, e.g., subjects with renal impairment, elderly subjects and subjects with on-going insulin therapy. This review summarizes how incretin therapy may meet the challenges of hypoglycaemia and suggests that incretin therapy is a therapy of choice to avoid hypoglycaemia, both in the general diabetes population and in subjects with increased risk or vulnerability for hypoglycaemia.

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins

The purpose of this review is to correlate predictions based on pre-clinical data with outcomes from clinical trials that examine the effects of incretin-based diabetes treatments on the kidney. The incretin-based treatments include agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of the enzyme, dipeptidyl peptidase-4 (DPP-4). In addition, what is known about the incretin-based therapies will be compared to what is known about the renal effects of SGLT2 inhibitors.. Large-scale clinical trials have shown that SGLT2 inhibitors reduce albuminuria and preserve estimated glomerular filtration rate (eGFR) in patients with diabetic nephropathy. A concise and plausible hemodynamic mechanism is supported by pre-clinical research on the physiology and pharmacology of SGLT2. Large-scale clinical trials have shown that incretin-based therapies mitigate albuminuria but have not shown beneficial effects on eGFR. Research on the incretin-based therapies has yielded a diverse array of direct effects throughout the body, which fuels speculation as to how these drugs might benefit the diabetic kidney and affect its function(s). But in vivo experiments have yet to confirm that the proposed mechanisms underlying emergent phenomena, such as proximal tubular fluid reabsorption, are the ones predicted by cell and molecular experiments. There may be salutary effects of incretin-based treatments on the diabetic kidney, but the system is complex and not amenable to simple explanation or prior prediction. This contrasts with the renal effects of SGLT2 inhibitors, which can be explained concisely.

Topics: Clinical Trials as Topic; Diabetes Mellitus; Hemodynamics; Humans; Incretins; Kidney; Treatment Outcome

Topics: Animals; Benzhydryl Compounds; Diabetes Mellitus; Drug Therapy, Combination; Glucagon; Glucosides; Humans; Hypoglycemic Agents; Incretins; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA.

Topics: Bariatric Surgery; Bile Acids and Salts; Constipation; Diabetes Mellitus; Energy Metabolism; Gastrointestinal Microbiome; Glucose; Homeostasis; Humans; Incretins; Lipid Metabolism; Metabolic Diseases; Metabolism; Obesity; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Thyroid Gland

This chapter deals with novel therapeutic approaches, predominantly for type 2 diabetes. Incretin-based therapies utilize the effects of glucagon-like peptide-1 (GLP-1), which stimulates insulin and inhibits glucagon secretion in a glucose-dependent manner. Incretin-based therapies comprise injectable GLP-1 receptor agonists and orally active dipeptidyl peptidase-IV inhibitors. Both have a low hypoglycaemia risk. GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide, albiglutide) reduce glycated haemoglobin levels more effectively than oral antidiabetic agents do and lead to weight loss as well as a slight decrease in systolic blood pressure. The most common side effects are nausea and fullness, especially during the start of therapy. Dipeptidyl peptidase-IV inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) are not inferior to sulfonylureas, causing significantly less hypoglycaemia and not inducing weight gain. Specific adverse effects have not been discovered yet, and cardiovascular safety has been demonstrated in respective studies. Sodium-glucose transporter-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin) were introduced recently. They block the tubular reabsorption of glucose in the kidney and represent an insulin-independent mode of action, with low hypoglycaemia risk and allowing weight loss. The most common side effects are genital and urinary tract infections. Other novel drugs in development (G-protein-coupled receptor agonists, interleukin-1 antagonists) are also described.

Topics: Animals; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium-glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential.. This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart.. SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins; Molecular Targeted Therapy; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Glucose-dependent insulinotropic polypepide (GIP) was first extracted from porcine gut mucosa and identified as "incretin" decades ago. Though early studies have shown the possible GIP isoforms by gel filtration profiles from porcine or human intestinal extracts analyzed by radioimmunoassay (RIA), GIP is currently believed to consist of 42 amino acids (GIP1-42), which are released from gut K-cells and promote postprandial insulin release. In fact, GIP1-42 is usually processed from proGIP by the action of prohormone convertase (PC) 1/3 in the gut. GIP expression is occasionally found in the intestinal glucagon-like peptide-1-secreting cells, suggesting gene expression of both GIP and proglucagon can co-exist in identical cells. However, GIP1-42 immunoreactivity is rarely found in α-cells or other pancreatic endocrine cells of wild-type mammals. Interestingly, we found that short-form GIP1-30 is expressed in and released from pancreatic α-cells and a subset of enteroendocrine cells through proGIP processing by PC2. GIP1-30 is also insulinotropic and modulates glucose-stimulated insulin secretion in a paracrine manner. It is also suggested that short-form GIP1-30 possibly plays a crucial role for the islet development. It has not been well elucidated whether expression of GIP1-30 is modulated in the diabetic status, and whether GIP1-30 might have therapeutic potentials. Our preliminary data suggest that short-form GIP1-30 might play important roles in glucose metabolism.

Topics: Animals; Diabetes Mellitus; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Glucagon-Secreting Cells; Glucose; Humans; Incretins; Mice; Peptide Fragments; Proprotein Convertase 1; Swine

Insulin secretion from the pancreatic β-cell (referred to as β-cell hereafter) plays a central role in glucose homeostasis. Impaired insulin secretion is a major factor contributing to the development of diabetes and, therefore, is an important target for treatment of the disease. Cyclic adenosine monophosphate is a key second messenger in β-cells that amplifies insulin secretion. Incretins released by the gut potentiate insulin secretion through cyclic adenosine monophosphate signaling in β-cells, which is the basis for the incretin-based diabetes therapies now being used worldwide. Despite its importance, the interaction between glucose metabolism and incretin/cyclic adenosine monophosphate signaling in β-cells has long been unknown. A recent study showed that cytosolic glutamate produced by glucose metabolism in β-cells is a key signal in incretin-induced insulin secretion. Here we review the physiological and pathophysiological roles of β-cell glutamate signaling in incretin-induced insulin secretion.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Glucose; Glutamic Acid; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Metabolomics; Obesity; Signal Transduction

Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

Topics: Adrenal Cortex; Animals; Corticotropin-Releasing Hormone; Diabetes Mellitus; Female; Fetal Development; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucocorticoids; Humans; Hypothalamo-Hypophyseal System; Incretins; Insulin Resistance; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Stress, Physiological

Parkinson's disease is a chronic neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. The pathophysiological mechanisms underlying Parkinson's are still unknown. Mitochondrial dysfunction, abnormal protein aggregation, increased neuroinflammation and impairment of brain glucose metabolism are shared processes among insulinresistance, diabetes and neurodegeneration and have been suggested as key mechanisms in development of Parkinson's and cognitive impairment.. To review experimental and clinical evidence of underlying Parkinson's pathophysiology in common with diabetes and cognitive impairment. Anti-diabetic agents and recent patents for insulin-resistance that might be repositioned in the treatment of Parkinson's also have been included in this review.. A narrative review using MEDLINE database.. Common antidiabetic treatments such as DPP4 inhibitors, GLP-1 agonists and metformin have shown promise in the treatment of Parkinson's disease and cognitive impairment in animals and humans. Study of the pathophysiology of neurodegeneration common between diabetes and Parkinson's disease has given rise to new treatment possibilities. Patents published in the last 5 years could be used in novel approaches to Parkinson's treatment by targeting specific pathophysiology proteins, such as Nurr1, PINK1 and NrF2, while patents to improve penetration of the blood brain barrier could allow improved efficacy of existing treatments.. Further studies using GLP-1 agonists and DPP-4 inhibitors to treat PD are warranted as they have shown promise.

Topics: Animals; Antiparkinson Agents; Brain; Cognition; Cognition Disorders; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Drug Repositioning; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Neuroprotective Agents; Parkinson Disease; Patents as Topic

Incretin-based therapies are revolutionizing the field of human diabetes mellitus (DM) by replacing insulin therapy with safer and more convenient long-acting drugs.. Incretin hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) are secreted from the intestinal tract in response to the presence of food in the intestinal lumen. GLP-1 delays gastric emptying and increases satiety. In the pancreas, GLP-1 augments insulin secretion and suppresses glucagon secretion during hyperglycemia in a glucose-dependent manner. It also protects beta cells from oxidative and toxic injury and promotes expansion of beta cell mass.. Clinical data have revealed that GLP-1 analog drugs are as effective as insulin in improving glycemic control while reducing body weight in people suffering from type 2 DM. Furthermore, the incidence of hypoglycemia is low with these drugs because of their glucose-dependent mechanism of action. Another significant advantage of these drugs is their duration of action. While insulin injections are administered at least once daily, long-acting GLP-1 analogs have been developed as once-a-week injections and could potentially be administered even less frequently than that in diabetic cats.. This article reviews the physiology of incretin hormones, and the pharmacology and use of GLP-1 analogs, with emphasis on recent research in cats. Further therapies that are based on incretin hormones, such as DPP-4 inhibitors, are also briefly discussed, as are some other treatment modalities that are currently under investigation.

Topics: Animals; Cat Diseases; Cats; Diabetes Mellitus; Glucagon-Like Peptide 1; Incretins

Pancreatic α-cell hyperplasia (ACH) was once an esoteric pathological entity, but it has become an important differential diagnosis of hyperglucagonemia after inactivating glucagon receptor (GCGR) genomic mutations were found in patients with ACH. Recently, the controversy over the pancreatic effects of incretins has stimulated much discussion of ACH that often includes inaccurate statements not supported by the literature.. Literature related to ACH was reviewed.. ACH is defined as a diffuse and specific increase in the number of α-cells. A dozen cases have been reported and fall into three clinical types: reactive, functional, and nonfunctional. Characterized by remarkable hyperglucagonemia without glucagonoma syndrome, reactive ACH is caused by inactivating GCGR mutations, and its main clinical significance is pancreatic neuroendocrine tumors diagnosed at middle age. The Gcgr(-/-) mice, a model of reactive ACH, exhibit a multistage tumorigenesis in their pancreata. Pharmacological agents that inhibit glucagon signaling also cause reactive ACH in animals and possibly in humans as well. The pancreata of incretin-treated humans and those of reactive ACH murine models share similarities. Functional ACH features hyperglucagonemia with glucagonoma syndrome. Nonfunctional ACH is associated with normal glucagon levels. The causes of functional and nonfunctional ACH are unknown as yet.. ACH is a histological diagnosis and clinically heterogeneous. Caused by GCGR mutations, reactive ACH is a preneoplastic lesion giving rise to slow-developing pancreatic neuroendocrine tumors. The effects of treatments targeting glucagon signaling in this regard remain controversial. The strong negative feedback control of glucagon signaling conserved in all mammals studied, including humans, makes long-term pancreatic tumor surveillance advisable for the glucagon signaling-targeting therapies.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Glucagon-Secreting Cells; Humans; Hyperplasia; Incretins; Mice; Mice, Knockout; Pancreatic Diseases; Receptors, Glucagon

Insulin therapy remains the standard of care for achieving and maintaining adequate glycemic control, especially in hospitalized patients with critical and noncritical illnesses. Insulin therapy is more effective against elevated fasting glycaemia but less in the reduction of postprandial hyperglycaemia. It is associated with a high incidence of hypoglycemia and weight gain. Contrary, GLP-1 mimetic therapy improves postprandial glycaemia without the hypoglycaemia and weight gain associated with aggressive insulin therapy. Moreover, it has the potential to reduce cardiovascular related morbidity. However, its increased immunogenicity and severe gastrointestinal adverse effects present a huge burden on patients. Thus, a right combination of basal insulin which has lowering effect on fasting plasma glucose and GLP-1 mimetic with its lowering effect on postprandial plasma glucose with minimal gastrointestinal adverse effects, seems the right therapy choice from a clinical point of view for some diabetic patients. In this article, we discuss the pros and cons of the use of insulin analogues and GLP-1 mimetics that are associated with the treatment of type 2 diabetes.

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulins; Peptides

Topics: Acarbose; Biguanides; Blood Glucose Self-Monitoring; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Routes; Drug Design; Drug Therapy, Combination; Education, Medical, Continuing; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Pyrazines; Sitagliptin Phosphate; Triazoles

Diabetes patients are at high risk for development of cardiovascular disease. The cardiovascular safety of antidiabetic medications is a concern. Incretin therapies, including glucagon-like peptide 1 receptor (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, have recently been introduced to clinical practice and are widely used. Data from phase 2 and 3 trials and retrospective analyses of clinical databases have shown favorable changes in cardiovascular risk factors and outcomes. However, only a few prospective trials have been designed with cardiovascular outcomes as a primary end point. From current data, alogliptin and saxagliptin do not change cardiovascular risk in type 2 diabetes mellitus (T2DM) patients. Vildagliptin does not alter myocardial function in T2DM patients with systolic dysfunction. However, the possibility of an increase in clinical heart failure and worsened outcomes in patients with existing heart failure is suggested by current data. Clinicians need to follow patients on DPP-4 inhibitors carefully for this possibility until more prospective randomized controlled data are available.

Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic

TRPM2 is a Ca(2+)-permeable non-selective cation channel that can be activated by adenosine dinucleotides, hydrogen peroxide, or intracellular Ca(2+). The protein is expressed in a wide variety of cells, including neurons in the brain, immune cells, endocrine cells, and endothelial cells. This channel is also well expressed in β-cells in the pancreas. Insulin secretion from pancreatic β-cells is the primary mechanism by which the concentration of blood glucose is reduced. Thus, impairment of insulin secretion leads to hyperglycemia and eventually causes diabetes. Glucose is the principal stimulator of insulin secretion. The primary pathway involved in glucose-stimulated insulin secretion is the ATP-sensitive K(+) (KATP) channel to voltage-gated Ca(2+) channel (VGCC)-mediated pathway. Increases in the intracellular Ca(2+) concentration are necessary for insulin secretion, but VGCC is not sufficient to explain [Ca(2+)]i increases in pancreatic β-cells and the resultant secretion of insulin. In this review, we focus on TRPM2 as a candidate for a [Ca(2+)]i modulator in pancreatic β-cells and its involvement in insulin secretion and development of diabetes. Although further analyses are needed to clarify the mechanism underlying TRPM2-mediated insulin secretion, TRPM2 could be a key player in the regulation of insulin secretion and could represent a new target for diabetes therapy.

Topics: Calcium; Diabetes Mellitus; Glucose; Humans; Incretins; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; TRPM Cation Channels

Glucagon-like peptide 1 (GLP1) is a major incretin hormone. This means that it is secreted by the gut in response to food and helps in reducing post-prandial glucose exertion. It achieves this through a number of mechanisms, including stimulating insulin release by pancreatic β-cells in a glucose-dependent manner; inhibition of glucagon release by pancreatic α-cells (also in a glucose-dependent manner); induction of central appetite suppression and by delaying gastric empting thereby inducing satiety and also reducing the rate of absorption of nutrients. However, GLP1 receptors have been described in a number of extra-pancreatic tissues, including the endothelium and the myocardium. This suggests that the physiological effects of GLP1 extend beyond post-prandial glucose control and raises the possibility that GLP1 might have cardiovascular effects. This is of importance in our understanding of incretin hormone physiology and especially because of the possible implications that it might have with regard to cardiovascular effects of incretin-based therapies, namely DPP-IV inhibitors (gliptins) and GLP1 analogues. This review analyzes the animal and human data on the effects of GLP1 on the cardiovascular system in health and in disease and the currently available data on cardiovascular effects of incretin-based therapies. It is the author's view that the physiological role of GLP1 is not only to minimize postprandial hypoglycaemia, but also protect against it.

Topics: Animals; Blood Glucose; Cardiovascular System; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Inflammation; Insulin-Secreting Cells; Oxidative Stress; Triglycerides

Noninsulin antidiabetic medications coupled with diet and exercise are effective in managing most patients with type 2 diabetes. However, it is essential to evaluate the safety and effectiveness of the home antidiabetic medication regimen when the patient is hospitalized. Prescribers need to be aware of the mechanism of action of each class, contraindications, precautions, and adverse effects to formulate a safe and effective management plan. This article details the different classes of noninsulin antidiabetic medications, the mechanism of action, metabolism, elimination, dose form, usual and maximum doses, contraindications, precautions, common adverse reactions, and implications for use in the hospitalized patient.

Topics: Benzamides; Biguanides; Bromocriptine; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glycoside Hydrolase Inhibitors; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Islet Amyloid Polypeptide; Metformin; Sulfonylurea Compounds; Thiazolidinediones

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, and somatostatin to facilitate glucose disposal. The actions of incretin hormones are terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) and through renal clearance. GLP-1 and GIP promote β-cell proliferation and survival in rodents. DPP-4 inhibitors expand β-cell mass, reduce α-cell mass, and inhibit glucagon secretion in preclinical studies; however, whether incretin-based therapies sustain functional β-cell mass in human diabetic subjects remains unclear. GLP-1 and GIP exert their actions predominantly through unique G protein-coupled receptors expressed on β-cells and other pancreatic cell types. Accurate localization of incretin receptor expression in pancreatic ductal or acinar cells in normal or diabetic human pancreas is challenging because antisera used for detection of the GLP-1 receptor often are neither sufficiently sensitive nor specific to yield reliable data. This article reviews recent advances and controversies in incretin hormone action in the pancreas and contrasts established mechanisms with areas of uncertainty. Furthermore, methodological challenges and pitfalls are highlighted and key areas requiring additional scientific investigation are outlined.

Topics: Acinar Cells; Animals; Atherosclerosis; Blotting, Western; Cell Proliferation; Cricetinae; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Inflammation; Insulin-Secreting Cells; Male; Mice; Pancreas; Rats; Real-Time Polymerase Chain Reaction; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

The central role of insulin in the management of patients with type 1 diabetes mellitus (T1DM) remains, nearly a century after its first use in humans. In patients with type 2 diabetes mellitus (T2DM), the role of insulin has evolved as other therapies have been introduced, with insulin now used across the spectrum of the disease. This article discusses the use of insulin in patients with T1DM or T2DM, including combined use with other agents in T2DM, with an emphasis on incretin-based therapies. In addition, new insulin products and concentrations are discussed along with their varied routes of administration.

Topics: Chemistry, Pharmaceutical; Diabetes Mellitus; Drug Combinations; Humans; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Insulins; Treatment Outcome

Heart failure (HF) and diabetes mellitus (DM) commonly co-exist, with a prevalence of DM of up to 40 % in HF patients. Treatment of DM in patients with HF is challenging since many of the contemporary therapies used for the treatment of DM are either contraindicated in HF or are limited in their use due to the high prevalence of co-morbidities such as significant renal dysfunction. This article presents an overview of the physiology of the incretin system and how it can be targeted therapeutically, highlighting implications for the management of patients with DM and HF. Receptors for the incretin glucagon-like peptide-1 (GLP-1) are expressed throughout the cardiovascular system and the myocardium and are up-regulated in HF. GLP-1 therapy improves cardiac function in animal models of HF through augmented glucose uptake in the myocardium mediated through a p38 MAP kinase pathway. Small clinical studies have shown that GLP-1 improves ejection fraction, reduces BNP levels and enhances functional capacity in patients with chronic HF. A number of randomized controlled trials are currently underway to define the utility of targeting the incretin system in HF patients with DM. Incretin-based therapy may represent a novel therapeutic strategy in the treatment of HF patients with diabetes, in particular for their cardioprotective effects independent of those attributable to tight glycemic control.

Topics: Comorbidity; Diabetes Mellitus; Glucagon-Like Peptide 1; Heart Failure; Humans; Incretins; Treatment Outcome

Type 3c diabetes mellitus (T3cDM) is a clinically relevant condition with a prevalence of 5-10% among all diabetic subjects in Western populations. Its prevalence and clinical importance have been underestimated and underappreciated so far. In contrast to the management of type 1 or type 2 diabetes, the endocrinopathy in T3cDM is very complex and complicated by additional present comorbidities such as maldigestion and concommitant qualitative malnutrition. The failure to correctly diagnose T3cDM leads to failure to implement an appropriate medical therapy of these patients. Physicians should screen for important and easily reversable pathological conditions such as exocrine insufficiency, lack of fat-soluble vitamins (especially vitamin D) and impairment of fat hydrolysis and incretin secretion which are found very commonly in T3cDM. Since most patients with T3cDM suffer from chronic pancreatitis, physicians must additionally be aware of the elevated risk of pancreatic cancer in this subset of patients.

Topics: Diabetes Mellitus; Diagnostic Errors; Early Diagnosis; Humans; Incretins; Malnutrition; Pancreas, Exocrine; Pancreatic Diseases; Prevalence; Risk Factors; Vitamins

Diabetes is the chronic progressive disease and blood glucose control mechanism fails for impaired insulin secretion and increased resistance to insulin action in the skeletal muscle and liver. Unfortunately, cure for diabetes cannot be achieved now, however, it may be possible to control blood glucose at the same level compared with non-diabetic individuals by combining treatment methods. Of course, dietary and exercise therapy are important, and oral hypoglycemic agents and insulin will be used appropriately further, to control not only the average of the blood glucose levels for but also the blood glucose change.

Topics: Blood Glucose; Diabetes Mellitus; Diet, Diabetic; Exercise Therapy; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells

Topics: Animals; Cyclobutanes; Diabetes Mellitus; Female; Humans; Incretins; Insulin; Lactones; Male; Metformin; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Sex Characteristics; Sulfonylurea Compounds

Insulin secretion is a highly dynamic process regulated by various factors including nutrients, hormones, and neuronal inputs. The dynamics of insulin secretion can be studied at different levels: the single β cell, pancreatic islet, whole pancreas, and the intact organism. Studies have begun to analyze cellular and molecular mechanisms underlying dynamics of insulin secretion. This review focuses on our current understanding of the dynamics of insulin secretion in vitro and in vivo and discusses their clinical relevance.

Topics: Animals; Circadian Rhythm; Cyclic AMP; Cytoplasmic Granules; Diabetes Mellitus; Eating; Glucose Metabolism Disorders; Guanine Nucleotide Exchange Factors; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Models, Biological; Obesity; Potassium Channels; Secretory Rate; Signal Transduction

Research has substantiated that patients with type 2 diabetes mellitus are at increased risk for cardiovascular (CV) disease. It is well established that aggressive management of metabolic risk factors is critical to reducing morbidity and mortality in patients with diabetes. A number of clinical trials are currently focusing on evaluating the safety and efficacy of therapeutic approaches to diabetes. These trials will provide additional information on the role of aggressive management of glucose in patients with diabetes and CV risk. This article provides a summary of these ongoing trials, and discusses the impact of glycemic control and strategies to promote CV risk reduction in patients with diabetes.

Topics: Adamantane; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drugs, Investigational; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Risk Assessment; Risk Reduction Behavior

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Incretins

Glucose homeostasis corresponds to the overall physiological, cellular, and molecular mechanisms which tightly maintain the glycaemia between ∼4.5 and ∼6 mM. The resulting blood glucose concentration is the consequence of a balance between the mechanisms that ensure the entry and the output of glucose in the blood. A dynamic balance needs hence to be perfectly achieved in order to maintain a physiological glycaemic concentration. Specialized cells from the intestine continuously detect changes in glucose concentration and send signals to peripheral tissues and the brain through the vagus nerve. The molecular mechanisms involved in glucose detection have not been perfectly defined but could resemble those from the insulin-secreting beta cells. The brain then integrates the enteric and circulating endocrine signals to generate a new signal towards peripheral tissues such as the pancreas, liver, muscles, and blood vessels. This metabolic reflex is called anticipatory since it allows the peripheral tissues to prepare for the adequate handling of nutrients. Diabetes is associated with an impaired anticipatory reflex, which hampers the proper detection of nutrients and leads to hyperglycaemic episodes. Recently, GLP-1-based therapies have demonstrated the improvement of glucose detection and their efficacy on glycaemic control. Although not yet fully demonstrated, GLP-1-based therapies regulate glucose sensors, which leads to the glycaemic improvement. Certainly other molecular targets could be identified to further generate new therapeutic strategies.

Topics: Animals; Autonomic Nervous System; Brain; Diabetes Mellitus; Glucose; Humans; Incretins; Intestines; Signal Transduction

Multiple hormones and transmitter systems contribute to glucose homeostasis and the control of metabolism. Recently, the gastrointestinal peptide hormones glucagon-like peptide 1 and amylin have been shown to significantly contribute to this complex physiology. These advances provide the foundation for new treatments for diabetes mellitus. Therapies based on glucagon-like peptide 1 and amylin have now been introduced into clinical practice. Rimonabant, the selective endocannabinoid receptor antagonist, had been used in European countries for the treatment of obesity; it has recently been withdrawn for this indication. This drug exhibited therapeutic benefits for metabolic variables and for type 2 diabetes mellitus. Anesthesia providers caring for patients with diabetes mellitus will need to understand the implications of these new therapies in perioperative settings, particularly with respect to side effects and interactions.

Topics: Amyloid; Anesthesia; Animals; Cannabinoid Receptor Modulators; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Islet Amyloid Polypeptide

Topics: Adamantane; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

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

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are produced predominantly by enteroendocrine cells and have multiple blood glucose-lowering effects. Recent years have seen a surge of interest in understanding the basic physiology and pathophysiology of incretins and in applying this knowledge to the treatment of diabetes and obesity. Considerable gains have been made in elucidating the mechanisms controlling incretin secretion, and there is growing evidence to suggest that incretins might be involved in the rapid reversal of diabetes observed in gastric bypass patients. Here, we review these recent advances and outline the multiple strategies being pursued to exploit the potential therapeutic benefits of GIP and GLP-1.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Eating; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Islets of Langerhans; Molecular Mimicry; Obesity

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

Topics: Animals; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Receptors, Glucagon

Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to beta-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.

Topics: Animals; Diabetes Mellitus; Exenatide; Glucose; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Current type 2 diabetes therapies are mainly targeted at stimulating pancreatic beta-cell secretion and reducing insulin resistance. A number of alternative therapies are currently being developed to take advantage of the actions of the incretin hormones Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP). These hormones are released from the small intestine in response to nutrient ingestion and stimulate insulin secretion in a glucose-dependent manner. One approach to potentiating their actions is based on inhibiting dipeptidyl peptidase IV (DPP IV), the major enzyme responsible for degrading the incretins in vivo. DPP IV exhibits characteristics that have allowed the development of specific orally administered inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes. A number of clinical trials have demonstrated that DPP IV inhibitors are effective in improving glucose disposal and reducing hemoglobin A1c levels in type 2 diabetic patients and one inhibitor, sitagliptin, is now in therapeutic use, with others likely to receive FDA approval in the near future. Studies aimed at elucidating the mode of action of the inhibitors are still ongoing. Both enhancement of insulin secretion and reduction in glucagon secretion, resulting from the blockade of incretin degradation, are believed to play important roles in DPP IV inhibitor action. Preclinical studies indicate that increased levels of incretins improve beta-cell secretory function and exert effects on beta-cell mitogenesis and survival that can preserve beta-cell mass. Roles for other hormones, neuropeptides and cytokines in DPP IV inhibitor-medicated responses are also possible.

Topics: Animals; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Glucagon; Glucose; Homeostasis; Humans; Incretins; Insulin; Insulin Resistance; Models, Biological

This is the second of a 2-part series focusing on newer therapies for type 2 diabetes and their cardiovascular implications. In the first segment, we reviewed the thiazolidinediones, highlighting emerging data concerning their cardiovascular effects, both positive and negative. Here, we present a corresponding discussion of the newest antihyperglycemic category, modulators of the incretin system, which include the glucagon-like peptide-1 mimetics and the dipeptidyl peptidase-4 inhibitors. In addition, we briefly survey several novel drug classes in development, provide summary recommendations for glucose-lowering regimens in specific patient types, underscore the importance of nonglucose cardiovascular risk reduction strategies, and comment on present and future considerations for the regulatory review of diabetes drugs.

Topics: Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Protease Inhibitors

Epidemiologic studies have revealed that consuming green tea or coffee reduces diabetes risk. We evaluated the effects of the combined consumption of green tea catechins and coffee chlorogenic acids (GTC+CCA) on postprandial glucose, the insulin incretin response, and insulin sensitivity. Eleven healthy men were recruited for this randomized, double-blinded, placebo-controlled crossover trial. The participants consumed a GTC+CCA-enriched beverage (620 mg GTC, 373 mg CCA, and 119 mg caffeine/day) for three weeks; the placebo beverages (PLA) contained no GTC or CCA (PLA: 0 mg GTC, 0 mg CCA, and 119 mg caffeine/day). Postprandial glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) responses were measured at baseline and after treatments. GTC+CCA consumption for three weeks showed a significant treatment-by-time interaction on glucose changes after the ingestion of high-fat and high-carbohydrate meals, however, it did not affect fasting glucose levels. Insulin sensitivity was enhanced by GCT+CCA compared with PLA. GTC+CCA consumption resulted in a significant increase in postprandial GLP-1 and a decrease in GIP compared to PLA. Consuming a combination of GTC and CCA for three weeks significantly improved postprandial glycemic control, GLP-1 response, and postprandial insulin sensitivity in healthy individuals and may be effective in preventing diabetes.

Topics: Blood Glucose; Catechin; Chlorogenic Acid; Cross-Over Studies; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Male; Postprandial Period; Tea

Granular study of metabolic responses to alterations in the ratio of dietary macro-nutrients can enhance our understanding of how dietary modifications influence patients with impaired glycemic control. In order to study the effect of diets enriched in fat or carbohydrates, fifteen healthy, normal-weight volunteers received, in a cross-over design, and in a randomized unblinded order, two weeks of an iso-caloric high-fat diet (HFD: 60E% from fat) and a high-carbohydrate diet (HCD: 60E% from carbohydrates). A mixed meal test (MMT) was performed at the end of each dietary period to examine glucose clearance kinetics and insulin and incretin hormone levels, as well as plasma metabolomic profiles. The MMT induced almost identical glycemia and insulinemia following the HFD or HCD. GLP-1 levels were higher after the HFD vs. HCD, whereas GIP did not differ. The HFD, compared to the HCD, increased the levels of several metabolomic markers of risk for the development of insulin resistance, e.g., branched-chain amino acid (valine and leucine), creatine and α-hydroxybutyric acid levels. In normal-weight, healthy volunteers, two weeks of the HFD vs. HCD showed similar profiles of meal-induced glycemia and insulinemia. Despite this, the HFD showed a metabolomic pattern implying a risk for a metabolic shift towards impaired insulin sensitivity in the long run.

Topics: Adaptation, Physiological; Adult; Appetite; Blood Glucose; Cross-Over Studies; Diabetes Mellitus; Diet, High-Fat; Dietary Carbohydrates; Discriminant Analysis; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycemic Control; Healthy Volunteers; Humans; Incretins; Insulin; Insulin Resistance; Least-Squares Analysis; Male; Metabolome; Risk Factors

The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads.. The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit. A total of 12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water.. Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin disposal (P < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (P < 0.001) in obese subjects.. It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance.. ClinicalTrials.gov NCT01875575.

Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus; Double-Blind Method; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Young Adult

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

Topics: Adult; ATP-Binding Cassette Transporters; Diabetes Mellitus; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Incretins; Insulin-Secreting Cells; Male; Middle Aged; Mutation; Peptides; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Receptors, Glucagon; Sulfonylurea Receptors; Venoms

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

G protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention.

Topics: Animals; Blood Glucose; Calcium; Cell Line; Cyclic AMP; Diabetes Mellitus; Enteroendocrine Cells; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; HEK293 Cells; HeLa Cells; Humans; Incretins; Insulin; Insulin Secretion; Intestinal Mucosa; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Obesity; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone

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

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

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

Topics: Diabetes Mellitus; Disease Progression; Gastric Inhibitory Polypeptide; Humans; Incretins; Insulin-Secreting Cells; Receptors, Gastrointestinal Hormone

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

Topics: Acute Coronary Syndrome; Attitude of Health Personnel; Biomarkers; Blood Glucose; Cardiologists; Diabetes Mellitus; Drug Prescriptions; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Health Care Surveys; Health Knowledge, Attitudes, Practice; Humans; Hypoglycemic Agents; Incretins; Patient Admission; Practice Patterns, Physicians'; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Topics: Biomedical Research; Diabetes Mellitus; Drug Development; Drug Industry; Drug-Related Side Effects and Adverse Reactions; History, 20th Century; History, 21st Century; Humans; Hypoglycemic Agents; Incretins; Risk Assessment

Immunosuppressive drugs used in transplantation patients, may contribute to the development of post-transplant diabetes mellitus through their possible adverse effects on incretins. We aimed to compare the effects of different immunosuppressive drugs used in renal transplantation patients on glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels.. Forty five subjects were enrolled in the study (cyclosporine-treated 15 and tacrolimus-treated renal transplant patients 15, and healthy volunteers as a control group 15). Oral glucose tolerance test with 75 gr glucose was performed. GLP-1 and GIP levels were measured at 0 (baseline), 30, 60, 90, 120 min using ELISA method.. A statistically significant level of difference was detected in GLP-1 levels at the baseline, 30th and 120th minutes among all three groups (p < 0,001, p = 0,026 and p = 0,022, respectively). Baseline GLP-1 levels in cyclosporine-treated renal transplant patients were higher than in both tacrolimus-treated renal transplant patients (p = 0,016) and control groups (p < 0,001). GLP-1 levels at the 30th minute were higher in tacrolimus-treated renal transplant patients when compared to the cyclosporine-treated renal transplant patients (p = 0,024). GLP-1 levels at the 120th minute were higher in tacrolimus-treated renal transplant patients than the control group (p = 0,024). The areas under the curve of GLP-1 was higher in tacrolimus-treated renal transplant patients when compared to the control group (p = 0,018). GIP levels at 120th was lower in cyclosporine-treated renal transplant patients when compared to control group (p = 0,003).. These findings showed a temporally affected incretin hormones in renal transplant patients, a preserved GLP-1 response to an oral glucose load in renal transplant patients on cyclosporine and increased GLP -1 response to an oral glucose load in those on tacrolimus.

Topics: Adult; Blood Glucose; Case-Control Studies; Cyclosporine; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Incretins; Insulin; Kidney Transplantation; Tacrolimus

Topics: Diabetes Mellitus; Humans; Incretins; Liver Cirrhosis; Metformin; Non-alcoholic Fatty Liver Disease

To investigate the incretin axis in people with cystic fibrosis.. Adults with cystic fibrosis-related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C-peptide, total and active glucagon-like peptide-1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min.. Five adults with cystic fibrosis-related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis-related diabetes group (cystic fibrosis-related diabetes vs control group: -6% vs 28%; p=0.03). No hyposecretion of glucagon-like peptide-1 or gastric inhibitory polypeptide was observed; conversely, 60-min incremental area under the curve for total glucagon-like peptide-1 was significantly higher in the cystic fibrosis-related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03] CONCLUSIONS: The incretin effect was lost in cystic fibrosis-related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

Topics: Adult; C-Peptide; Cystic Fibrosis; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Incretins; Infusions, Intravenous; Insulin; Male

Reverse cholesterol transport (RCT) is an important cardioprotective mechanism and the decrease in cholesterol efflux can result in the dyslipidemia. Although liraglutide, a glucagon like peptide-1 analogue, has mainly impacted blood glucose, recent data has also suggested a beneficial effect on blood lipid. However, the exact mechanism by which liraglutide modulates lipid metabolism, especially its effect on RCT, remain undetermined. Hence, the aim of the present study was to investigate the potential impacts and potential underlying mechanisms of liraglutide on the cholesterol efflux in both db/db mice and HepG2 cells.. Liraglutide could improve lipid metabolism and hepatic lipid accumulation in db/db mice fed with HFD by promoting reversal of cholesterol transport, which was associated with the up-regulation of ABCA1 mediated by the ERK1/2 phosphorylation.

Topics: Animals; ATP Binding Cassette Transporter 1; Blood Glucose; Cholesterol; Diabetes Mellitus; Diet, High-Fat; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Liver; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Signal Transduction

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Humans; Incretins; Insulin Secretion; Quinolones

In this prospective case-control study we tested the hypothesis that, while long-term improvements in insulin sensitivity (S. Forty participants with type 2 diabetes and 22 participants without diabetes from the Longitudinal Assessment of Bariatric Surgery (LABS-2) study were enrolled in a separate, longitudinal cohort (LABS-3 Diabetes) to examine the mechanisms of postsurgical diabetes improvement. Study procedures included measures of S. Postoperatively, weight loss and S. For up to 2 years following RYGB, obese participants without diabetes showed improvements in DI that approach population norms. Those with type 2 diabetes recovered islet-cell insulin secretion response yet continued to manifest abnormal insulin processing, with DI values that remained well below population norms. These data suggest that, rather than waiting for lifestyle or medical failure, RYGB is ideally considered before, or as soon as possible after, onset of type 2 diabetes.. ClinicalTrials.gov NCT00433810.

Topics: Adult; Diabetes Mellitus; Female; Gastric Bypass; Humans; Incretins; Insulin; Islets of Langerhans; Longitudinal Studies; Male; Middle Aged; Obesity; Postoperative Period; Prospective Studies; Remission Induction; Time Factors; Weight Loss

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol homeostasis, is associated with glucose metabolism. Liraglutide, a glucagon-like peptide-1 receptor agonist, can increase insulin secretion in a glucose-dependent manner and lower blood glucose. We aimed to investigate the relationship between liraglutide and PCSK9.. At the cellular level, the expressions of PCSK9 and hepatocyte nuclear factor 1 alpha (HNF1α) protein in HepG2 cells stimulated by liraglutide was examined using Western blot. Seven-week old db/db mice and wild type (WT) mice were administered either liraglutide (200 μg/kg) or equivoluminal saline subcutaneously, twice daily for 7 weeks. Fasting glucose level, food intake and body weight were measured every week. After the 7-week treatment, the blood was collected for lipid and PCSK9 levels detection and the liver was removed from the mice for oil red O staining, immunohistochemical analysis, immunofluorescence test and Western bolt.. Firstly, liraglutide suppressed both PCSK9 and HNF1α expression in HepG2 cells in a time and concentration dependent manner. Secondly, liraglutide induced weight loss in WT and db/db mice, decreased serum PCSK9, glucose and lipid levels and improved hepatic accumulation in db/db but not WT mice. Thirdly, liraglutide reduced both hepatic PCSK9 and low-density lipoprotein receptor (LDLR) expression with a decrease in HNF1α in db/db mice but not in WT mice.. Liraglutide suppressed PCSK9 expression through HNF1α-dependent mechanism in HepG2 cells and db/db mice, and decreased LDLR possibly via PCSK9-independent pathways in db/db mice.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Hep G2 Cells; Hepatocyte Nuclear Factor 1-alpha; Hepatocytes; Humans; Hypoglycemic Agents; Incretins; Lipids; Liraglutide; Male; Mice; Proprotein Convertase 9; Receptors, LDL; Signal Transduction; Time Factors

Preclinical Research & Development The purpose of the present study is to evaluate the neuroprotective effect of recombinant human glucagon-like peptide-1 (rhGLP-1) as well as to explore corresponding mechanisms in diabetic rats with cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion (MCAO). Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. The rats were pretreated with rhGLP-1 (20 μg/kg intraperitoneally, thrice a day) for 14 days. Thereafter, the rats were subjected to MCAO 90 min/reperfusion 24 hr. At 2 and 24 hr of reperfusion, the rats were assessed for neurological deficits and subsequently executed for the evaluation of cerebral infarct volume, oxidative stress parameters, and the expression of excitatory amino acid transporter 2 (EAAT2) and apoptotic markers. Results indicate that rhGLP-1 significantly ameliorated neurological deficits and reduced cerebral infarct volume in diabetic MCAO rats. In addition, oxidative stress parameters in ischemic penumbra were significantly alleviated in rhGLP-1-pretreated diabetic MCAO rats. rhGLP-1 significantly upregulated the ratio of Bcl-2/Bax and EAAT2 expression and downregulated cleaved caspase-3 expression in ischemic penumbra of diabetic MCAO rats. Our results suggest that rhGLP-1 could significantly ameliorate neurological deficits and reduce cerebral infarct volume in diabetic MCAO rats, which may be due to the inhibition of oxidative stress and apoptosis and the promotion of EAAT2 expression.

Topics: Animals; Apoptosis; Brain Ischemia; Diabetes Complications; Diabetes Mellitus; Excitatory Amino Acid Transporter 2; Glucagon-Like Peptide 1; Humans; Incretins; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Oxidative Stress; Rats; Recombinant Proteins; Reperfusion Injury

Enhancement of glucagon-like peptide-1 (GLP-1) reduces glucose levels and preserves pancreatic β-cell function, but its effect against restenosis is unknown.. We investigated the effect of subcutaneous injection of exenatide or local delivery of a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into carotid artery, in reducing the occurrence of restenosis following balloon injury. As a control, we inserted β-galactosidase cDNA in the same vector (rAd-βGAL). Otsuka Long-Evans Tokushima rats were assigned to three groups (n = 12 each): (1) normal saline plus rAd-βGAL delivery (NS + rAd-βGAL), (2) exenatide plus rAd-βGAL delivery (Exenatide + rAd-βGAL), and (3) normal saline plus rAd-GLP-1 delivery (NS + rAd-GLP-1). Normal saline or exenatide were administered subcutaneously from 1 week before to 2 weeks after carotid injury. After 3 weeks, the NS + rAd-βGAL group showed the highest intima-media ratio (IMR; 3.73 ± 0.90), the exenatide + rAd-βGAL treatment was the next highest (2.80 ± 0.51), and NS + rAd-GLP-1 treatment showed the lowest IMR (1.58 ± 0.48, P < 0.05 vs. others). The proliferation and migration of vascular smooth muscle cells and monocyte adhesion were decreased significantly after rAd-GLP-1 treatment, showing the same overall patterns as the IMR. In injured vessels, the apoptosis was greater and MMP2 expression was less in the NS + rAd-GLP-1 than in the exenatide or rAd-βGAL groups. In vitro expressions of matrix metalloproteinases-2 and monocyte chemoattractant protein-1 and nuclear factor-kappa-B-p65 translocation were decreased more in the NS + rAd-GLP-1 group than in the other two groups (all P < 0.05).. Direct GLP-1 overexpression showed better protection against restenosis after balloon injury via suppression of vascular smooth muscle cell migration, increased apoptosis, and decreased inflammatory processes than systemic exenatide treatment. This has potential therapeutic implications for treating macrovascular complications in diabetes.

Topics: Adenoviridae; Animals; Apoptosis; Carotid Artery Injuries; Carotid Artery, External; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Coronary Stenosis; Diabetes Mellitus; Disease Models, Animal; Exenatide; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glucagon-Like Peptide 1; Human Umbilical Vein Endothelial Cells; Hypoglycemic Agents; Incretins; Male; Matrix Metalloproteinase 2; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Peptides; Rats, Inbred OLETF; Transcription Factor RelA; Transfection; Venoms

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

When incretin mimetic (IM) medications were introduced in 2005, their effectiveness compared with other less-expensive second-line diabetes therapies was unknown, especially for older adults. Physicians likely had some uncertainty about the role of IMs in the diabetes treatment armamentarium. Regional variation in uptake of IMs may be a marker of such uncertainty.. To investigate the extent of regional variation in the use of IMs among beneficiaries and estimate the cost implications for Medicare.. This was a cross-sectional analysis of 2009-2010 claims data from a nationally representative sample of 238 499 Medicare Part D beneficiaries aged ≥65 years, who were continuously enrolled in fee-for-service Medicare and Part D and filled ≥1 antidiabetic prescription. Beneficiaries were assigned to 1 of 306 hospital-referral regions (HRRs) using ZIP codes. The main outcome was adjusted proportion of antidiabetic users in an HRR receiving an IM.. Overall, 29 933 beneficiaries (12.6%) filled an IM prescription, including 26 939 (11.3%) for sitagliptin or saxagliptin and 3718 (1.6%) for exenatide or liraglutide. The adjusted proportion of beneficiaries using IMs varied more than 3-fold across HRRs, from 5th and 95th percentiles of 5.2% to 17.0%. Compared with non-IM users, IM users faced a 155% higher annual Part D plan ($1067 vs $418) and 144% higher patient ($369 vs $151) costs for antidiabetic prescriptions.. Among older Part D beneficiaries using antidiabetic drugs, substantial regional variation exists in the use of IMs, not accounted for by sociodemographics and health status. IM use was associated with substantially greater costs for Part D plans and beneficiaries.

Topics: Aged; Aged, 80 and over; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypoglycemic Agents; Incretins; Male; Medicare Part D; Metformin; Sulfonylurea Compounds; Thiazolidinediones; United States

Although mitochondrial oxidative phosphorylation (OxPhos) dysfunction is believed to be responsible for beta cell dysfunction in insulin resistance and mitochondrial diabetes, the mechanisms underlying progressive beta cell failure caused by defective mitochondrial OxPhos are largely unknown.. We examined the in vivo phenotypes of beta cell dysfunction in beta cell-specific Crif1 (also known as Gadd45gip1)-deficient mice. CR6-interacting factor-1 (CRIF1) is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane.. Crif1(beta-/-) mice exhibited impaired glucose tolerance with defective insulin secretion as early as 4 weeks of age without defects in islet structure. At 11 weeks of age, Crif1(beta-/-) mice displayed characteristic ultrastructural mitochondrial abnormalities as well as severe glucose intolerance. Furthermore, islet area and insulin content was decreased by approximately 50% compared with wild-type mice. Treatment with the glucoregulatory drug exenatide, a glucagon-like peptide-1 (GLP-1) agonist, was not sufficient to preserve beta cell function in Crif1(beta-/-) mice.. Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1(beta-/-) mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.

Topics: Age Factors; Animals; Autophagy; Blood Glucose; Cell Cycle Proteins; Cell Line; Diabetes Mellitus; Disease Models, Animal; Disease Progression; Exenatide; Genotype; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Oxidative Phosphorylation; Peptides; Phenotype; Time Factors; Venoms

To assess the association between use of incretin-based drugs for diabetes mellitus and the occurrence of acute pancreatitis. A population-based, nested case-control study was performed within a cohort of 166,591 patients from the Lombardy region (Italy) aged 40 years or older who were newly treated with oral antihyperglycaemic agents between 2004 and 2007. Cases were 666 patients who experienced acute pancreatitis from April 1, 2008 until December 31, 2012. For each case patient, up to 20 controls were randomly selected from the cohort and matched on gender, age at cohort entry, and date of index prescription. Conditional logistic regression was used to model the risk of acute pancreatitis associated with use of incretin-based drugs within 30 days before hospitalization, after adjustment for several risk factors, including the use of other antihyperglycaemic agents. Sensitivity analyses were performed in order to account for possible sources of systematic uncertainty. Use of incretin-based drugs within 30 days was reported by 17 (2.6%) cases of acute pancreatitis versus 193 (1.5%) controls. The corresponding multivariate odds ratio was 1.75 (95% confidence interval, 1.02 to 2.99). Slightly lower and no significant excess risks were observed by shortening (15 days) and increasing (60 and 90 days) the time-window at risk. This study supports a possible increased risk of acute pancreatitis in relation to use of incretin-based drugs reported in a few previous studies. However, given the potential for bias and the inconsistency with other studies, additional investigations are needed to clarify the safety of incretin-based-drugs.

Topics: Adult; Aged; Case-Control Studies; Databases, Factual; Diabetes Mellitus; Female; Hospitalization; Humans; Hypoglycemic Agents; Incretins; Italy; Logistic Models; Male; Middle Aged; Odds Ratio; Pancreatitis; Prevalence; Risk Factors

Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent epidemiological studies showed that the diabetes epidemic affects 382 million people worldwide in 2013, and this figure is expected to be 600 million people by 2035. Diabetes is associated with microvascular and macrovascular complications resulting in accelerated endothelial dysfunction (ED), atherosclerosis, and cardiovascular disease (CVD). Unfortunately, the complex pathophysiology of diabetic cardiovascular damage is not fully understood. Therefore, there is a clear need to better understand the molecular pathophysiology of ED in diabetes, and consequently, better treatment options and novel efficacious therapies could be identified. In the light of recent extensive research, we re-investigate the association between diabetes-associated metabolic disturbances (IR, subclinical inflammation, dyslipidemia, hyperglycemia, dysregulated production of adipokines, defective incretin and gut hormones production/action, and oxidative stress) and ED, focusing on oxidative stress and endothelial progenitor cells (EPCs). In addition, we re-emphasize that oxidative stress is the final common pathway that transduces signals from other conditions-either directly or indirectly-leading to ED and CVD.

Topics: Adipokines; Animals; Diabetes Mellitus; Dyslipidemias; Endothelial Progenitor Cells; Endothelium, Vascular; Ghrelin; Humans; Hyperglycemia; Incretins; Inflammation; Insulin Resistance; Oxidative Stress

Over the last decade there have been significant changes in the prescribing of antidiabetic therapies. It is of interest to know about these trends and variations in the Irish population so that future prescribing patterns can be estimated.. To examine the trends in prescribed antidiabetic treatments, including variations across age, gender, socioeconomic status and regions in the Irish population over the last 10 years.. The Irish national pharmacy claims database was used to identify patients ≥ 16 years dispensed antidiabetic agents (oral or insulin) from January 2003 to December 2012 through the two main community drug schemes for diabetes. The rate of prescribing per 1,000 population was calculated. Logistic regression was used to examine variations in prescribing in patients with diabetes.. There was a significant increase in the prescribing of fast and long-acting insulin analogues with a rapid decline in the prescribing of human insulin (p < 0.0001). Increased prescribing of metformin, incretin modulators and fixed oral combination agents was observed (p < 0.0001). Females and older aged patients were more likely to be prescribed human insulin than other insulins. Metformin was less likely while sulphonylureas were more likely to be prescribed in older than younger aged patients. Socioeconomic differences were observed in increased prescribing of the newer and more expensive antidiabetic agents in the non-means tested scheme. Regional variations were observed in the prescribing of both insulin and oral antidiabetic agents.. There has been an increase over time in the prescribing of both insulin and oral antidiabetic agents in the Irish population with increasing uptake of newer antidiabetic agents. This has implications for projecting future uptake and expenditure of these agents given the rising level of diabetes in the population.

Topics: Age Factors; Aged; Databases, Factual; Diabetes Mellitus; Drug Prescriptions; Female; Humans; Hypoglycemic Agents; Incretins; Insulin; Ireland; Male; Metformin; Middle Aged; Sex Factors; Young Adult

Glucagon-like peptide 1-based therapies, collectively described as incretins, produce glycemic benefits in the treatment of type 2 diabetes. Recent publications raised concern for a potential increased risk of pancreatitis and pancreatic cancer with incretins based in part on findings from a small number of rodents. However, extensive toxicology assessments in a substantial number of animals dosed up to 2 years at high multiples of human exposure do not support these concerns. We hypothesized that the lesions being attributed to incretins are commonly observed background findings and endeavored to characterize the incidence of spontaneous pancreatic lesions in three rat strains (Sprague-Dawley [S-D] rats, Zucker diabetic fatty [ZDF] rats, and rats expressing human islet amyloid polypeptide [HIP]; n = 36/group) on a normal or high-fat diet over 4 months. Pancreatic findings in all groups included focal exocrine degeneration, atrophy, inflammation, ductular cell proliferation, and/or observations in large pancreatic ducts similar to those described in the literature, with an incidence of exocrine atrophy/inflammation seen in S-D (42-72%), HIP (39%), and ZDF (6%) rats. These data indicate that the pancreatic findings attributed to incretins are common background findings, observed without drug treatment and independent of diet or glycemic status, suggesting a need to exercise caution when interpreting the relevance of some recent reports regarding human safety.

Topics: Animals; Diabetes Mellitus; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Incretins; Pancreas; Pancreatic Diseases; Pancreatitis; Rats; Rats, Sprague-Dawley; Rats, Zucker; Weight Gain

Ferrets are an important emerging model of cystic fibrosis related diabetes. However, there is little documented experience in the use of advanced techniques to quantify aspects of diabetes pathophysiology in the ferret. Glycemic clamps are the gold standard technique to assess both insulin sensitivity and insulin secretion in humans and animal models of diabetes. We therefore sought to develop techniques for glycemic clamps in ferrets. To assess insulin sensitivity, we performed euglycemic hyperinsulinemic clamps in 5-6 week old ferrets in the anesthetized and conscious states. To assess insulin secretion, we performed hyperglycemic clamps in conscious ferrets. To evaluate responsiveness of ferret islet and entero-insular hormones to low glucose, a portion of the hyperglycemic clamps were followed by a hypoglycemic clamp. The euglycemic hyperinsulinemic clamps demonstrated insulin responsiveness in ferrets similar to that previously observed in humans and rats. The anesthetic isoflurane induced marked insulin resistance, whereas lipid emulsion induced mild insulin resistance. In conscious ferrets, glucose appearance was largely suppressed at 4 mU/kg/min insulin infusion, whereas glucose disposal was progressively increased at 4 and 20 mU/kg/min insulin. Hyperglycemic clamp induced first phase insulin secretion. Hypoglycemia induced a rapid diminishment of insulin, as well as a rise in glucagon and pancreatic polypeptide levels. The incretins GLP-1 and GIP were affected minimally by hyperglycemic and hypoglycemic clamp. These techniques will prove useful in better defining the pathophysiology in ferrets with cystic fibrosis related diabetes.

Topics: Analysis of Variance; Animals; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Ferrets; Glucose Clamp Technique; Hyperglycemia; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Isoflurane

Topics: Cell Transplantation; Diabetes Mellitus; Humans; Hypoglycemic Agents; Incretins; Insulin; Islets of Langerhans Transplantation; Nanoparticles; Nanotechnology

The therapeutic options for type 2 diabetes have grown considerably in recent years with the successive emergence on the market of glitazones, incretin mimetics, gliptins and very soon gliflozins. Meanwhile, physicians have been advised to take into account individual patient characteristics and preferences when setting glycemic targets and choosing the most appropriate molecule. Faced with an abundance of options, clinicians, even those specialized in diabetology, are left confused and are divided in their choices. To guide them in their practice, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) jointly published a position statement in 2012. The guidelines posit that the main criteria to be considered are glucose-lowering efficacy, risk of hypoglycemia, effect on body weight, side effects and costs. Not surprisingly, they propose metformin as first line treatment but do not formulate a precise indication regarding the molecule to be introduced in case of metformin contra-indication, intolerance or monotherapy failure. In addition, there is no mention of gliflozins, which were still under evaluation at the time but are now approved and already marketed in some countries. Here we review the mechanisms of action, efficacy and side effects of the two most recent drug classes, namely incretin-based therapies and gliflozins, and try to position them in the therapeutic algorithm of type 2 diabetes.

Topics: Administration, Oral; Diabetes Mellitus; Humans; Hypoglycemic Agents; Incretins; Practice Guidelines as Topic; Receptors, Glucagon; Sodium-Glucose Transporter 2 Inhibitors

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk.

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

Topics: Diabetes Mellitus; Drug Industry; Europe; Glucagon-Like Peptide 1; Humans; Incretins; Pancreatic Diseases

Topics: Diabetes Mellitus; Drug Industry; Glucagon-Like Peptide 1; Humans; Incretins; Pancreatic Diseases

Topics: Biomimetic Materials; Diabetes Mellitus; Endocrinology; Gastrointestinal Agents; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Receptors, Glucagon

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

To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes.. To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of the binding of excipient to GLP-1, the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, the in vitro bio-activity of excipient-formulated GLP-1, the in vivo pharmacokinetics of excipient-formulated GLP-1, and the efficacy of the excipient-formulated GLP-1 in diabetic rats.. We showed reproducible synthesis of PGC excipient, high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day.. PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.

Topics: Animals; Delayed-Action Preparations; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Excipients; Exenatide; Fatty Acids; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Insulin-Secreting Cells; Peptides; Polyethylene Glycols; Polylysine; Protein Stability; Rats; Rats, Sprague-Dawley; Rats, Zucker; Venoms

Pharmacological modulation of the glucagon-like peptide-1 (GLP-1) system has emerged as a new therapeutic option for treatment of diabetes mellitus. In addition to the glucose lowering potential GLP-1 was found to have a variety of cardioprotective effects. GLP-1 reduced the size of myocardial infarction during acute ischemia by activation of prosurvival pathways including PI3-kinase, Akt und ERK1/2. In addition, GLP-1 prevented atherosclerotic lesion formation in experimental models and improved endothelial function while acting anti-inflammatory. Furthermore GLP-1 was found to improve chronic heart failure by increasing insulin independent cellular glucose transport. Consequently GLP-1 based therapies might reduce cardiovascular events in diabetic patients which is currently evaluated in clinical endpoint studies.

Topics: Cardiotonic Agents; Diabetes Complications; Diabetes Mellitus; Humans; Hypoglycemic Agents; Incretins; Myocardial Infarction; Treatment Outcome

Topics: Blood Pressure; Cardiovascular System; Diabetes Mellitus; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypertension; Incretins; Liraglutide; Practice Guidelines as Topic; Societies, Medical; South Africa

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins

Patients with diabetes may undergo an approximately 24-h fast for a voluntary religious observance or in preparation for a medical procedure. Commonly, patients will manage their diabetes before and during such fasting without guidelines from their doctors, often because they did not ask for advice. The physician should therefore take the lead in advising patients how to fast safely, in order to avoid the situation wherein the patient manages medication changes on his/her own. Furthermore, it sends a message to the patient that having diabetes does not preclude living a reasonably 'normal' life, even when it comes to religious observances.

Topics: Blood Glucose Self-Monitoring; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Female; Humans; Hypoglycemic Agents; Incretins; Insulin; Physician-Patient Relations; Pregnancy; Pregnancy in Diabetics; Religion and Medicine

Old and modern architecture go hand in hand along the many waterfronts in Stockholm, just as old (established) and new (investigational) drugs for treating diabetes shared time and space at the oral and poster sessions during the 2010 European Association for the Study of Diabetes (EASD) meeting in Älfsjö. Old and new drugs shared the spotlight at the meeting, the main declared objective of which was to promote excellence in diabetes care through research and education. Although it is important to attend the EASD meeting in order to obtain information on what's new firsthand-new drugs, new indications, new treatment modalities... as well as news on negative aspects and limitations of drug therapy-not all healthcare professionals can attend so many annual meetings, and those who can, cannot attend many of the parallel sessions, and thus alternative sources of information are needed. Indeed, education has a major role in the management and prevention of diabetes, obesity and related disorders, all of which carry a high cardiovascular risk, but if educating patients and the general population is essential, so is informing healthcare professionals about new therapies and new findings related with the management of diabetes. In line with the previously stated attendance limitations and alternative sources of information-or education-this is the scope of the following report, which complements other information on subjects discussed during the EASD meeting in Stockholm available online through other channels.

Topics: Animals; Diabetes Complications; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Genetic Therapy; Humans; Hypoglycemic Agents; Immunotherapy; Incretins; Insulin; Sodium-Glucose Transporter 2 Inhibitors; Sweden; Thiazolidinediones

Incretins including GLP-1 and GIP have pleiotropic effects on islet biology especially on beta-cell function. Not only enhancing glucose-stimulated insulin secretion, but incretins exert beta-cell mass maintaining effects by upregulation of proliferation and prevention of cell death (apoptosis). Recent research data revealed detailed molecular mechanisms underlying these effects of incretin on beta-cell biology. These beneficial effects of incretins on the regulation of beta-cell mass could contribute to future therapeutic approaches to diabetes focusing on preservation and upregulation of beta-cell mass as well as function.

Topics: Cell Survival; Diabetes Mellitus; Humans; Incretins; Insulin-Secreting Cells

Topics: Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hungary; Hypoglycemic Agents; Incidence; Incretins; Patient Education as Topic

The discovery of incretins-glucagon-like peptide (GLP)-1 and glucose-dependent insulinotrop peptide (GIP)-, clarification of their physiological properties as well as therapeutic application of incretin-based blood glucose lowering drugs opened new perspectives in the medical management of type 2 diabetes. New results of basic research investigations led to revaluation of the role of GIP in metabolic processes and a more established use of GLP-1 action. The article overviews the most relevant data of production and effects of incretins, as well as future possibilities of their therapeutic use.

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Incretins

Walking the streets in Lisbon is not a matter of inertia, at least when going uphill through the small streets crowding the slopes around the Alfama and Bairro Alto neighborhoods. However, when treating diabetes, clinical inertia seems to be the rule, despite the availability of effective therapies and recommendations for early insulin replacement to improve glucose control and prevent diabetes complications. This was further confirmed in the SOLVE study presented during this year's European Association for the Study of Diabetes (EASD) meeting (Khunti, K. et al., Abst 377), highlighting the importance of understanding healthcare habits to implement policies aimed at appropriate treatment intensification and even initiation to achieve earlier glycemic control of type 2 diabetes. However, preventing type 2 diabetes is crucial, in which regard physical activity has been repeatedly reported to reduce the risk of acquiring type 2 diabetes, and does so independently of its impact on general and abdominal adiposity (Ekelund, U. et al., Abst 225), resulting in a clearly cost-effective option to avoid the disease and the need for treatments. Although physical activity improves fitness but not glycemic control in type 1 diabetes (Valletta, J.J. et al., Abst 602), this is feasible through educational campaigns aimed at improving eating habits, routine physical exercise and healthy lifestyles, which, as demonstrated among students in Mexico, reduced the incidence of obesity and overweight (Martínez, M.E., Abst 858). Nevertheless, type 2 diabetes is a reality that is actually on the rise and requires treatments aimed at maintaining glycemic control, thus avoiding diabetic complications, while minimizing the risk of hypoglycemia and its consequences. Reducing hemoglobin A1c levels below 7%, as recommended by most guidelines for the treatment of diabetes, was confirmed to be associated with a reduced risk of death and diabetes-related morbidity in a population study in patients with type 2 diabetes (Skriver, M.V. et al., Abst 54). Hence, treatments are critical for achieving glycemic goals and preventing undue deaths. A wide range of therapies are currently available, but new drugs are under research that may potentially improve outcomes with a lower risk for adverse events, or may offer efficacy in patients currently not at goal because of insufficient efficacy of the drugs they are receiving, or because the doses they would require would cause excessive toxicity or an

Topics: Biguanides; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Activators; Glucokinase; Humans; Hypoglycemic Agents; Incretins; Insulin; Islets of Langerhans Transplantation; Potassium Channel Blockers; Sodium-Phosphate Cotransporter Proteins; Sulfonylurea Compounds; Thiazolidinediones

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Germany; Humans; Hypoglycemic Agents; Incretins; Molecular Biology; Pharmacology

Topics: Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Incretins; Liver Cirrhosis; Portasystemic Shunt, Transjugular Intrahepatic

To evaluate the impact of Medicare Part D coverage gap (donut hole) on adherence to diabetes medications.. Retrospective cohort analysis based on pharmacy claims data.. The sample included 12,881 Medicare Part D beneficiaries with diabetes who entered the coverage gap in 2008. Sample patients had 3 different levels of coverage in the donut hole: no coverage, generic drug coverage only, and both generic and brand-name drug coverage. Adherence was measured by the proportion of days covered. We used a difference-in-difference model to evaluate the effect of coverage gap on adherence.. In the donut hole, the average copayment for diabetes medications increased substantially for beneficiaries with no coverage and beneficiaries with generic drug coverage only, whereas the average copayment for beneficiaries with both generic and brand-name medication coverage declined slightly. Compared with beneficiaries with full coverage of both generic and brand-name drugs, beneficiaries with no coverage (odds ratio[OR] = 0.617, P <.0001, 95% confidence interval [CI] = 0.523, 0.728) and beneficiaries with generic drug coverage only (OR = 0.702, P <.0001, 95% CI = 0.604, 0.816) were significantly less likely to be adherent after entering the donut hole. The difference between having generic coverage and no coverage was not significant (P = .1586).. The coverage gap in the Medicare Part D program has a significant negative impact on medication adherence among beneficiaries with diabetes. Availability of brand-name drug coverage in the donut hole is critical to adherence to diabetes medications.

Topics: Aged; Cohort Studies; Confidence Intervals; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Health Services Accessibility; Humans; Hypoglycemic Agents; Incretins; Insulin; Insurance Claim Review; Insurance Coverage; Male; Medicare Part D; Medication Adherence; Metformin; Odds Ratio; Retrospective Studies; Sulfonylurea Compounds; Thiazolidinediones; United States

Topics: Diabetes Mellitus; Diet, Diabetic; Exercise Therapy; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion

Obesity has reached epidemic proportions in the USA with a nearly fourfold rise in the prevalence of childhood obesity. There are many possible etiologies of obesity as the adipose tissue plays a significant, complex role in the physiology of fuel metabolism and hormone regulation. The development of obesity represents a pathophysiologic increase in fat mass in which multiple metabolic pathways are deranged. The consequences of these metabolic derangements, including insulin resistance and inflammation, are reflected in obesity-related comorbidities and can be seen in the setting of pediatric obesity. Obese adolescents demonstrate increased rates of early maturation, orthopedic growth abnormalities, diabetes mellitus, obstructive sleep apnea, hypertension, steatosis, and polycystic ovarian syndrome, placing this group of children at risk for long-term health problems and reduced quality of life. Given the negative short- and long-term impact of obesity on children, careful attention should be paid to the unique health issues of this "at-risk" population with both prevention and early intervention strategies.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adolescent; Animals; Body Mass Index; Diabetes Mellitus; Evidence-Based Medicine; Female; Humans; Hypercholesterolemia; Hypertension; Incretins; Metabolic Syndrome; Obesity; Ohio; Polycystic Ovary Syndrome; Prevalence; Quality of Life; Risk Factors; Sleep Apnea, Obstructive

Topics: Blood Glucose; Clinical Trials as Topic; Congresses as Topic; Consensus; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hypertension; Incretins; Obesity; Weight Gain

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Lizards

The 'Second Giessen International Workshop on Interactions of Exocrine and Endocrine Pancreatic Diseases' was organized in order to reflect and discuss recent developments in the field, especially the progress that has been achieved since the first meeting in March 2005. About thirty international specialists were invited to share their experience and thoughts covering the main topics of: A) pancreatic diabetes (type 3c); B) chronic inflammation of the pancreas. The presentations of session A covered an overview about the frequency of exocrine dysfunction in diabetes mellitus, the relation between diabetes, celiac disease and the exocrine pancreas, the prevalence of type 3c diabetes, damage to the pancreas caused by genes, the role of incretins in type 2 and type 3 diabetes, the role of exocrine tissue in beta cell homeostasis, peculiarities in the treatment of type 3c diabetes and a lecture on incretins: from concept to treatment. Session B included presentations about the frequency of chronic inflammation of the pancreas and therapeutical implications, the role of ACE in the pancreas, genomics and the metabolic hypothesis of chronic pancreatitis, nutritional aspects of pancreatic diseases, the stellate cell concept, autoimmunity, genetic background of chronic pancreatitis and the hypothesis of chronic obstruction induced by gallstone disease. The meeting resulted in several new projects that will be started by the participants in the near future.

Topics: Aged; Alcohol Drinking; Cell Differentiation; Chronic Disease; Comorbidity; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Diet Therapy; Female; Genetic Predisposition to Disease; Germany; Hepatocyte Nuclear Factor 1-beta; Humans; Hypoglycemic Agents; Incretins; Islets of Langerhans; Japan; Lipase; Male; Middle Aged; Mutation; Nutritional Support; Pancreas, Exocrine; Pancreatic Diseases; Prevalence; Renin-Angiotensin System; Risk Factors; United States

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dogs; Glucagon-Like Peptide 1; Humans; Incretins; Rats

The incretin effect is reduced and the insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is abolished in patients with type 2 diabetes mellitus (T2DM).. To evaluate the causality of this deficiency we investigated 8 patients with chronic pancreatitis (CP) and normal glucose tolerance (NGT) (fasting plasma glucose (FPG): 5.5 (4.5-6.0) mM (mean (range); HbA(1c): 5.8 (5.4-6.3) %) and 8 patients with CP and secondary diabetes not requiring insulin (FPG: 7.1 (6.0-8.8) mM; HbA(1c): 7.0 (5.8-10.0) %) during three 15-mM hyperglycaemic clamps with continuous iv infusion of saline, glucagon-like peptide-1 (GLP-1) or GIP.. The initial (0-20 min) insulin and C-peptide responses were enhanced significantly in both groups by GLP-1 and GIP, respectively, compared to saline (P<0.05). In both groups GLP-1 infusion resulted in significantly greater insulin and C-peptide responses from 20-120 min compared with saline infusion. During GIP infusion the late-phase insulin response (20-120 min) was 3.1+/-1.0 fold greater than during saline infusion in the group of patients with CP and NGT (P<0.05), whereas there was no significant differences in patients with CP and DM.. The lack of GIP amplification of the late insulin response to iv glucose develops alongside the deterioration of glucose tolerance in patients with CP, suggesting that the same may be true for the loss of the GIP effect in patients with T2DM.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Pancreatitis, Chronic