incretins and Obesity

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

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

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

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

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

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

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

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

Obesity is a complex disease characterized by excessive fat accumulation which is caused by genetic, environmental and other factors. In recent years, there has been an increase in the morbidity, disability rate,and mortality due to obesity, making it great threat to people's health and lives, and increasing public health care expenses. Evidence from previous studies show that weight loss can significantly reduce the risk of obesity-related complications and chronic diseases. Diet control, moderate exercise, behavior modification programs, bariatric surgery and prescription drug treatment are the major interventions used to help people lose weight. Among them, anti-obesity drugs have high compliance rates and cause noticeable short-term effects in reducing obese levels. However, given the safety or effectiveness concerns of anti-obesity drugs, many of the currently used drugs have limited clinical use. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a group of drugs that targets incretin hormone action, and its receptors are widely distributed in nerves, islets, heart, lung, skin, and other organs. Several animal experiments and clinical trials have demonstrated that GLP-1R agonists are more effective in treating or preventing obesity. Therefore, GLP-1R agonists are promising agents for the treatment of obese individuals. This review describes evidence from previous research on the effects of GLP-1R agonists on obesity. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop obesity treatments based on GLP-1R agonists.

Topics: Animals; Anti-Obesity Agents; Glucagon-Like Peptide-1 Receptor; Incretins; Obesity; Weight Loss

The occurrence of obesity is an increasing issue worldwide, especially in industrialized countries. Weight loss is important both to treat obesity and to prevent the development of complications. Currently, several drugs are used to treat obesity, but their efficacy is modest. Thus, new anti-obesity treatments are needed. Recently, there has been increased interest in the development of incretins that combine body-weight-lowering and glucose-lowering effects. Therefore, a new drug that simultaneously coactivates both the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R) has been developed. Tirzepatide, the first in this class, improves glycemic control by increasing insulin sensitivity and lipid metabolism as well as by reducing body weight. Combining the activation of the two receptors, greater improvement of β-cell function offers more effective treatment of diabetes and obesity with fewer adverse effects than selective GLP-1R agonists. In the present review, we discuss the progress in the use of GIPR and GLP-1R coagonists and review literature from

Topics: Animals; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Incretins; Obesity; Weight Loss

The intestine has garnered attention as a target organ for developing new therapies for impaired glucose tolerance. The intestine, which produces incretin hormones, is the central regulator of glucose metabolism. Glucagon-like peptide-1 (GLP-1) production, which determines postprandial glucose levels, is regulated by intestinal homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD

Topics: AMP-Activated Protein Kinases; Biology; Cytokines; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Homeostasis; Humans; Incretins; NAD; Nicotinamide Phosphoribosyltransferase; Obesity

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

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

The prevalence of obesity in the United States and across the world continues to climb, imparting increased risk of chronic disease. This impact is doubly felt in nephrology because obesity not only increases the risk of chronic kidney disease (CKD) but also exacerbates existing cardiovascular morbidity and mortality. The role of medical weight loss therapy in CKD has been debated, but increasing evidence suggests that intentional weight loss is protective against adverse kidney and cardiovascular outcomes. This may be particularly true with the advent of novel pharmacotherapies taking advantage of the incretin system, resulting in weight loss approaching that seen with surgical interventions. Moreover, these novel therapies have repeatedly demonstrated protective effects on the cardiovascular system. Here, we review the impact of obesity and weight loss on CKD, and the biological basis and clinical evidence for incretin therapy. This perspective provides recommended prescribing practices as a practical tool to engage nephrologists and patients with CKD in the treatment of obesity-related morbidity.

Topics: Humans; Incretins; Nephrologists; Obesity; Renal Insufficiency, Chronic; United States; Weight Loss

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretins that play an important role in glucose metabolism, by increasing glucose-induced insulin secretion from pancreatic β-cells and help regulate bodyweight. Although they show a similar action on glucose-induced insulin secretion, two incretins are distinct in various aspects. GIP is secreted from enteroendocrine K cell mainly expressed in the upper small intestine, and GLP-1 is secreted from enteroendocrine L cells mainly expressed in the lower small intestine and colon by the stimulation of various nutrients. The mechanism of GIP secretion induced by nutrients, especially carbohydrates, is different from that of GLP-1 secretion. GIP promotes fat deposition in adipose tissue, and contributes to fat-induced obesity. In contrast, GLP-1 participates in reducing bodyweight by suppressing food consumption and/or slowing gastric emptying. There is substantial evidence that GIP and GLP-1 might differently contribute to bodyweight control. Although meal contents influence both glycemic and weight control, we do not fully understand whether incretin actions differ depending on the contents of the meal and what kind of signaling is involved in its context. We focus on the molecular mechanism of GIP secretion induced by nutrients, as well as the roles of GIP in weight changes caused by various diets.

Topics: Blood Glucose; Diet; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Obesity

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Obesity is responsible for an increased risk of sub-fecundity and infertility. Obese women show poorer reproductive outcomes regardless of the mode of conception, and higher body mass index (BMI) is associated with poorer fertility prognosis. Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility, and many women with PCOS are also overweight or obese.. The aim of the present narrative review is to describe the mechanisms responsible for the development of infertility and PCOS in women with obesity/overweight, with a focus on the emerging role of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) as a therapeutic option for obese women with PCOS.. Weight reduction represents the most significant factor affecting fertility and pregnancy outcomes. Current experimental and clinical evidence suggests the presence of an underlying pathophysiological link between obesity, GLP-1 kinetic alterations, and PCOS pathogenesis. Based on the positive results in patients affected by obesity, with or without diabetes, the administration of GLP-1 RA (mainly liraglutide) alone or in combination with metformin has been investigated in women with obesity and PCOS. Several studies demonstrated significant weight loss and testosterone reduction, with mixed results relative to improvements in insulin resistance parameters and menstrual patterns.. The weight loss effects of GLP-1 RA offer a unique opportunity to expand the treatment options available to PCOS patients.

Topics: Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Infertility, Female; Liraglutide; Metformin; Obesity; Polycystic Ovary Syndrome; Randomized Controlled Trials as Topic; Testosterone; Treatment Outcome; Weight Loss

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

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

The gut-brain hormone glucagon-like peptide-1 (GLP-1) has received immense attention over the last couple of decades for its widespread metabolic effects. Notably, intestinal GLP-1 has been recognized as an endogenous satiation signal. Yet, the underlying mechanisms and the pathophysiological relevance of intestinal GLP-1 in obesity remain unclear. This review first recapitulates early findings indicating that intestinal GLP-1 is an endogenous satiation signal, whose eating effects are primarily mediated by vagal afferents. Second, on the basis of recent findings challenging a paracrine action of intestinal GLP-1, a new model for the mediation of GLP-1 effects on eating by two discrete vagal afferent subsets will be proposed. The central mechanisms processing the vagal anorexigenic signals need however to be further delineated. Finally, the idea that intestinal GLP-1 secretion and/or effects on eating are altered in obesity and play a pathophysiological role in the development of obesity will be discussed. In summary, despite the successful therapeutic use of GLP-1 receptor agonists as anti-obesity drugs, the eating effects of intestinal GLP-1 still remain to be elucidated. Specifically, the findings presented here call for a further evaluation of the vago-central neuronal substrates activated by intestinal GLP-1 and for further investigation of its pathophysiological role in obesity.

Topics: Animals; Appetite; Brain; Disease Models, Animal; Eating; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Intestinal Mucosa; Liraglutide; Obesity; Satiation; Signal Transduction; Vagus Nerve

For the management of obesity in childhood and adolescence, nonoperative approaches have limited efficacy, including community-based and behavioral interventions and pharmacotherapy approved for use in adults. Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy are efficacious in reducing weight, body mass index, and comorbidities in adolescents. Understanding the phenotype associated with obesity provides an opportunity to individualize patients' treatments directed at the brain-gut axis. These phenotypes include rapid gastric emptying, increased fasting gastric volume, reduced postprandial incretins, and central mechanisms that impact appetite and satiation including hedonic eating and affective disorders. Further studies are required in adolescents. Identifying phenotypes could enhance the efficacy of behavioral, dietary, and pharmacotherapeutic interventions alone or in combination in children and adolescents.

Topics: Adult; Child; Gastric Bypass; Humans; Incretins; Obesity; Postprandial Period; Weight Loss

This paper describes the early history of Gastric Inhibitory Polypeptide, better referred to simply as GIP, from its isolation by purification from a crude preparation of CCK-PZ (cholecystokinin/pancreozymin) to its recognition as a key player in the pathogenesis of obesity and other metabolic disorders far removed from the enterogastrone properties by which it was originally identified. Augmentation of glucose mediated insulin release, the incretin effect, was discovered soon after GIP was first isolated and only much later was its important role in the pathogenesis of obesity, through mechanism other than insulin secretion, appreciated. Immunoassay - the only method by which the concentration of GIP was measured in plasma until quite recently - was found to be flawed and to depend upon which specific epitope of the hormone an assay detected. This was especially true if it was an amino-acid sequence specific to porcine rather than human GIP. A further confounder was the discovery that much of the GIP measured by immunoassay was its biological antagonist produced by cleavage of its two N-terminal amino-acids in the circulation by the same dipeptidyl-peptidase as de-activates GLP-1. Potential use of synthetic agonistic and antagonistic GIP analogues in therapeutics was barely alluded to before year 2000.

Topics: Cholecystokinin; Epitopes; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide Receptors; Glucose; Humans; Incretins; Insulin; Obesity; Peptides

The prevalence of nonalcoholic liver disease (NAFLD) is increasing worldwide in conjunction with the epidemic increase in obesity and metabolic risk factors. Consequently, NAFLD has become a leading indication for liver transplantation. Although genetic factors play an important role in the pathogenesis of NAFLD, detrimental lifestyle trends favoring a calorically unrestricted diet rich in carbohydrates and unsaturated fat, prolonged sedentary periods or limited physical activity have major metabolic implications. In aggregate these physiological dysregulations constitute the main risk factors for the metabolic syndrome and NAFLD. The cornerstone of the treatment of NAFLD, is lifestyle changes, including modifications to diet and physical activity, to reduce body weight and liver fat, however adherence is notoriously poor and the epidemic of NAFLD continues to grow unimpeded. In the face of this unmet clinical need, the pharmacologic therapy of NAFLD has been expanding as the varied mechanistic pathways of NAFLD are elucidated. Beyond these approaches to treating NAFLD, the prevention of other liver diseases is additionally important. Chief among these is alcoholic liver disease, and heavy use is detrimental irrespective of underlying NAFLD. However, the impact of mild to moderate alcohol use in patients with mild or nonadvanced forms NAFLD is undefined. This article summarizes the results of the International Liver Transplantation Society consensus meeting on NAFLD in liver transplantation. It describes the available evidence and provides consensus guidance on the lifestyle and pharmacologic therapies of NAFLD, and the consensus position on alcohol use in patients with NAFLD.

Topics: Alcohol Drinking; Antioxidants; Bariatric Surgery; Comorbidity; Consensus Development Conferences as Topic; Diet, Carbohydrate Loading; Exercise; Healthy Lifestyle; Humans; Hypoglycemic Agents; Incretins; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Transplantation; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Patient Compliance; Practice Guidelines as Topic; Prevalence; Risk Factors; Weight Loss

Nonalcoholic-fatty-liver-disease/nonalcoholic steatohepatitis (NAFLD/NASH) is expected to become the leading liver disease worldwide. Typical liver-related complications are fibrosis, cirrhosis, and the development of hepatocellular cancer (HCC) with the need for liver transplantation. Up to now there is no approved pharmacotherapy. Indeed, this might be due to the complexity of this disease. While the cheapest therapeutic approach is still a lifestyle change leading to weight loss, the proportion of people achieving sufficient weight reduction without additional support is low. Newly developed drugs are expensive and lack a breakthrough in therapeutic success. One reason might be that drugs developed often derive from murine models. Unfortunately, there is little overlap between genes in human and mice that are responsible for the development of NAFLD/NASH. This review aims at summarizing latest developments as well as stress again that more translational research is necessary.. Therapy of NAFLD/NASH is easy and very complex at the same time, as the current main target is weight reduction. Since this is in fact not easily achieved and maintained by many affected individuals, pharmacotherapy to halt the progression of NAFLD/NASH is urgently warranted. More translational studies are needed to understand the metabolic mechanisms and interactions between the liver, gut, oxidative stress and the processes leading to NAFLD progression and HCC development, even in the absence of cirrhosis.

Topics: Animals; Bariatric Surgery; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Humans; Hypolipidemic Agents; Incretins; Life Style; Lipogenesis; Liver; Liver Cirrhosis; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Species Specificity; Translational Research, Biomedical; Weight Loss; Weight Reduction Programs

Energy homeostasis is coordinated by bidirectional communication pathways between the brain and peripheral organs, including adipose tissue, muscle, the pancreas, liver, and gut. Disruption of the integrated chemical, hormonal, and neuronal signals that constitute the gut-brain axis significantly contributes to disorders of metabolism and body weight. Initial studies of glucagon-like peptide-1 (GLP-1), a gut hormone released in response to the ingestion of nutrients, focused on its incretin actions to improve postprandial glucose homeostasis by enhancing meal-induced insulin secretion. However, GLP-1 is also a key player in the gut-brain regulatory axis with multiple effects on appetite and energy metabolism outside of its peripheral glucoregulatory actions. In this review, we explore the function of GLP-1 as a component of the gut-brain axis in the regulation of energy homeostasis, and consider the implications of this role for the development of therapeutic treatment options for obesity.

Topics: Adiposity; Animals; Appetite; Brain; Energy Metabolism; Gastrointestinal Microbiome; Gastrointestinal Motility; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Incretins; Intestines; Mice; Obesity; Rats; Vagus Nerve; Weight Loss

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

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

Bariatric surgery is now the most widely used intervention for the treatment of human obesity. A large body of literature has demonstrated its efficacy in sustained weight loss and improvement in its associated comorbidities. Here, we review the effect of bariatric surgery in gut hormone physiology, bone remodeling and the reproductive axis. Rapid improvements in insulin release and sensitivity appear to be weight loss independent and occur immediately after surgery. These effects on pancreatic beta cells are mostly due to increased gut hormone secretion due to augmented nutrient delivery to the small intestine. Bone remodeling is also affected by gut hormones. Phenotypic skeletal changes observed in mice deficient in GLP-1 or GIP suggest that increased incretins may improve bone density. However, these positive effects may be counterbalanced by the association between weight loss and a reduction in bone density. Finally, studies have shown a marked improvement following bariatric surgery in infertility and PCOS in women and hypogonadism in men. Thus, the net effect on endocrine systems after bariatric surgery will likely vary on an individual basis and depend on factors such as comorbidities, peri-menopausal state, amount of weight loss, and likelihood to adhere to vitamin supplementation after surgery.

Topics: Adipokines; Animals; Bariatric Surgery; Bone and Bones; Bone Density; Bone Remodeling; Female; Fertility; Gonadal Steroid Hormones; Humans; Incretins; Insulin Resistance; Male; Obesity; Signal Transduction; Treatment Outcome; Weight Loss

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The obesity pandemic poses a unique set of problems for acute pancreatitis - both by increasing acute pancreatitis incidence, and worsening acute pancreatitis severity. This review explores these associations, underlying mechanisms, and potential therapies.. We review how the obesity associated increase in gallstones, surgical, and endoscopic interventions for obesity management, diabetes, and related medications such as incretin-based therapies and hypertriglyceridemia may increase the incidence of acute pancreatitis. The mechanism of how obesity may increase acute pancreatitis severity are discussed with a focus on cytokines, adipokines, damage-associated molecular patterns and unsaturated fatty acid-mediated lipotoxicity. The role of obesity in exacerbating pancreatic necrosis is discussed; focusing on obesity-associated pancreatic steatosis. We also discuss how peripancreatic fat necrosis worsens organ failure independent of pancreatic necrosis. Last, we discuss emerging therapies including choice of intravenous fluids and the use of lipase inhibitors which have shown promise during severe acute pancreatitis.. We discuss how obesity may contribute to increasing acute pancreatitis incidence, the role of lipolytic unsaturated fatty acid release in worsening acute pancreatitis, and potential approaches, including appropriate fluid management and lipase inhibition in improving acute pancreatitis outcomes.

Topics: Enzyme Inhibitors; Fatty Acids, Unsaturated; Humans; Hypertriglyceridemia; Incretins; Lipase; Lipolysis; Obesity; Pancreatitis; Severity of Illness Index

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

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

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females and is often associated with a number of cardiometabolic disorders such as central obesity, dyslipidaemia, hypertension, insulin resistance, hyperinsulinaemia, glucose intolerance and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a gut hormone secreted after a meal, enhances glucosestimulated insulin secretion and additionally suppresses appetite and gastric motility. Most studies found impaired GLP-1 kinetics in obese individuals, whereas small studies in PCOS reported reduced, normal or even elevated GLP-1 levels. Apart from their efficacy in patients with T2DM, some GLP-1 receptor agonists (GLP-1 RAs) have been successfully tested in terms of both efficiency and safety in obese individuals without diabetes and liraglutide 3 mg once daily has been approved as an antiobesity drug in the USA and the European Union. Recently, some small trials of short duration using GLP-1 RAs as monotherapy or combined with metformin in obese PCOS women showed positive results regarding weight reduction and a decrease in testosterone levels but without significant effects on insulin levels, insulin sensitivity and menstrual patterns. Longer term studies with more patients and higher doses of liraglutide (as this drug is already approved for obese individuals) are required to determine the precise indications of GLP-1 RAs in PCOS and to evaluate safety issues.

Topics: Animals; Anti-Obesity Agents; Biomarkers; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Kinetics; Liraglutide; Obesity; Polycystic Ovary Syndrome; Signal Transduction; Treatment Outcome

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

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

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

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

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

Obesity is a major public health problem worldwide. Obesity-related illnesses, such as coronary heart disease, type 2 diabetes, hypertension, dyslipidemia, stroke, sleep apnea, and several forms of cancer (endometrial, breast, and colon), contribute to a significant number of deaths in the USA. Bariatric surgery, including the Roux-en-Y gastric bypass (RYGB) procedure, has demonstrated significant improvements in obesity and obesity-related co-morbidities and is becoming more popular as the number of obese individuals rises. Despite the reported benefits of bariatric surgery, there are potential complications that physicians need to be aware of as the number of patients undergoing these procedures continues to increase. One challenging and potentially life-threatening complication that to date is not well understood is post-RYGB surgery hypoglycemia (PGBH). In this review, we will present the definition, historical perspective, diagnostic approach, currently available treatment options, and anecdotal assessment and treatment algorithm for this disorder.

Topics: Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemia; Incretins; Obesity

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

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

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

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

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

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

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

Precise control of blood glucose is dependent on adequate β-cell mass and function. Thus, reductions in β-cell mass and function lead to insufficient insulin production to meet demand, and result in diabetes. Recent evidence suggests that paracrine signaling in the islet might be important in obesity, and disruption of this signaling could play a role in the pathogenesis of diabetes. For example, we recently discovered a novel islet incretin axis where glucagon-like peptide-1 regulates β-cell production of another classic gut hormone, cholecystokinin. This axis is stimulated by obesity, and plays a role in enhancing β-cell survival. In the present review, we place our observations in the wider context of the literature on incretin regulation in the islet, and discuss the potential for therapeutic targeting of these pathways.

Topics: Animals; Cholecystokinin; Glucagon-Like Peptide 1; Humans; Incretins; Islets of Langerhans; Obesity; Paracrine Communication

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

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

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

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

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

Topics: Cholecystitis; Combined Modality Therapy; Diet Therapy; Exercise Therapy; Humans; Hypoglycemia; Incretins; Liraglutide; Obesity; Overweight; Pancreatitis

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

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

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

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

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

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

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

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

Currently, obesity and its associated complications are considered major public health problems worldwide. Because the causes are multifactorial and complex, different treatment methods are used, which include diet and exercise, as well as the use of drugs, although they can have adverse side effects. A new target for the treatment of obesity may be the incretin system, which consists of hormones that seem to contribute to weight loss. In this sense, some studies have shown a relationship between weight loss and drugs related to incretin system, including glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. The objective of this review is to summarize the association between the incretin system and obesity treatment.

Topics: Animals; Anti-Obesity Agents; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Obesity; Receptors, Gastrointestinal Hormone

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

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

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

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

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

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

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

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

Despite advances in understanding the roles of adiposity, food intake, GI and adipocyte-related hormones, inflammatory mediators, the gut-brain axis and the hypothalamic nervous system in the pathophysiology of obesity, the effects of different therapeutic interventions on those pathophysiological mechanisms are controversial. There are still no low-cost, safe, effective treatments for obesity and its complications. Currently, bariatric surgical approaches targeting the GI tract are more effective than non-surgical approaches in inducing weight reduction and resolving obesity-related comorbidities. However, current guidelines emphasise non-surgical approaches through lifestyle modification and medications to achieve slow weight loss, which is not usually sustained and may be associated with medication-related side effects. This review analyses current central, peripheral or hormonal targets to treat obesity and addresses challenges and opportunities to develop novel approaches for obesity.

Topics: Bariatric Surgery; Central Nervous System; Humans; Incretins; Microbiota; Obesity; Weight Reduction Programs

Pancreatic beta cells sense glucose flux and release as much insulin as required in order to maintain glycaemia within a narrow range. Insulin secretion is regulated by many factors including glucose, incretins, and sympathetic and parasympathetic tones among other physiological factors. To identify the mechanisms linking obesity-related insulin resistance with impaired insulin secretion represents a central challenge. Recently, it has been argued that a crosstalk between skeletal muscle and the pancreas may regulate insulin secretion. Considering that skeletal muscle is the largest organ in non-obese subjects and a major site of insulin- and exercise-stimulated glucose disposal, it appears plausible that muscle might interact with the pancreas and modulate insulin secretion for appropriate peripheral intracellular glucose utilization. There is growing evidence that muscle can secrete so-called myokines that can have auto/para/endocrine actions. Although it is unclear in which direction they act, interleukin-6 seems to be a possible muscle-derived candidate protein mediating such inter-organ communication. We herein review some of the putative skeletal muscle-derived factors mediating this interaction. In addition, the evidence coming from in vitro, animal and human studies that support such inter-organ crosstalk is thoroughly discussed.

Topics: Glucose; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Muscle, Skeletal; Obesity; Pancreas; Receptor Cross-Talk

Over the past decade, treatment for obesity has been limited because of an incomplete understanding of the pathophysiology of obesity, lack of recognition of it as a disease, and limited efficacy of treatment options. Safety concerns related to medical and surgical approaches for obesity have also been a major barrier. The challenging nature of obesity management is reflected in a survey of primary care physicians which indicated that treating patients with obesity can be as difficult as treating patients with nicotine or alcohol dependence.

Topics: Anti-Obesity Agents; Bupropion; Dopamine Uptake Inhibitors; Forecasting; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Liraglutide; Naltrexone; Narcotic Antagonists; Obesity; Receptors, Glucagon

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In addition to its effects on reproductive health, it is now well recognized that polycystic ovary syndrome (PCOS) is a metabolic disorder, characterized by decreased insulin sensitivity which leads to an excess lifetime risk of type 2 diabetes and cardiovascular disease. PCOS patients are often obese, hypertensive, dyslipidemic and insulin resistant; they have obstructive sleep apnea and have been reported to have higher aldosterone levels in comparison to normal healthy controls. These are all components of an adverse cardiovascular risk profile. Many studies exploring subclinical atherosclerosis using different methods (flow-mediated dilatation, intima media thickness, arterial stiffness, coronary artery calcification) as well as assessing circulating cardiovascular risk markers, point toward an increased cardiovascular risk and early atherogenesis in PCOS. The risk and early features of subclinical atherosclerosis can be reversed by non-medical (normalization of weight, healthy lifestyle) and medical (metformin, thiazolidinediones, spironolactone, and statins) interventions. However, the long-term risk for cardiovascular morbidity and mortality as well as the clinical significance of different interventions still need to be properly addressed in a large prospective study.

Topics: Adolescent; Adult; Androstenes; Atherosclerosis; Cardiovascular Diseases; Carotid Intima-Media Thickness; Coronary Artery Disease; Female; Humans; Hypertension; Incretins; Insulin Resistance; Life Style; Metformin; Middle Aged; Obesity; Polycystic Ovary Syndrome; Postmenopause; Renin-Angiotensin System; Risk Factors; Sleep Apnea, Obstructive; Thiazolidinediones; Vascular Stiffness; Weight Reduction Programs

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

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

Consumption of milk and dairy products has been associated with reduced risk of metabolic disorders and cardiovascular disease. Milk contains two primary sources of protein, casein (80%) and whey (20%). Recently, the beneficial physiological effects of whey protein on the control of food intake and glucose metabolism have been reported. Studies have shown an insulinotropic and glucose-lowering properties of whey protein in healthy and Type 2 diabetes subjects. Whey protein seems to induce these effects via bioactive peptides and amino acids generated during its gastrointestinal digestion. These amino acids and peptides stimulate the release of several gut hormones, such as cholecystokinin, peptide YY and the incretins gastric inhibitory peptide and glucagon-like peptide 1 that potentiate insulin secretion from β-cells and are associated with regulation of food intake. The bioactive peptides generated from whey protein may also serve as endogenous inhibitors of dipeptidyl peptidase-4 (DPP-4) in the proximal gut, preventing incretin degradation. Indeed, recently, DPP-4 inhibitors were identified in whey protein hydrolysates. This review will focus on the emerging properties of whey protein and its potential clinical application for obesity and Type 2 diabetes.

Topics: Appetite; Cholecystokinin; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Milk Proteins; Obesity; Peptide YY; Thermogenesis; Whey Proteins

Recent research has indicated that appetite-regulating hormones from the gut may have therapeutic potential. The incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral and central pathways mediating satiation. Several studies have also indicated that GLP-1 levels and responses to meals may be altered in obese subjects. Clinical trial results have shown further that two GLP-1 receptor agonists (GLP-1 RAs), exenatide and liraglutide, which are approved for the treatment of hyperglycemia in patients with type 2 diabetes, also produce weight loss in overweight subjects without diabetes. Thus, GLP-1 RAs may provide a new option for pharmacological treatment of obesity.

Topics: Animals; Eating; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Peptides; Receptors, Glucagon; Satiation; Signal Transduction; Venoms; Weight Loss

Type 2 diabetes mellitus, also called non-insulin dependent diabetes mellitus, is a chronic endocrine disease characterized by insulin resistance in tissues such as fat, liver and skeletal muscle, and impaired insulin secretion in pancreatic β cells. The prevalence and incidence of type 2 diabetes exploded over last decades along with increased population obesity owing to western lifestyle factors such as lack of exercise and high calorie diets. As diabetes progresses without appropriate treatment, many micro- and macro-vascular complications occur, leading to increased risk of mortality. Although lifestyle modifications including a healthier diet and more frequent exercise are suggested as initial therapy for type 2 diabetes, pharmacotherapy is required in many cases. Currently, several anti-diabetic drugs with different mechanisms of action are available, but increased effectiveness and tolerability are a still unmet need for diabetes pharmacotherapy. Thus, the development of new anti-diabetic drugs is an active research area in both academia and the pharmaceutical industry. This review focuses on the targets in the latest developments of non-insulin anti-diabetics that attract the most interest in this disease area.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomedical Research; Diabetes Mellitus, Type 2; Drug Discovery; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Obesity

It has been demonstrated that fatty acids (FAs) are physiological ligands of G-protein-coupled receptors (GPRs). Activation of the GPRs (40, 41, 43, 84, 119 and 120) by FAs or synthetic agonists modulates several responses. In this review, we discuss the current knowledge on the actions of FA-activated GPRs and their relevance in normal and pathological conditions.. Studies have shown that FA-activated GPRs modulate hormone secretion (incretin, insulin and glucagon), activation of leukocytes and several aspects of metabolism.. Understanding GPR actions and their involvement in the development of insulin-resistance, β-cell failure, dyslipidemia and inflammation associated with obesity, type 2 diabetes, metabolic syndrome and cardiovascular diseases is important for the comprehension of the mechanisms underlying these pathological conditions and for the establishment of new and effective interventions.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Acids; Feeding Behavior; Gastrointestinal Tract; Humans; Incretins; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leukocytes; Ligands; Obesity; Receptors, G-Protein-Coupled

GLP-1 receptors are expressed in the brain, especially in the regions responsible for the regulation of food intake, and intracerebroventricular injection of GLP-1 results in inhibition of food intake. Peripheral administration of GLP-1 dose-dependently enhances satiety and reduces food intake in normal and obese subjects as well as in type 2 diabetic patients. So far, the mechanisms by which GLP-1 exerts its effects are not completely clear. Interactions with neurons in the gastrointestinal tract or possibly direct access to the brain through the blood-brain barrier as observed in rats are possible and discussed in this chapter as well as a novel hypothesis based on the finding that GLP-1 is also expressed in taste cells. Finally, the role of GLP-1 receptor agonists as a possible treatment option in obesity is discussed as well as the role of GLP-1 in the effects of bariatric surgery on adiposity and glucose homeostasis.

Topics: Animals; Appetite Depressants; Appetite Regulation; Bariatric Surgery; Body Weight; Brain; Eating; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity; Receptors, Glucagon; Satiety Response; Signal Transduction

Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretins physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide (GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic approach, since it is dually manifested by promoting weight reduction, in the case of GLP-1, or favoring lipid accumulation, in the case of GIP. The complete spectrum of incretin actions related to energy homeostasis is yet to be fully elucidated. Currently, new drugs based on incretin physiology are available for treatment of type 2 diabetes mellitus, whereas the implication of similar drugs in the treatment of obesity is under investigation. These agents exert several beneficial effects that minimize cardiovascular risk.

Topics: Animals; Anti-Obesity Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Design; Energy Metabolism; Feedback, Physiological; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Obesity; Risk Factors; Signal Transduction; Treatment Outcome

Studies of patients going into diabetes remission after gastric bypass surgery have demonstrated the important role of the gut in glucose control. The improvement of type 2 diabetes after gastric bypass surgery occurs via weight dependent and weight independent mechanisms. The rapid improvement of glucose levels within days after the surgery, in relation to change of meal pattern, rapid nutrient transit, enhanced incretin release and improved incretin effect on insulin secretion, suggest mechanisms independent of weight loss. Alternatively, insulin sensitivity improves over time as a function of weight loss. The role of bile acids and microbiome in the metabolic improvement after bariatric surgery remains to be determined. While most patients after bariatric surgery experienced sustained weight loss and improved metabolism, small scale studies have shown weight regain and diabetes relapse, the mechanisms of which remain unknown.

Topics: Bariatric Surgery; Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Follow-Up Studies; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance; Malnutrition; Metagenome; Obesity; Recurrence; Weight Loss

Postprandial glucose, together with related hyperinsulinemia and lipidaemia, has been implicated in the development of chronic metabolic diseases like obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). In this review, available evidence is discussed on postprandial glucose in relation to body weight control, the development of oxidative stress, T2DM, and CVD and in maintaining optimal exercise and cognitive performance. There is mechanistic evidence linking postprandial glycaemia or glycaemic variability to the development of these conditions or in the impairment in cognitive and exercise performance. Nevertheless, postprandial glycaemia is interrelated with many other (risk) factors as well as to fasting glucose. In many studies, meal-related glycaemic response is not sufficiently characterized, or the methodology with respect to the description of food or meal composition, or the duration of the measurement of postprandial glycaemia is limited. It is evident that more randomized controlled dietary intervention trials using effective low vs. high glucose response diets are necessary in order to draw more definite conclusions on the role of postprandial glycaemia in relation to health and disease. Also of importance is the evaluation of the potential role of the time course of postprandial glycaemia.

Topics: Blood Glucose; Body Weight; Chronic Disease; Humans; Hyperglycemia; Incretins; Obesity; Postprandial Period; Risk Factors

The incidence of obesity and obesity-associated diseases, such as type-2 diabetes, has reached epidemic proportions in recent years. It is predicted that by 2015 over 1.5 billion consumers will be overweight or obese. Several of the current drug-based treatments on the market for weight management and appetite control either lack efficacy or are associated with adverse side-effects. There is, therefore, an opportunity to develop functional foods which are both nutritionally beneficial but which also aid in weight management. Peptides produced in the gastrointestinal tract, which function to regulate feed intake and satiety, have been identified as key targets for bioactive ingredients in functional foods. These peptides are produced and released by specialised enteroendocrine cells. Understanding the interaction of foods with these cells is vital to the development of food matrices with positive health benefits. This review describes enteroendocrine cell populations in detail and focuses on the peptides that they produce in addition to their other functions, including taste transduction. Several food-based sources of bioactives and current food products on the market with beneficial effects on satiety and glycaemia will also be discussed.

Topics: Appetite Regulation; Enteroendocrine Cells; Gastrointestinal Hormones; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glycemic Index; Humans; Incretins; Obesity; Peptide Hormones; Satiation; Signal Transduction

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

Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diabetic Retinopathy; Epigenesis, Genetic; Female; Fetal Development; Genetic Predisposition to Disease; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Life Style; Liver; Muscle, Skeletal; Myocardium; Obesity; Prediabetic State; Pregnancy

Roux-en-Y gastric bypass surgery (GBP) results in 30-40% sustained weight loss and improved type 2 diabetes in up to 80% of patients. The relative contribution of the gut neuroendocrine changes after GBP versus the weight loss has not been fully elucidated. There are clear differences between weight loss by GBP and by dietary intervention or gastric banding. One of them is the enhanced post-prandial release of incretin hormones and the recovery of the incretin effect on insulin secretion after GBP, not seen after diet-induced weight loss. The favorable changes in incretin hormones after GBP result in recovery of the early phase insulin secretion and lower post-prandial glucose levels during oral glucose administration. The enhanced incretin response may be related to the neuroglycopenia post-GBP. In parallel with changes of glucose metabolism, a larger decrease of circulating branched-chain amino acids in relation to improved insulin sensitivity and insulin secretion is observed after GBP compared to diet. The mechanisms of the rapid and longterm endocrine and metabolic changes after GBP are not fully elucidated. Changes in rate of eating, gastric emptying, nutrient absorption and sensing, bile acid metabolism, and microbiota may all be important. Understanding the mechanisms by which incretin release is exaggerated post-prandially after GBP may help develop new less invasive treatment options for obesity and diabetes. Equally important would be to identify biological predictors of success or failure and to understand the mechanisms of weight regain and/or diabetes relapse.

Topics: Amino Acids; Animals; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Incretins; Obesity; Obesity, Morbid; Recurrence; Severity of Illness Index; Weight Loss

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gut peptides which are secreted by endocrine cells in the intestinal mucosa. Their plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Incretins; Obesity

It has long been known that peptide hormones from the gastrointestinal tract have significant impact on the regulation of nutrient metabolism. Among these hormones, incretins have been found to increase insulin secretion, and thus incretin-based therapies have emerged as new modalities for the treatment of type 2 diabetes. In contrast to other antidiabetic treatments, these agents have a positive outcome profile on body weight. Worldwide there are 500 million obese people, and 3 million are dying every year from obesity-related diseases. Recently, incretin-based therapy was proposed for the treatment of obesity. Currently two different incretin therapies are widely used in the treatment of type 2 diabetes: 1) the GLP-1 receptor agonists which cause significant and sustained weight loss in overweight patients, and 2) dipeptidyl peptidase 4 (DPP-4) inhibitors being weight neutral. These findings have led to a greater interest in the physiology of intestinal peptides with potential weight-reducing properties. This review discusses the effects of the incretin-based therapies in obesity, and provides an overview of intestinal peptides with promising effects as potential new treatments for obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Humans; Incretins; Obesity

Type 2 diabetes mellitus and comorbidities related to overweight/obesity are risk factors for the development of cardiovascular disease (CVD). In addition to insulin resistance and progressive beta-cell failure as key factors in the pathogenesis of type 2 diabetes mellitus, defects in the incretin system are now known to contribute as well. Lifestyle modifications including diet and exercise are often insufficient for reducing glucose and weight, and most patients with type 2 diabetes will require pharmacotherapy to treat their hyperglycemia. Goals of therapy should be to reduce blood glucose to as low as possible, for as long as possible, without weight gain and hypoglycemia, and correcting cardiovascular risk factors. Numerous antidiabetes medications lower blood glucose; however, many are associated with weight gain and do not address risk factors present for CVD. Newer pharmacotherapies include the glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and amylinomimetics. The GLP-1 receptor agonists and amylinomimetics reduce glucose while promoting weight loss and improving other cardiovascular risk factors with a low incidence of hypoglycemia. The DPP-4 inhibitors effectively lower glucose and are weight neutral.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Life Style; Liraglutide; Obesity; Overweight; Peptides; Receptors, Glucagon; Venoms; Weight Loss

Obesity has reached epidemic proportions and is continuing to grow into one of the leading healthcare issues worldwide. With this development, bariatric surgery has emerged as an acceptable treatment for morbid obesity, generally achieving meaningful and sustained weight loss. In a surprising turn of events, bariatric surgery was also found to be the most effective therapy for type 2 diabetes mellitus (T2DM). This observation has sparked a great deal of research that has improved our understanding of T2DM pathophysiology; it has facilitated the development of medical treatment and is expanding the indications for bariatric surgery. It was traditionally accepted that bariatric surgery causes weight loss by restriction of gastric volume, intestinal malabsorption, or a combination of the two. Laparoscopic adjustable gastric banding (LAGB) is considered a purely restrictive procedure that involves the placement of an adjustable band around the cardia of the stomach, creating a 15 ml pouch. Laparoscopic sleeve gastrectomy (LSG) is the resection of the fundus all along the greater curvature of the stomach. LSG was once considered a restrictive procedure, but this presumption has recently come under scrutiny. Bilio-pancreatic diversion (BPD) is an example of a procedure that was considered predominantly malabsorptive. In this operation, the ingested nutrients are diverted from the stomach to the ileum, bypassing a large segment of proximal bowel. Roux-en-Y gastric bypass (RYGB) traditionally combines both mechanisms, partitioning a small pouch from the proximal stomach and diverting the ingested nutrients to the jejunum with a roux-en-Y gastro-jejunostomy. However, recent investigation suggests additional mechanisms of action including hormonal. Today, RYGB is the procedure of choice for morbidly obese patients. The effect of bariatric surgery on T2DM was initially described in 1995 by Pories et al., who reported that there was an overall T2DM resolution after RYGB of 82.9% (1). A resolution rate of approximately 80% has been demonstrated repeatedly (2,3). The initial assumption was that the mechanism causing this effect was through weight loss. It is becoming evident that the anti-diabetic effect is not entirely weight loss as there is a consistent observation that the improvement of glucose and insulin levels occurs within days after RYGB, clearly too soon to be due to the weight loss (1,4). The ensuing body of literature has generated two leading theories att

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

Most patients with type 2 diabetes present with comorbid overweight or obesity. Reaching and maintaining acceptable glycemic control is more difficult in overweight and obese patients, and these conditions are associated with increased risk for cardiovascular and other diseases. Glycemic management for these patients is complicated by the fact that insulin and many of the oral medications available to treat type 2 diabetes produce additional weight gain. However, an increasing number of therapeutic options are available that are weight neutral or lead to weight loss in addition to their glycemic benefits. This article evaluates the evidence from clinical trials regarding the relative glycemic benefits, measured in terms of glycated hemoglobin change, versus the impact on body weight of each medication currently approved for type 2 diabetes. In general, the sulfonylureas, thiazolidinediones, and D-phenylalanine derivatives have been shown to promote weight gain. The dipeptidyl peptidase-4 inhibitors are weight neutral, while the biguanides, incretin mimetics, and amylin mimetics promote weight loss. Trials examining the glycemic benefits of the weight loss agents orlistat and sibutramine are also examined. Awareness of this evidence base can be used to inform medication selection in support of weight management goals for patients with type 2 diabetes.

Topics: Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Obesity

Type 2 diabetes patients are usually overweight or obese. Further weight gain induced by antidiabetic treatment should be avoided if possible. Much attention has been focussed recently on the potential for GLP-1 mimetics, in particular, to reduce weight.. Effects on weight are but one of several important criteria in selecting antidiabetic therapy, however. This review explores the effects on weight of older classes of antidiabetic agents (metformin, sulfonylureas, thiazolidinediones) and the newer drugs acting via the GLP-1 system. Other aspects of their therapeutic profiles and current therapeutic use are reviewed briefly to place effects on weight within a broader context.. Comparative trials demonstrated weight neutrality or weight reduction with metformin, and weight increases with a sulfonylurea or thiazolidinedione. There was no clinically significant change in weight with DPP-4 inhibitors and a small and variable decrease in weight (about 3 kg or less) with GLP-1 mimetics. Improved clinical outcomes have been demonstrated for metformin and a sulfonylurea (cardiovascular and microvascular benefits, respectively, in the UK Prospective Diabetes Study), and secondary endpoints improved modestly with pioglitazone in the PROactive trial. No outcome benefits have been demonstrated to date with GLP-1-based therapies, and these agents exert little effect on cardiovascular risk factors. Concerns remain over long-term safety of these agents and this must be weighed against any potential benefit on weight management.. Considering effects on weight within the overall risk-benefit profile of antidiabetic therapies, metformin continues to justify its place at the head of current management algorithms for type 2 diabetes, due to its decades-long clinical evidence base, cardiovascular outcome benefits and low cost.

Topics: Blood Glucose; Body Weight; Decision Making; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Obesity; Randomized Controlled Trials as Topic; Treatment Outcome

The global obesity epidemic fuelled by our obesogenic environment, and the prevention and treatment of obesity are some of the most important health-care challenges of our time. Although influenced largely by genetic factors, body mass index (BMI) is also heavily dependent upon environmental (principally dietary) factors. Whilst bariatric surgery often results in weight loss, its associated cost is prohibitive for widespread application. Current options for medical treatment of obesity are limited by recent withdrawals of Rimonabant and Sibutramine, enhancing the need for further development of novel weight-loss drugs. The incretin effect results from release of the incretin hormones Glucagon like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP) from intestinal cells in response to glucose ingestion. This in turn has direct effects on the endocrine pancreas to enhance insulin release in a glucose-dependent manner and suppress glucagon release, the net effects of which are to reduce post-prandial excursions of plasma glucose. Administration of novel GLP-1-mimetic therapies to patients with type 2 diabetes mellitus (T2D) has been shown to improve and stabilise glycaemic control. In addition, such treatment often leads to substantial and sustained weight loss through pleiotropic effects. These include primary central suppressive effects on hypothalamic appetite control and secondary central effects including inhibition of gastric emptying inducing a feeling of fullness during meals. Although not currently licensed for use as weight-loss therapies, application of GLP-1-mimetic drugs for such a purpose would seem to offer great potential, and should be a focus for further research including a full assessment of safety issues.

Topics: Adipose Tissue; Anti-Obesity Agents; Appetite Depressants; Body Mass Index; Controlled Clinical Trials as Topic; Drug Therapy, Combination; Humans; Incretins; Insulin; Obesity; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Weight Loss

Type 2 diabetes mellitus (T2DM) is rapidly increasing in prevalence and is a major public health problem. It is a progressive disease which commonly requires multiple pharmacotherapy. Current options for treatment may have undesirable side effects (particularly weight gain and hypoglycaemia) and contraindications, and little effect on disease progression. Incretin based therapy is one of several newer therapies to improve glycaemia and is available in two different forms, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Use of these agents results in a 'glucose-dependant' increase in insulin secretion and glucagon suppression resulting in improved glycaemia with low incidence of hypoglycaemia. DPP-4 inhibitors are oral drugs which are weight neutral, while GLP-1 agonists are injected subcutaneously and help promote weight loss while improving glycaemia. GLP-1 agonists have also been shown to increase beta cell mass in rat models. Bariatric surgery is another option for the obese patient with T2DM, with blood glucose normalizing in over half of the patients following surgery. Other therapies in development for the treatment of T2DM include sodium-glucose transporter 2 (SGLT-2) inhibitors, glucagon receptor antagonists, glucokinase activators and sirtuins. In this article, we will review the various existing and emerging treatment options for T2DM.

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

The function of the stomach and the gut hormonal responses to food ingestion constitute highly integrated homeostatic responses that maintain euglycemia and normal digestion. This intrinsic feedback involves vagal and hormonal mechanisms. Important signals such as GLP-1 and PYY that arise peripherally induce satiation and also delay gastric emptying or increase insulin secretion. Novel therapies are being developed to mimic or enhance these feedback mechanisms and to control appetite as a means to treat obesity.

Topics: Animals; Anti-Obesity Agents; Appetite; Gastrointestinal Motility; Glucagon-Like Peptide 1; Humans; Incretins; Obesity; Peptide YY; Satiation

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

Patients with type 2 diabetes, approximately 85% of whom are overweight or obese, often have an increased incidence of cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia. Both type 2 diabetes and obesity are independent risk factors for CVD. Unfortunately, many therapies aimed at maintaining and improving glucose control are associated with weight gain. Among the older antidiabetes agents, most, including the insulin secretagogues and sensitizers, can lead to weight gain, except for metformin, which is weight-neutral. Among the newer agents, the dipeptidyl peptidase-4 inhibitors generally are weight-neutral in addition to lowering glucose, while the glucagon-like peptide-1 receptor agonists lead to weight reduction. Patients with type 2 diabetes are at an increased risk for both diabetes- and CV-related outcomes, and weight reduction is an important component of diabetes management. Weight gain in patients with type 2 diabetes can contribute to patient frustration and may negatively impact their compliance to therapeutic regimens. The selection of antidiabetes agents that not only improve glucose control but reduce or have a neutral effect on weight with beneficial effects on lipids are ideal options for managing patients with type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Exenatide; Glucagon-Like Peptide 1; Health Knowledge, Attitudes, Practice; Humans; Hypoglycemic Agents; Incretins; Motivation; Obesity; Patient Compliance; Peptides; Risk Management; Self Care; Venoms; Weight Gain

Obesity is associated with increased insulin resistance and is a well-recognized factor for the development of type 2 diabetes. Unfortunately, most diabetes therapies are associated with further weight gain, a most unwelcome characteristic, given the association of weight gain with deteriorating metabolic control, worsening cardiovascular profiles and decreased adherence to treatment. Therapies that effectively control glycaemia without weight gain or with concomitant weight loss are needed. The aim of this article was to review the existing preclinical and clinical evidences, showing that the family of glucagon-like peptide-1 (GLP-1)-based therapies fulfils these criteria by harnessing the beneficial properties of GLP-1, a naturally occurring incretin hormone with a strong blood glucose-lowering action and the ability to induce weight loss.

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

Many data are available on the epidemiology of type 2 diabetes in France (ENTRED 2007, DIABASIS 2008). It is currently estimated that 2.2 million people (3.8% of the population) have type 2 diabetes, with a higher prevalence among those with lower socioeconomic status. Ninety-five per cent of patients are over 45 years of age, 52% are male, 71% are overweight, 54% have hypertension, 18% have elevated LDL cholesterol, 19% have elevated triglyceride levels, and 13% are smokers. The main complications are cardiac (16.7%), retinal (16.6%), and renal disorders (elevated plasma creatinine in 19%), and foot ulcers (9.9%). HbA1c values exceed 7% in 41% of cases. Most patients are treated by general practitioners (93%), while 20% are followed by a diabetologist. Education is provided more often by hospital diabetologists (71%) than by general practitioners (11%). Nine out of ten patients are treated with oral antidiabetic drugs, consisting of metformin (62%), sulfonylurea (50%), glitazones (13%), glinides (8%), and alpha glucosidase inhibitors (8%), usually alone (43%) or in dual-agent combinations (29%). Insulin is prescribed to 17% of patients, an average of 13.8 years after initial diagnosis. Three-quarters of patients are prescribed antihypertensives, 47% statins and 40% antiplatelet drugs. One-third of patients are poorly adherent to their treatment and three-quarters experience adverse effects. Only one-quarter of patients follow dietary measures. The estimated annual per-patient cost of type 2 diabetes is 5400 euros, a sum that is fully reimbursed in 89% of cases. Patient management in France started to improve markedly in 2001 (ENTRED 2001), with more attention being paid to risk factors, and more widespread use of antihypertensive drugs, statins and antiplatelet agents. If the dramatic increase in the incidence of type 2 diabetes is to be reversed, patients at risk must be identified and managed earlier. In particular, plasma glucose levels must be determined regularly in all people over 45 years of age and in all subjects at risk of diabetes. Management of hyperglycemia and other risk factors must be more aggressive and adapted to disease progression. Patient follow-up must be improved, taking in account the entire healthcare infrastructure, and especially structures involved in the treatment of obesity and diabetes.

Topics: Adult; Aged; Bariatric Surgery; Combined Modality Therapy; Comorbidity; Cost of Illness; Diabetes Mellitus, Type 2; Diet, Diabetic; Exercise Therapy; Female; France; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidence; Incretins; Male; Metabolic Syndrome; Middle Aged; Obesity; Patient Compliance; Risk Factors; Socioeconomic Factors

The aims of this review are (1) to examine the pathophysiologic relationship between type 2 diabetes and obesity, (2) to provide an overview of current and emerging treatments for type 2 diabetes and their effects on body weight.. A MEDLINE search was performed for literature published in the English language from 1966 to 2006. Abstracts and presentations from the American Diabetes Association Scientific Sessions (2002-2006) and the European Association for the Study of Diabetes Annual Meetings (1998-2006) were also searched for relevant studies. Preclinical and clinical data were selected for inclusion based on novelty and pertinence to treatment of the obese patient.. Recent guidelines suggest that all patients with type 2 diabetes should initially receive metformin as well as lifestyle intervention, followed by rapid administration of other oral anti-diabetic agents or insulin if glycemic goals are not met or maintained. Many oral anti-diabetic drugs, and insulin, are associated with weight gain. New agents with anti-diabetic activity that may be advantageous in obese patients with type 2 diabetes have recently become available. These include injectable incretin mimetics, which reduce blood glucose while reducing body weight but commonly cause nausea and vomiting. A new class of oral agents, the dipeptidyl peptidase-4 inhibitors, is weight-neutral and largely devoid of gastrointestinal side-effects. The cannabinoid receptor antagonist rimonabant is the first of a new class of anti-obesity agents that reduces central obesity and improves multiple aspects of vascular risk.. New agents offer the prospect of improved glycemic control without weight gain. However, the ultimate roles of these agents in the treatment of obese patients with type 2 diabetes remain to be established.

Topics: Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Obesity; Risk Factors

Among the challenges in improving outcomes in patients with diabetes is effectively implementing existing pharmacotherapies. However, current therapies for diabetes are often limited by adverse effects such as edema, hypoglycemia, and weight gain. Understanding the role of the incretin effect on the pathophysiology of diabetes has led to the development of new therapeutic agents. Exenatide is the first in a new class of agents termed "incretin mimetics," which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1. In clinical trials, patients with type 2 diabetes treated with exenatide demonstrate sustained improvements in glycemic control, with reductions in fasting and postprandial glucose levels and improvements in glycosylated hemoglobin levels. Improvements in glycemic control with exenatide are coupled with reductions in body weight. Lipid parameters, blood pressure, and C-reactive protein have been shown to improve favorably in patients treated with exenatide. The sustained glycemic improvements and progressive reduction in body weight with exenatide treatment support a shift toward a more favorable cardiovascular risk profile and may have a positive impact on decreasing the risk of associated long-term complications.

Topics: C-Reactive Protein; Comorbidity; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Obesity; Peptides; Protein Binding; Risk Factors; Venoms; Weight Loss

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive beta cell dysfunction as well as abnormalities in pancreatic alpha cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance. These strategies are typically used in a stepwise manner: employing oral glucose lowering agents, followed by insulin therapy. This traditional approach fails to address the progressive decline in beta cell function. Moreover, these therapies are often associated with weight gain in overweight or obese patients with type 2 diabetes. Both exogenous insulin and insulin secretagogues are associated with an increased risk of hypoglycemia. Recently, new treatments that leverage the glucoregulatory effects of incretin hormones, such as glucagon like peptide 1 have been introduced. Both incretin mimetics and DPP-4 inhibitors address both the underlying pathophysiology and overcome several of the limitations of established therapies by providing improvements in glycemia, and control of body weight with minimal risk of hypoglycemia.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incidence; Incretins; Insulin; Insulin Secretion; Life Style; Liraglutide; Obesity; Overweight; Peptides; Prevalence; Venoms

The vast majority of patients with type 2 diabetes are overweight or obese. Lifestyle intervention to lose weight is recommended in most diabetic patients to improve glycaemic control and reduce associated risk factors for microvascular and macrovascular complications. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors, although achieving this level of weight reduction remains difficult for many patients. Complicating the matter, many agents used to target hyperglycaemia are associated with weight gain, making management of overweight or obese patients with type 2 diabetes quite challenging. Incretin-based therapies with the new classes of glucagon-like peptide-1 mimetics (e.g. exenatide, liraglutide) and dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g. sitagliptin, vildagliptin) may be of particular value in the treatment of overweight/obese type 2 diabetic patients because of their efficacy in improving glycaemic control and their favourable or neutral effects on body weight. In addition, DPP-4 inhibitors have a low risk for causing hypoglycaemia, undesirable gastrointestinal effects, or other prominent adverse effects that might limit their use. These classes of drugs hold promise for the treatment of type 2 diabetes, alone or in combination with other classes of antidiabetic agents.

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

To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms.. Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR).. Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1).. Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.

Topics: Diet, Reducing; Fibrinolysis; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Inflammation; Insulin Resistance; Liraglutide; Obesity; Plasminogen Activator Inhibitor 1; Prediabetic State; Sitagliptin Phosphate; Weight Loss

To investigate the potential synergistic effects of olive oil releasing 2-oleoylglycerol and hydrolyzed pine nut oil containing 20% pinolenic acid on GLP-1 secretion, glucose tolerance, insulin secretion and appetite in healthy individuals, when delivered to the small intestine as potential agonists of GPR119, FFA1 and FFA4.. Nine overweight/obese individuals completed three 6-h oral glucose tolerance tests (OGTTs) in a crossover design. At -30 min, participants consumed either: no oil, 6 g of hydrolyzed pine nut oil (PNO-FFA), or a combination of 3 g hydrolyzed pine nut oil and 3 g olive oil (PNO-OO) in delayed-release capsules. Repeated measures of glucose, insulin, C-peptide, GLP-1, GIP, ghrelin, subjective appetite and gastrointestinal tolerability were done.. PNO-FFA augmented GLP-1 secretion from 0-360 min compared to no oil and PNO-OO (. In support of previous findings, 6 g of delayed-release hydrolyzed pine nut oil enhanced postprandial GLP-1 secretion and reduced appetite. However, no synergistic effect of combining hydrolyzed pine nut oil and olive oil on GLP-1 secretion was observed. These results need further evaluation in long-term studies including effects on bodyweight and insulin sensitivity.

Topics: Appetite; Blood Glucose; Cross-Over Studies; Delayed-Action Preparations; Dietary Fats, Unsaturated; Dietary Supplements; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Nuts; Obesity; Olive Oil; Overweight; Pinus; Plant Oils; Postprandial Period

To examine the effects of common treatments for polycystic ovary syndrome (PCOS) on a panel of hormones (reproductive/metabolic).. Secondary analysis of blood from a randomized controlled trial of three 16-week preconception interventions designed to improve PCOS-related abnormalities: continuous oral contraceptive pills (OCPs, N = 34 subjects), intensive lifestyle modification (Lifestyle, N = 31), or a combination of both (Combined, N = 29).. Post-treatment levels of activin A and B, inhibin B, and follistatin (FST), as well as Insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 2 (IGFBP-2), glucagon, glucagon-like peptide 1 (GLP-1) and 2, and oxyntomodulin were compared to baseline, and the change from baseline in these parameters were correlated with outcomes.. Oral contraceptive pill use was associated with a significant suppression in activin A, inhibin A, and anti-mullerian hormone (AMH), but a significant increase in FST. IGF-1, IGFBP-2, glucagon, and GLP-2 levels were significantly decreased. Oxyntomodulin was profoundly suppressed by OCPs (ratio of geometric means: 0.09, 95% confidence interval [CI]: 0.05, 0.18, P < 0.001). None of the analytes were significantly affected by Lifestyle, whereas the effects of Combined were similar to OCPs alone, although attenuated. Oxyntomodulin was significantly positively associated with the change in total ovarian volume (rs = 0.27; 95% CI: 0.03, 0.48; P = 0.03) and insulin sensitivity index (rs = 0.48; 95% CI: 0.27, 0.64; P < 0.001), and it was inversely correlated with change in area under the curve (AUC) glucose [rs = -0.38; 95% CI: -0.57, -0.16; P = 0.001]. None of the hormonal changes were associated with live birth, only Activin A was associated with ovulation (risk ratio per 1 ng/mL increase in change in Activin A: 6.0 [2.2, 16.2]; P < 0.001).. In women with PCOS, OCPs (and not Lifestyle) affect a wide variety of reproductive/metabolic hormones, but their treatment response does not correlate with live birth.

Topics: Adolescent; Adult; Behavior Therapy; Combined Modality Therapy; Contraceptives, Oral; Female; Hormones; Humans; Incretins; Life Style; Obesity; Polycystic Ovary Syndrome; Retrospective Studies; Transforming Growth Factor beta; Treatment Outcome; United States; Young Adult

High Protein diets may be associated with endocrine responses that favor improved metabolic outcomes. We studied the response to High Protein (HP) versus High Carbohydrate (HC) Diets in terms of incretin hormones GLP-1 and GIP, the hunger hormone ghrelin and BNP, which is associated with cardiac function. We hypothesized that HP diets induce more pronounced release of glucose lowering hormones, suppress hunger and improve cardiac function.. 24 obese women and men with prediabetes were recruited and randomized to either a High Protein (HP) (n = 12) or High Carbohydrate (HC) (n = 12) diet for 6 months with all food provided. OGTT and MTT were performed and GLP-1, GIP, Ghrelin, BNP, insulin and glucose were measured at baseline and 6 months on the respective diets. Our studies showed that subjects on the HP diet had 100% remission of prediabetes compared to only 33% on the HC diet with similar weight loss. HP diet subjects had a greater increase in (1) OGTT GLP-1 AUC(p = 0.001) and MTT GLP-1 AUC(p = 0.001), (2) OGTT GIP AUC(p = 0.005) and MTT GIP AUC(p = 0.005), and a greater decrease in OGTT ghrelin AUC(p = 0.005) and MTT ghrelin AUC(p = 0.001) and BNP(p = 0.001) compared to the HC diet at 6 months.. This study demonstrates that the HP diet increases GLP-1 and GIP which may be responsible in part for improved insulin sensitivity and β cell function compared to the HC diet. HP ghrelin results demonstrate the HP diet can reduce hunger more effectively than the HC diet. BNP and other CVRF, metabolic parameters and oxidative stress are significantly improved compared to the HC diet. CLINICALTRIALS.. NCT01642849.

Topics: Adult; Appetite Regulation; Biomarkers; Diet, High-Protein; Dietary Carbohydrates; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Heart Disease Risk Factors; Humans; Hunger; Incretins; Male; Middle Aged; Natriuretic Peptide, Brain; Obesity; Prediabetic State; Prospective Studies; Remission Induction; Tennessee; Time Factors; Treatment Outcome; Weight Loss; Young Adult

Topics: Adamantane; Adult; Aged; Biomarkers; Blood Glucose; Cross-Over Studies; Dietary Fats; Dipeptides; Double-Blind Method; Exenatide; Female; Forearm; Humans; Incretins; Insulin; Lipids; Male; Middle Aged; Obesity; Postprandial Period; Prediabetic State; Texas; Time Factors; Treatment Outcome; Vasodilation

Long-term treatment with up to 1.8 mg liraglutide improves cardiovascular and all-cause mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) and is currently under investigation in subjects without diabetes. Aim of our study was to investigate whether high dose (3 mg) short-term (5 weeks) treatment with liraglutide in obese patients with no overt type 2 diabetes affects metabolites, lipid and lipoprotein profile and components of activin-follistatin axis in cardiovascular beneficial or detrimental way.. Twenty obese patients participated in a randomized, placebo-controlled, cross-over, double-blind study and were administrated liraglutide 3 mg or placebo for 5 weeks. Metabolites, fatty acids, lipid-lipoprotein profile and concentrations of activins and follistatins (250 parameters) were assessed in serum at start and completion of each treatment.. Concentrations of important cardiovascular markers such as total, free and remnant cholesterol were reduced with liraglutide before and after adjusting for weight loss. Similarly, reductions in number of small and medium size LDL particles and in their total lipid concentration were observed with liraglutide and partially weight-loss related. Tyrosine levels were reduced and behenic acid levels were increased whereas only minor changes were observed in HDL, VLDL and IDL. Concentrations of activin AB and follistatin were significantly reduced in liraglutide-treated group.. Treatment of obese patients without overt type 2 diabetes with high dose of liraglutide for a short period of time induces changes in lipid-lipoprotein and hormonal profile that are suggestive of lower risk of atherosclerosis and CVD. Trial registration ClinicalTrials.gov Identifier: NCT02944500. Study ID Number 2015P000327. Registered November 2016.

Topics: Biomarkers; Boston; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Follistatin; Humans; Incretins; Inhibin-beta Subunits; Lipid Metabolism; Lipids; Lipoproteins; Liraglutide; Male; Obesity; Time Factors; Treatment Outcome

The success rate of weight loss maintenance is limited. Therefore, the purpose of this study is to investigate the maintenance of weight loss and immunometabolic health outcomes after diet-induced weight loss followed by 1-year treatment with a glucagon-like peptide-1 receptor agonist (liraglutide), physical exercise or the combination of both treatments as compared with placebo in individuals with obesity.. The trial has been approved by the ethical committee of the Capital Region of Denmark and the Danish Medicines Agency. The trial will be conducted in agreement with the Declaration of Helsinki and monitored to follow the guidelines for good clinical practice. Results will be submitted for publication in international peer-reviewed scientific journals.. 2015-005585-32.

Topics: Adolescent; Adult; Aged; Caloric Restriction; Denmark; Exercise; Female; Humans; Incretins; Liraglutide; Male; Middle Aged; Obesity; Randomized Controlled Trials as Topic; Weight Loss

Topics: Anti-Obesity Agents; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Combinations; Drug Monitoring; Drug Resistance, Multiple; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Metformin; Obesity; Overweight; Weight Gain; Weight Loss

Previously in the SCALE Obesity and Prediabetes trial, at 1 year, participants with obesity (or overweight with comorbidities) and prediabetes receiving liraglutide 3.0 mg experienced greater improvements in health-related quality of life (HRQoL) than those receiving placebo. The current study extends these findings by examining 3-year changes in HRQoL. HRQoL was assessed using the obesity-specific Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire, as well as the Short-Form 36 v2 (SF-36) health survey. At 3 years, mean change (±standard deviation) in IWQOL-Lite total score from baseline for liraglutide (n = 1472) was 11.0 ± 14.2, vs. 8.1 ± 14.7 for placebo (n = 738) (estimated treatment difference [ETD] 3.4 [95% confidence interval (CI): 2.0, 4.7], P < 0.0001). Mean change in SF-36 physical component summary (PCS) score from baseline for liraglutide was 3.1 ± 7.3, vs. 2.6 ± 7.6 for placebo (ETD 0.87 [95% CI: 0.17, 1.6], P = 0.0156). Mean change in SF-36 mental component summary score did not significantly differ between groups. Both IWQOL-Lite total score and PCS score demonstrated an association between greater HRQoL improvement with higher weight loss. Liraglutide 3.0 mg was also associated with improved health utility (Short-Form-6D and EuroQol-5D, mapped from IWQOL-Lite and/or SF-36) vs. placebo. Liraglutide 3.0 mg, plus diet and exercise, is associated with long-term improvements in HRQoL with obesity or overweight with comorbidity vs. placebo.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Cost of Illness; Double-Blind Method; Female; Health Status; Humans; Incretins; Liraglutide; Male; Mental Health; Middle Aged; Obesity; Quality of Life; Surveys and Questionnaires; Time Factors; Treatment Outcome; Weight Loss; Young Adult

After digestion, dietary triacylglycerol stimulates incretin release in humans, mainly through generation of 2-monoacylglycerol, an agonist for the intestinal G protein-coupled receptor 119 (GPR119). Enhanced incretin release may have beneficial metabolic effects. However, dietary fat may promote weight gain and should therefore be restricted in obesity. We designed C4-dietary oil (1,3-di-butyryl-2-oleoyl glycerol) as a 2-oleoyl glycerol (2-OG)-generating fat type, which would stimulate incretin release to the same extent while providing less calories than equimolar amounts of common triglycerides, e.g., olive oil.. We studied the effect over 180 min of (a) 19 g olive oil plus 200 g carrot, (b) 10.7 g C4 dietary oil plus 200 g carrot and (c) 200 g carrot, respectively, on plasma responses of gut and pancreatic hormones in 13 overweight patients with type 2 diabetes (T2D). Theoretically, both oil meals result in formation of 7.7 g 2-OG during digestion.. Both olive oil and C4-dietary oil resulted in greater postprandial (P ≤ 0.01) glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses (incremental area under curve (iAUC)): iAUC. C4-dietary oil enhanced secretion of GLP-1 and GIP to almost the same extent as olive oil, in spite of liberation of both 2-OG and oleic acid, which also may stimulate incretin secretion, from olive oil. Thus, C4-dietary oil is more effective as incretin releaser than olive oil per unit of energy and may be useful for dietary intervention.

Topics: Aged; Area Under Curve; Diabetes Mellitus, Type 2; Dietary Fats, Unsaturated; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycerides; Glycerol; Humans; Incretins; Male; Meals; Middle Aged; Obesity; Oleic Acid; Olive Oil; Overweight; Postprandial Period; Prodrugs; Receptors, G-Protein-Coupled; Single-Blind Method; Triglycerides

To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin.. This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose.. Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events.. Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.

Topics: Aged; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Male; Middle Aged; Obesity; Weight Loss

Bone morphogenetic protein 4 (BMP-4) has been proven to regulate white adipogensis. We aimed to demonstrate the correlation of BMP-4 with fat distribution and Exenatide treatment on it.. We enrolled 69 obese patients. Anthropometric and metabolic indexes were collected. Fat distribution was measured by dual-energy X-ray absorptiometry. BPM-4 levels were assessed using enzyme-link immunosorbent assay kit. 30 obese patients were treated with Exenatide twice a day. Change in body weight, metabolic-related indices and BPM-4 levels were evaluated after 18 weeks.. 1) The mean(±SD) BMP-4 levels were 763.98 ± 324.11 pg/ml in the obese. BPM-4 levels were significantly positively correlated with estimated visceral adipose tissue mass in all subjects and also in females (r = 0.377, r = 0.625, respectively,all P < 0.05). BPM-4 levels were also significantly positively correlated with body mass index, hip circumference and total fat% in females (r = 0.375,r = 0.429,r = 0.493,respectively, all P < 0.05). BPM-4 levels were negatively correlated with total cholesterol(TC) in all subjects and males also (r = -0.373,r = -0.332,respectively, all P < 0.05). BPM-4 levels were also significantly positively correlated with free triiodothyronine in males (r = 0.441, P < 0.05). 3) Multivariate analyses showed that TC was risk factor of BMP-4 concentration in males and Est.VAT Area was risk factor of BMP-4 levels in females. 4) BMP-4 levels were significantly higher in the obesity with slightly increased thyroid stimulating hormone(TSH) than the obesity without slightly increased TSH (902.08 ± 354.74 pg/ml vs. 720.24 ± 306.41 pg/ml, P < 0.05). 5) Exenatide treatment leads to a significant decreased in BMP-4 from 860.05 ± 352.65 pg/ml to 649.44 + 277.49 pg/ml independent of weight loss(P < 0.05).. BMP-4 levels were associated with the visceral adipose tissue and may play a certain role in fat distribution and subclinical hypothyroidism in obesity. Exenatide treatment reduced BMP-4 levels independent of weight loss.. Clinicaltrials.gov Identifier: NCT02118376 , Registered 16 April.

Topics: Absorptiometry, Photon; Adiposity; Adult; Body Mass Index; Bone Morphogenetic Protein 4; China; Cholesterol; Drug Monitoring; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Intra-Abdominal Fat; Male; Middle Aged; Obesity; Peptides; Reproducibility of Results; Sex Characteristics; Thyrotropin; Triiodothyronine; Venoms; Weight Loss

The gut microbiota affects host lipid and glucose metabolism, satiety, and chronic low-grade inflammation to contribute to obesity and type 2 diabetes. Fermentation end products, in particular the short-chain fatty acid (SCFA) acetate, are believed to be involved in these processes. We investigated the long-term effects of supplementation with galacto-oligosaccharides (GOS), an acetogenic fiber, on the composition of the human gut microbiota and human metabolism.. We performed a double-blinded, placebo-controlled, parallel intervention study of 44 overweight or obese (body mass index, 28-40 kg/m. Supplementation of diets with GOS, but not placebo, increased the abundance of Bifidobacterium species in feces by 5-fold (P = .009; q = 0.144). Microbial richness or diversity in fecal samples were not affected. We did not observe any differences in fecal or fasting plasma SCFA concentrations or in systemic concentrations of gut-derived hormones, incretins, lipopolysaccharide-binding protein, or other markers of inflammation. In addition, no significant alterations in peripheral and adipose tissue insulin sensitivity, body composition, and energy and substrate metabolism were found.. Twelve-week supplementation of GOS selectively increased fecal Bifidobacterium species abundance, but this did not produce significant changes in insulin sensitivity or related substrate and energy metabolism in overweight or obese prediabetic men and women. ClincialTrials.gov number, NCT02271776.

Topics: Acetic Acid; Acute-Phase Proteins; Adiposity; Aged; Bifidobacterium; Blood Glucose; Body Mass Index; Carrier Proteins; Cytokines; Dietary Supplements; DNA, Bacterial; Double-Blind Method; Energy Metabolism; Feces; Female; Galactose; Gastrointestinal Microbiome; Humans; Incretins; Insulin; Insulin Resistance; Male; Membrane Glycoproteins; Middle Aged; Obesity; Oligosaccharides; Prediabetic State

Bariatric surgery, incretin-based therapy (glucagon-like peptide-1 analogues), and sodium-glucose co-transporter 2 (SGLT2) inhibitors have antidiabetic properties in morbidly obese patients. However, their comparative efficacy in treating type 2 diabetes mellitus (T2DM) in class I obese patients specifically in Indian has not been studied yet. This study evaluates and compares the efficacy and side effect of surgical and advanced medical management of T2DM in class I obese patients.. T2DM patients with body mass index ranging from 30 to 35 kg/m. There was statistically significant lowering of HbA1c and FPG after 12 months in all the three groups. However, this lowering was clinically insignificant in GLP-1 and SGLT2 groups. There was also improvement in lipid profile values in all the three groups with significantly higher percentage change in bariatric surgery group when compared to other modalities.. Bariatric surgery is a safe and effective procedure to treat T2DM in class I obese patients. It is also superior to advance medical treatment modalities such as GLP-1 analogues and SGLT2 inhibitors.

Topics: Adult; Bariatric Surgery; Body Mass Index; Combined Modality Therapy; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Obesity; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels. Since cannabinoid receptors (CBRs) are expressed on incretin-secreting cells in rodents, we hypothesized that endocannabinoids are involved in the regulation of incretin secretion. We compared plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses during oral glucose tolerance test (OGTT) in 20 lean and 20 obese participants from the Baltimore Longitudinal Study of Aging (BLSA). Next, we recruited 20 healthy men to evaluate GIP and GLP-1 responses during OGTT after administering placebo or nabilone (CBR agonist) in a randomized, double-blind, crossover fashion. Compared with the BLSA lean group, the BLSA obese group had significantly higher fasting and post-OGTT GIP levels, but similar fasting GLP-1 and significantly lower post-OGTT GLP-1 levels. In the nabilone vs. placebo study, when compared with placebo, nabilone resulted in significantly elevated post-dose fasting GIP levels and post-OGTT GIP levels, but no change in post-dose fasting GLP-1 levels together with significantly lower post-OGTT GLP-1 levels. Glucose levels were not different with both interventions. We conclude that elevated GIP levels in obesity are likely a consequence of increased endocannabinoid levels. CBRs exert tonic control over GIP secretion, which may have a homeostatic effect in suppressing GLP-1 secretion. This raises the possibility that gut hormones are influenced by endocannabinoids.

Topics: Adult; Blood Glucose; Cannabinoid Receptor Agonists; Case-Control Studies; Cross-Over Studies; Double-Blind Method; Dronabinol; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Longitudinal Studies; Male; Middle Aged; Obesity; Prospective Studies; Receptors, Cannabinoid; Young Adult

Prader-Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS.. The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS.. Ten overweight and obese subjects with PWS (13-25 years) were recruited for a 6-month open-label, non-randomized, longitudinal study conducted at Children's Hospital Los Angeles. Exenatide was given using standard diabetes dosing without dietary modifications. Weight, body mass index (BMI), truncal fat, appetite and plasma acylated ghrelin were measured over 6 months. Mixed meal tolerance tests were performed at 0 and 6 months.. Appetite scores significantly decreased from baseline (32.2 ± 8.7) after 1, 3 and 6 moths of treatment (27.5 ± 8.8, 25.4 ± 9.3, and 25.4 ± 7.2 respectively; p = 0.004). Hemoglobin A1c decreased significantly after treatment, but weight, BMI z-score and adiposity did not. There was no significant change in ghrelin.. This is the first longitudinal investigation of the effects of exenatide in subjects with PWS. It was effective in decreasing appetite, without change in weight or BMI in the short term. Larger, controlled, longer-term trials in patients with PWS are needed to confirm the efficacy and safety of exenatide and to evaluate whether its use might induce weight loss when given in conjunction with behavioural modification.

Topics: Adolescent; Adult; Appetite; Body Mass Index; Body Weight; Exenatide; Female; Ghrelin; Humans; Hyperphagia; Incretins; Longitudinal Studies; Male; Obesity; Peptides; Prader-Willi Syndrome; Venoms; Young Adult

Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D. Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis.. Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment.. Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia.

Topics: Absorptiometry, Photon; Adult; Antipsychotic Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Composition; Body Weight; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Incretins; Male; Middle Aged; Obesity; Peptides; Schizophrenia; Treatment Outcome; Venoms; Waist Circumference; Waist-Hip Ratio; Weight Loss; Young Adult

Studies concerning the glycaemic response to oral glucose, or meals in obesity have usually failed to account for gastric emptying. It has been suggested that the incretin effect may be diminished in obesity as a result of a reduction in glucagon-like peptide-1 (GLP-1) secretion. We sought to determine the effect of two different rates of intraduodenal glucose infusions on glycaemic, insulinaemic and incretin hormone responses in lean and obese subjects and compare the effects of oral and intraduodenal glucose in obese subjects.. Eleven obese subjects (age 37.5±4.1 years, body mass index (BMI) 35.7±1.4 kg m. In both the groups (P<0.001), the incremental areas under the curve (iAUC). The rate of duodenal glucose delivery is a major determinant of glycaemia, insulinaemia and incretin hormone release in obese subjects. Obesity is not apparently associated with impaired GLP-1 secretion.

Topics: Adult; Appetite Regulation; Blood Glucose; Body Mass Index; Duodenum; Enteral Nutrition; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Motility; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Incretins; Male; Obesity; Postprandial Period

Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified.. To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT) and to investigate possible relationships between incretin response and triglyceride-rich lipoprotein (TRL) response to a fat-rich meal.. Glucose, insulin, GLP-1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5-40.2 kg/m(2)) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2) were measured after the fat-rich meal.. Postprandial responses (area under the curve, AUC) for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins.. The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p<0.0001; r = 0.46, p<0.001 and r = 0.69, p<0.001, respectively). Glucose and insulin AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2 and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest.. In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion was fasting triglycerides. The contribution of endogenous GLP-1, GLP-2 and GIP to explaining the variance in postprandial TG excursion was minor.

Topics: Adult; Aged; Apolipoprotein B-100; Apolipoprotein B-48; Area Under Curve; Blood Glucose; Chylomicrons; Dietary Fats; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Tolerance Test; Humans; Hyperlipidemias; Incretins; Lipid Metabolism; Male; Meals; Middle Aged; Obesity; Postprandial Period; Triglycerides

Liraglutide 3.0 mg, an acylated GLP-1 analogue approved for weight management, lowers body weight through decreased energy intake. We conducted exposure-response analyses to provide important information on individual responses to given drug doses, reflecting inter-individual variations in drug metabolism, absorption and excretion.. We report efficacy and safety responses across a wide range of exposure levels, using data from one phase II (liraglutide doses 1.2, 1.8, 2.4 and 3.0 mg), and two phase IIIa [SCALE Obesity and Prediabetes (3.0 mg); SCALE Diabetes (1.8; 3.0 mg)] randomized, placebo-controlled trials (n = 4372).. There was a clear exposure-weight loss response. Weight loss increased with greater exposure and appeared to level off at the highest exposures associated with liraglutide 3.0 mg in most individuals, but did not fully plateau in men. In individuals with overweight/obesity and comorbid type 2 diabetes, there was a clear exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased with higher plasma liraglutide concentration (plateauing at ∼21 nM); however, for individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No exposure-response relationship was identified for any safety outcome, with the exception of gastrointestinal adverse events (AEs). Individuals with gallbladder AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not have higher liraglutide exposure compared with the overall population.. These analyses support the use of liraglutide 3.0 mg for weight management in all subgroups investigated; weight loss increased with higher drug exposure, with no concomitant deterioration in safety/tolerability besides previously known gastrointestinal side effects.

Topics: Appetite Depressants; Body Mass Index; Cohort Studies; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Reducing; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Middle Aged; Obesity; Overweight; Prediabetic State; Sex Characteristics; Weight Loss

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

To investigate the effect of exenatide treatment on serum ghrelin levels in obese female patients with type 2 diabetes mellitus.. Fourteen female patients with type 2 diabetes mellitus being treated with metformin and exenatide were enrolled. A mixed meal test was applied to the patients while continuing with their daily medications. Blood samples were taken before and at 60, 120, and 180 minutes following mixed meal test to measure serum total ghrelin, glucose, and insulin levels. The following week, exenatide treatment of the patients was paused for 24 hours and the same experimental procedures were repeated.. Serum ghrelin levels were suppressed significantly at 180 minutes with exenatide treatment compared with baseline (294.4 ± 57.5 versus 234.5 ± 59.4 pg/mL) (p < 0.001). Serum ghrelin levels at 180 minutes were statistically different when percentage change in serum ghrelin levels after mixed meal tests with and without exenatide usage were compared (p = 0.001). Estimated total area under the curve values for serum ghrelin concentrations was also significantly lower with exenatide compared with omitted treatment (p = 0.035).. These results suggest that the effect of exenatide on weight loss may be related with the suppression of serum ghrelin levels, which is an orexigenic peptide.

Topics: Adult; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Down-Regulation; Drug Therapy, Combination; Eating; Exenatide; Female; Ghrelin; Humans; Hypoglycemic Agents; Incretins; Metformin; Middle Aged; Obesity; Peptides; Postprandial Period; Prospective Studies; Time Factors; Treatment Outcome; Venoms; Weight Loss

Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain.. In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance.. Soluble leptin receptor increase was 59% lower; 2.1±0.7 vs 5.1±0.8 ng ml(-1) (-3.0 (95% confidence interval (CI)=-0.5 to -5.5)), P<0.001 and free leptin index decrease was 43% smaller; -62±15 vs -109±20 (-47 (95% CI=-11 to -83)), P<0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (-2.3 kg (95% CI=-0.6 to -4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=-0.6 to -1)), P<0.001. Fasting glucose was decreased by an additional -0.2±0.1 mmol l(-1) in the GLP-1RA group in contrast to the control group, where glucose increased 0.3±0.1 mmol l(-1) to the level before weight loss (-0.5mmol l(-1) (95% CI=-0.1 to -0.9)), P<0.005. Meal response of peptide PYY3-36 was higher at week 52 in the GLP-1RA group compared with the control group, P<0.05.. The weight maintaining effect of GLP-1RAs may be mediated by smaller decrease in free leptin and higher PYY3-36 response. Low dose GLP-1RA therapy maintained 12% weight loss for 1 year and may prevent pre-diabetes in obesity.

Topics: Adult; Appetite; Body Mass Index; Caloric Restriction; Denmark; Female; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Leptin; Liraglutide; Male; Obesity; Prediabetic State; Treatment Outcome; Weight Loss

Obesity, type 2 diabetes and associated metabolic diseases are characterized by low-grade systemic inflammation which involves interplay of nutrition and monocyte/macrophage functions. We suggested that some factors such as nutrient components, neuropeptides involved in the control of gastrointestinal functions, and gastrointestinal hormones might influence immune cell functions and in this way contribute to the disease pathogenesis. The aim of this study was to investigate the mRNA expression of twelve nutrition-associated receptors in peripheral blood mononuclear cells (PBMC), isolated monocytes and monocyte-derived macrophages and their regulation under the switching from the high-carbohydrate low-fat diet to the low-carbohydrate high-fat (LC/HFD) isocaloric diet in healthy humans. The mRNA expression of receptors for short chain fatty acids (GPR41, GPR43), bile acids (TGR5), incretins (GIPR, GLP1R), cholecystokinin (CCKAR), neuropeptides VIP and PACAP (VIPR1, VIPR2), and neurotensin (NTSR1) was detected in PBMC and monocytes, while GPR41, GPR43, GIPR, TGR5, and VIPR1 were found in macrophages. Correlations of the receptor expression in monocytes with a range of metabolic and inflammatory markers were found. In non-obese subjects, the dietary switch to LC/HFD induced the increase of GPR43 and VIPR1 expression in monocytes. No significant differences of receptor expression between normal weight and moderately obese subjects were found. Our study characterized for the first time the expression pattern of nutrition-associated receptors in human blood monocytes and its dietary-induced changes linking metabolic responses to nutrition with immune functions in health and metabolic diseases.

Topics: Adult; Case-Control Studies; Cholecystokinin; Diet, Fat-Restricted; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Female; Gene Expression Regulation; Humans; Incretins; Macrophages; Male; Monocytes; Neuropeptides; Obesity; Organ Specificity; Primary Cell Culture; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Neurotensin

The weight lowering potential of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) is inter-individually different and clinically unpredictable. The potential role of genetic variability of GLP-1R on body weight response to GLP-1 RAs in obese women with polycystic ovary syndrome (PCOS) has not yet been evaluated.. Fifty-seven obese women with PCOS (aged 30.7 ± 7.0, BMI 38.6 ± 5.3 kg/m(2)) were assigned to liraglutide 1.2 mg QD s.c. for 12 weeks and classified as strong responders regarding weight loss if they lost 5% or more of their initial body weight. They were genotyped for common GLP-1R single nucleotide polymorphisms (SNPs) rs6923761 and rs10305420. Changes of measures of obesity were measured before and at the end of the treatment.. Twenty out of 57 subjects were strong responders and lost 7.38 ± 1.74 compared to 2.11 ± 2.17 kg lost in poor responders. Carriers of at least one polymorphic rs10305420 allele had poor treatment response compared to carriers of two wild type alleles (OR = 0.27, 95% CI = 0.09-0.85, P = 0.025). Carriers of at least one polymorphic rs6923761 allele tended to have stronger treatment response compared to carriers of two wild type alleles (OR = 3.06, 95% CI = 0.96-9.74, P = 0.058). Fasting glucose and glucose after oral glucose tolerance test (OGTT) comparably decreased in both groups when compared to baseline, whereas no within treatment differences were found in androgen profile. Gastrointestinal adverse events were transit and balanced between strong and poor responders.. GLP-1R rs10305420 polymorphism explained some of the inter-individual differences in response to liraglutide regarding weight loss in obese PCOS women.

Topics: Adult; Female; Gene Frequency; Genotype; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Liraglutide; Logistic Models; Obesity; Odds Ratio; Phenotype; Pilot Projects; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Slovenia; Treatment Outcome; Weight Loss; Young Adult

Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release of glucagon-like peptides (GLP)-1 and -2.. A prospective, double-blind, randomized trial was performed in 21 glucose-tolerant humans (11 lean: age 49 ± 7 years, BMI 23.6 ± 1.7 kg/m(2); 10 obese: age 51 ± 7 years, BMI 35.5 ± 4.9 kg/m(2)). Participants ingested 10(10) b.i.d. L. reuteri SD5865 or placebo over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess incretin effect and GLP-1 and GLP-2 secretion, and euglycemic-hyperinsulinemic clamps with [6,6-(2)H2]glucose were used to measure peripheral insulin sensitivity and endogenous glucose production. Muscle and hepatic lipid contents were assessed by (1)H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays.. In glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2 release by 76% (P < 0.01) and 43% (P < 0.01), respectively, compared with placebo, along with 49% higher insulin (P < 0.05) and 55% higher C-peptide secretion (P < 0.05). However, the intervention did not alter peripheral and hepatic insulin sensitivity, body mass, ectopic fat content, or circulating cytokines.. Enrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may serve as a novel therapeutic approach to improve glucose-dependent insulin release.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Limosilactobacillus reuteri; Male; Middle Aged; Obesity; Oxidative Stress; Pilot Projects; Probiotics; Prospective Studies; Protein Precursors

Prior research has shown an increase in GLP-1 concentrations during exercise but this exercise bout was conducted postprandially. The purpose of this study was to examine the incretin response to a meal following an exercise bout of different intensities in obese subjects. Eleven women (BMI>37.3±7.0kg/m(2); Age 24.3±4.6year) participated in 3 counter- balanced study days, where a standardized meal was preceded by: (1) No exercise (NoEx), (2) ModEx (55% VO2max), and (3) IntEx (4min (80% VO2max)/3min (50% VO2max). Frequent blood samples were analyzed for glucose, lactate, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and C-peptide concentrations throughout 280min of testing. Glucose concentrations were not different between conditions during exercise or meals. There were no differences between conditions in insulin levels during exercise and recovery, but postprandial insulin incremental area under the curve was lower in ModEx vs. NoEx (p<0.01). GIP and GLP-1 levels were not different between conditions during exercise, but during exercise recovery, GLP-1 concentrations were higher in ModEx vs. NoEx (p=0.03). The meal increased the incretin responses (p<0.01) but this response was not affected by prior exercise. Glucagon concentrations increased with exercise (p<0.05) and continued to be elevated during recovery, with the greatest increase with IntEx compared with NoEx (p<0.05). No differences between conditions were detected for hepatic insulin extraction, insulin secretion, or insulin sensitivity. Exercise prior to an evening meal has no impact on the incretin response to the subsequent meal, yet insulin concentrations were lower during the meals that followed exercise. Exercise intensity had no impact on this response.

Topics: Adult; Blood Glucose; Eating; Exercise; Female; Glucagon; Humans; Incretins; Obesity

The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Energy Intake; Gastric Inhibitory Polypeptide; Gastrointestinal Motility; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins; Male; Metformin; Obesity; Pyrazines; Sitagliptin Phosphate; Triazoles

Strong epidemiological evidence suggests that slow prenatal or postnatal growth is associated with an increased risk of CVD and other metabolic diseases. However, little is known whether early growth affects postprandial metabolism and, especially, the appetite regulatory hormone system. Therefore, we investigated the impact of early growth on postprandial appetite regulatory hormone responses to two high-protein and two high-fat content meals. Healthy, 65-75-year-old volunteers from the Helsinki Birth Cohort Study were recruited; twelve with a slow increase in BMI during the first year of life (SGI group) and twelve controls. Subjects ate a test meal (whey meal, casein meal, SFA meal and PUFA meal) once in a random order. Plasma glucose, insulin, TAG, NEFA, ghrelin, peptide tyrosine-tyrosine (PYY), glucose-dependent insulinotropic peptide, glucagon-like peptide-1 and a satiety profile were measured in the fasting state and for 4 h after each test meal. Compared with the controls, the SGI group had about 1·5-fold higher insulin responses after the whey meal (P= 0·037), casein meal (P= 0·023) and PUFA meal (P= 0·002). TAG responses were 34-69 % higher for the SGI group, but only the PUFA-meal responses differed significantly between the groups. The PYY response of the SGI group was 44 % higher after the whey meal (P= 0·046) and 115 % higher after the casein meal (P= 0·025) compared with the controls. No other statistically significant differences were seen between the groups. In conclusion, early growth may have a role in programming appetite regulatory hormone secretion in later life. Slow early growth is also associated with higher postprandial insulin and TAG responses but not with incretin levels.

Topics: Appetite Regulation; Body Mass Index; Case-Control Studies; Caseins; Diet, High-Fat; Dietary Fats; Dietary Proteins; Fatty Acids; Fatty Acids, Unsaturated; Female; Ghrelin; Growth; Humans; Incretins; Infant; Infant, Newborn; Insulin; Male; Milk Proteins; Obesity; Peptide Hormones; Peptide YY; Postprandial Period; Triglycerides; Whey Proteins

The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI × 10⁴ min⁻¹·pM⁻¹: 1.11 ± 0.44 vs. 0.62 ± 0.22, P < 0.015, in controls and 0.79 ± 0.34 vs. 0.40 ± 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 ± 1.36 vs. 1.13 ± 0.78 × 10⁶, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 ± 1.05 vs. 1.09 ± 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes.

Topics: Adult; Bariatric Surgery; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Duodenum; Enteral Nutrition; Female; Food; Glucose Intolerance; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Intubation, Gastrointestinal; Jejunum; Male; Middle Aged; Obesity

Resveratrol, a natural polyphenolic compound produced by various plants (e.g. red grapes) and found in red wine, has glucose-lowering effects in humans and rodent models of obesity and/or diabetes. The mechanisms behind these effects have been suggested to include resveratrol-induced secretion of the gut incretin hormone glucagon-like peptide-1. We investigated postprandial incretin hormone and glucagon responses in obese human subjects before and after 30 days of resveratrol supplementation.. Postprandial plasma responses of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide and glucagon were evaluated in 10 obese men [subjects characteristics (mean ± standard error of the mean): age 52 ± 2 years; BMI 32 ± 1 kg/m(2), fasting plasma glucose 5.5 ± 0.1 mmol/l] who had been given a dietary supplement of resveratrol (Resvida(®) 150 mg/day) or placebo for 30 days in a randomized, double-blind, crossover design with a 4-week washout period. At the end of each intervention period a standardized meal test (without co-administration of resveratrol) was performed.. Resveratrol supplementation had no impact on fasting plasma concentrations or postprandial plasma responses (area under curve values) of glucose-dependent insulinotropic polypeptide (11.2 ± 2.1 vs. 11.8 ± 2.2 pmol/l, P = 0.87; 17.0 ± 2.2 vs. 14.8 ± 1.6 min × nmol/l, P = 0.20) or glucagon-like peptide-1 (15.4 ± 1.0 vs. 15.2 ± 0.9 pmol/l, P = 0.84; 5.6 ± 0.4 vs. 5.7 ± 0.3 min × nmol/l, P = 0.73). Resveratrol supplementation significantly suppressed postprandial glucagon responses (4.4 ± 0.4 vs. 3.9 ± 0.4 min × nmol/l, P = 0.01) without affecting fasting glucagon levels (15.2 ± 2.2 vs. 14.5 ± 1.5 pmol/l, P = 0.56).. Our data suggest that 30 days of resveratrol supplementation does not affect fasting or postprandial incretin hormone plasma levels in obese humans, but suppresses postprandial glucagon responses.

Topics: Antioxidants; Blood Glucose; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Fasting; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Male; Middle Aged; Obesity; Postprandial Period; Resveratrol; Stilbenes; Time Factors; Treatment Outcome

Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

Topics: Adult; Animals; Comorbidity; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Glucose; Hemodynamics; Humans; Incretins; Male; Middle Aged; Myocardium; Obesity; Oxygen Consumption; p38 Mitogen-Activated Protein Kinases; Physical Conditioning, Animal; Regional Blood Flow; Rest; Signal Transduction; Swine; Treatment Outcome

The endoluminal mechanical device SatiSphere is a new endoscopically implantable device designed to delay transit time of nutrients through the duodenum. It consists of a 1-mm nitinol wire with pigtail ends and several mesh spheres mounted along its course, released in the duodenum and gastric antrum to conform to the duodenal C loop configuration and thereby self-anchor.. The objective is to test the safety, efficacy, and effect on body weight in a 2:1 randomized study, as well as incretin secretion in a subgroup.. Of 31 included cases (11 men, mean age 42.9 years, mean BMI 41.3 kg/m2), 21 patients treated with endoscopic device insertion with scheduled device removal after 3 months were compared with 10 controls. In 10 of 21 patients, device migration occurred, in two cases necessitating emergency surgery, which led to termination of the trial. Weight loss after 3 months was 6.7, 4.6, and 2.2 kg in the groups completing therapy, all treatment cases using intention to treat (ITT) analysis and controls. Excess weight loss was significantly increased by endoluminal mechanical device insertion (18.4, 12.2, and 4.4% in completers, ITT analysis group and controls; p = 0.02 for completers vs. controls). Measuring glucose, insulin, and glucagon-like peptide 1 (GLP-1) following a mixed-meal test with the device in place and after removal (n = 7), the device delayed glucose absorption and insulin secretion and altered kinetics in GLP-1 levels.. The device might be short-term effective in reducing body weight, which might be mediated through alterations in incretin metabolism. However, frequent device migration necessitates device modifications.

Topics: Adult; Blood Glucose; Device Removal; Duodenum; Eating; Endoscopy, Gastrointestinal; Equipment Design; Feasibility Studies; Female; Foreign-Body Migration; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Intestinal Absorption; Male; Middle Aged; Obesity; Postoperative Complications; Treatment Outcome; Weight Loss

To compare the effects of miglitol [an alpha-glucosidase inhibitor (AGI) absorbed in the intestine] and voglibose (an AGI not absorbed) on plasma glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels, 26 and 24 Japanese type 2 diabetic patients were randomly assigned to receive miglitol or voglibose, respectively. After 12-week administration of both drugs, during 2-h meal tolerance test, plasma glucose, serum insulin and total GIP were significantly decreased and active GLP-1 was significantly increased. Miglitol group showed a significantly lower total GIP level than voglibose group. Miglitol, but not voglibose, significantly reduced body weight (BW). In all participants, the relative change in BW was positively correlated with that of insulin significantly and of GIP with a weak tendency, but not of GLP-1. In conclusion, both drugs can enhance postprandial GLP-1 responses and reduce GIP responses. The significant BW reduction by miglitol might be attributable to its strong GIP-reducing efficacy.

Topics: 1-Deoxynojirimycin; Asian People; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Inositol; Male; Middle Aged; Obesity; Postprandial Period

Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500-600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women.. Seventeen overweight women (BMI > 28) were recruited to the study. Glucose, insulin and lipid metabolism were evaluated by euglycemic clamp technique, indirect calorimetry and an oral glucose tolerance test (OGTT). Insulin sensitivity was calculated as glucose disposal rate (GDR) and insulin sensitivity index (ISI), and also by HOMA-IR. Insulin secretion rate (ISR) was calculated from plasma C-peptide measurements. Secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) was measured during an oral glucose tolerance test. Abdominal fat distribution was assessed by dual x-ray absorptiometry scan and computed tomography.. Ten women completed the intervention. The subjects lost an average 11% of their baseline weight. There was a significant loss of subcutaneous abdominal fatty tissue (p < 0.01) and intra-abdominal fatty tissue (p =0.05). Whole body (HOMA-IR) (p < 0.05) insulin sensitivity increased significantly, but peripheral (ISI) insulin sensitivity was unaltered after weight loss. GIP increased (p < 0.05) and GLP-1 was unaltered after the dietary intervention. Insulin responses did not differ before and after dietary intervention, however, a significant increase in insulin clearance (p < 0.05) was observed. The weight loss resulted in a significant decrease in free testosterone.. A VLCD is an effective weight loss treatment, which results in an immediate improvement in several metabolic parameters.

Topics: Adult; Androgens; Body Composition; Body Weight; Caloric Restriction; Dihydrotestosterone; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Intra-Abdominal Fat; Lipid Mobilization; Obesity; Testosterone; Treatment Outcome; Young Adult

To study the effects of three weight-maintenance diets with different macronutrient composition on carbohydrate, lipid metabolism, insulin and incretin levels in insulin-resistant subjects.. A prospective study was performed in eleven (7 W, 4 M) offspring of obese and type 2 diabetes patients. Subjects had a BMI > 25 Kg/m2, waist circumference (men/women) > 102/88, HBA1c < 6.5% and were regarded as insulin-resistant after an OGTT (Matsuda ISIm <4). They were randomly divided into three groups and underwent three dietary periods each of 28 days in a crossover design: a) diet high in saturated fat (SAT), b) diet rich in monounsaturated fat (MUFA; Mediterranean diet) and c) diet rich in carbohydrate (CHO).. Body weight and resting energy expenditure did not changed during the three dietary periods. Fasting serum glucose concentrations fell during MUFA-rich and CHO-rich diets compared with high-SAT diets (5.02 +/- 0.1, 5.03 +/- 0.1, 5.50 +/- 0.2 mmol/L, respectively. Anova < 0.05). The MUFA-rich diet improved insulin sensitivity, as indicated by lower homeostasis model analysis-insulin resistance (HOMA-ir), compared with CHO-rich and high-SAT diets (2.32 +/- 0.3, 2.52 +/- 0.4, 2.72 +/- 0.4, respectively, Anova < 0.01). After a MUFA-rich and high-SAT breakfasts (443 kcal) the postprandial integrated area under curve (AUC) of glucose and insulin were lowered compared with isocaloric CHO-rich breakfast (7.8 +/- 1.3, 5.84 +/- 1.2, 11.9 +/- 2.7 mmol . 180 min/L, Anova < 0.05; and 1004 +/- 147, 1253 +/- 140, 2667 +/- 329 pmol . 180 min/L, Anova <0.01, respectively); while the integrated glucagon-like peptide-1 response increased with MUFA and SAT breakfasts compared with isocaloric CHO-rich meals (4.22 +/- 0.7, 4.34 +/- 1.1, 1.85 +/- 1.1, respectively, Anova < 0.05). Fasting and postprandial HDL cholesterol concentrations rose with MUFA-rich diets, and the AUCs of triacylglycerol fell with the CHO-rich diet. Similarly fasting proinsulin (PI) concentration fell, while stimulated ratio PI/I was not changed by MUFA-rich diet.. Weight maintenance with a MUFA-rich diet improves HOMA-ir and fasting proinsulin levels in insulin-resistant subjects. Ingestion of a virgin olive oil-based breakfast decreased postprandial glucose and insulin concentrations, and increased HDL-C and GLP-1 concentrations as compared with CHO-rich diet.

Topics: Analysis of Variance; Area Under Curve; Blood Glucose; Calorimetry, Indirect; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Fats, Unsaturated; Fatty Acids; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Obesity; Postprandial Period; Prospective Studies

The epicardial adipose tissue, which is referred to as fats surrounding the myocardium, is an active organ able to induce cardiovascular problems in pathophysiologic conditions through several pathways, such as inflammation, fibrosis, fat infiltration, and electrophysiologic problems. So, control of its volume and thickness, especially in patients with diabetes, is highly important. Incretin-based pharmacologic agents are newly developed antidiabetics that could provide further cardiovascular benefits through control and modulating epicardial adiposity. They can reduce cardiovascular risks by rapidly reducing epicardial adipose tissues, improving cardiac efficiency. We are at the first steps of a long way, but current evidence demonstrates the sum of possible mechanisms. In this study, we evaluate epicardial adiposity in physiologic and pathologic states and the impact of incretin-based drugs.

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

Amino acids powerfully release glucagon but their contribution to postprandial hyperglucagonemia in type 2 diabetes remains unclear. Exogenously applied GIP stimulates, while GLP-1 inhibits, glucagon secretion in humans. However, their role in mixed meals is unclear, which we therefore characterized.. In three experiments, participants with type 2 diabetes and obese controls randomly received different loads of sugars and/or proteins. In the first experiment, participants ingested the rapidly cleaved saccharose (SAC) or slowly cleaved isomaltulose (ISO) which is known to elicit opposite profiles of GIP and GLP-1 secretion. In the second one participants received test meals which contained saccharose or isomaltulose in combination with milk protein. The third set of participants underwent randomized oral protein tests with whey protein or casein. Incretins, glucagon, C-peptide, and insulin were profiled by specific immunological assays.. 50 g of the sugars alone suppressed glucagon in controls but slightly less in type 2 diabetes patients. Participants with type 2 diabetes showed excessive glucagon responses within 15 min and lasting over 3 h, while the obese controls showed small initial and delayed greater glucagon responses to mixed meals. The release of GIP was significantly faster and greater with SAC compared to ISO, while GLP-1 showed an inverse pattern. The glucagon responses to whey or casein were only moderately increased in type 2 diabetes patients without a left shift of the dose response curve.. The rapid hypersecretion of glucagon after mixed meals in type 2 diabetes patients compared to controls is unaffected by endogenous incretins. The defective suppression of glucagon by glucose combined with hypersecretion to protein is required for the exaggerated response.. NCT03806920, NCT02219295, NCT04564391.

Topics: Blood Glucose; Caseins; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Meals; Obesity; Sucrose; Sugars

Obesity is a major cause of infertility in females with a direct correlation between energy intake and reproductive dysfunction. To explore underlying mechanisms, disturbances in reproductive health and incretin/reproductive hormone receptor expression were studied in female Wistar rats fed a high-fat-diet for 20-weeks. Metabolic parameters and ovarian/adrenal gene expression were monitored along with estrous cycling and fertility upon mating. High-fat-feeding significantly increased body weight, plasma insulin and HOMA-IR, indicative of obesity and insulin resistance. Estrous cycles were prolonged compared to normal chow-fed rats, with 50 % having an average cycle length ≥ 7days. Reproductive outcomes revealed high-fat-diet reduced litter size by 48 %, with 16 % rats unable to achieve pregnancy. Furthermore, 80 % of the high-fat group took > 35 days to become pregnant compared to 33 % fed a normal-diet. Also, 35 % of pups born to high-fat-fed rats were eaten by mothers or born dead which was not observed with control rats. These changes were associated with downregulation of Amh, Npy2R and GcgR gene expression in ovaries with upregulation of InsR and Glp-1R genes. In adrenals, Glp-1R, GipR, Npy2R, InsR, GcgR, GshR and Esr-1 genes were upregulated. Histological analysis of high-fat-diet ovaries and adrenals revealed changes in morphology with significantly increased number of cysts and reduced adrenal capsule thickness. Circulating levels of insulin, testosterone and progesterone was significantly higher in high-fat group with reduced FSH levels in plasma. These data demonstrate that high-fat feeding disrupts female reproductive function and suggest important interactions between gut and reproductive hormones in ovaries and adrenals which merit further investigation.

Topics: Animals; Diet, High-Fat; Female; Fertility; Gene Expression; Incretins; Insulin; Obesity; Ovary; Pregnancy; Rats; Rats, Wistar

Topics: Humans; Incretins; Obesity

Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.

Topics: Adult; Diabetes Mellitus, Type 2; Humans; Incretins; Obesity; Sleep Apnea, Obstructive; Weight Loss

Duodenal ablation improves glycaemic control and weight loss, so it has been applied using hydrothermal catheters in obese and type 2 diabetes patients, indicating similar mechanisms and therapeutic effects as bariatric surgeries. Endoscopic photodynamic therapy is an innovative procedure that easily accessible to endocrine or gastrointestinal organs, so it is critical for the sprayed photosensitizer (PS) to long-term interact with target tissues for enhancing its effects. Surfactant-like PS was more stable in a wide range of pH and 2.8-fold more retained in the duodenum at 1 h than hydrophilic PS due to its amphiphilic property. Endoscopic duodenal ablation using surfactant-like PS was performed in high fat diet induced rat models, demonstrating body weight loss, enhanced insulin sensitivity, and modulation of incretin hormones. Locoregional ablation of duodenum could affect the profiles of overall intestinal cells secreting meal-stimulated hormones and further the systemic glucose and lipid metabolism, regarding gut-brain axis. Our strategy suggests a potential for a treatment of minimally invasive bariatric and metabolic therapy if accompanied by detailed clinical trials.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Duodenum; Humans; Incretins; Obesity; Photosensitizing Agents; Rats; Surface-Active Agents

Incretin receptor agonists are now standard of care in treating obesity. Their efficacy and tolerability might be further improved by combining them with compounds that offer orthogonal mechanisms of action. The cannabinoid type 1 receptor (CB1R) is a clinically validated therapeutic target in obesity, and several experimental CB1R inverse agonists have been shown to induce weight loss.. This study characterizes a novel CB1R inverse agonist (CRB-913) with similar preclinical potency to rimonabant but markedly reduced brain penetration. CRB-913 was tested as monotherapy and in combination with tirzepatide, semaglutide, or liraglutide in the diet-induced obesity (DIO) mouse model for body weight reduction.. CRB-913 in combination with incretin analogues could deliver meaningful improvements over current standards of care for obesity and related conditions.

Topics: Animals; Body Weight; Diet; Drug Inverse Agonism; Incretins; Liraglutide; Mice; Obesity; Receptors, Cannabinoid; Rimonabant; Weight Loss

In youths with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on β cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high-incretin effect group demonstrated a longitudinal increase in β cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of β cell function and weight in youths with obesity.

Topics: Adolescent; Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Obesity

Dual activation of the glucagon-like peptide 1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor has potential as a novel strategy for treatment of diabesity. Here, we created a hybrid peptide which we named 19W, and show that it is more stable in presence of murine plasma than exendin-4 is. In vitro studies were performed to reveal that 19W could stimulate insulin secretion from INS-1 cells in a dose-dependent manner, just like the native peptide GIP and exendin-4 do. 19W effectively evoked dose-dependent cAMP production in cells targeting both GLP-1R and GIPR. In healthy C57BL/6J mice, the single administration of 19W significantly improved glucose tolerance. When administered in combination with sodium deoxycholate (SDC), its oral hypoglycemic activity was enhanced. Pharmacokinetics studies in Wistar rats revealed that 19W was absorbed following oral uptake, while SDC increased its bioavailability. A long-term (28 days) exposure study of twice-daily oral administration to high fat-fed (HFF) mice showed that 19W significantly reduced animal food intake, body weight, fasting blood glucose, total serum cholesterol (T-CHO), non-esterified free fatty acids (NEFA), and low-density lipoprotein cholesterol (LDL-C) levels. It also significantly improved glucose tolerance and the pancreatic β/α cell ratio, and decreased the area of liver fibrosis. These results clearly demonstrate the beneficial action of this novel oral GLP-1/GIP dual receptor agonist to reduce adiposity and hyperglycemia in diabetic mice and to ameliorate liver fibrosis associated with obesity. This dual-acting peptide can be considered a good candidate for novel oral therapy to treat obesity and diabetes.

Topics: Animals; Cyclic AMP; Diabetes Mellitus, Experimental; Eating; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Metabolic Diseases; Mice; Obesity; Rats; Receptors, Gastrointestinal Hormone

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

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are increasingly used in treating type 2 diabetes and obesity. Exendin-4 (Ex-4), a long acting GLP-1ra, was previously reported to decrease oxidative stress in hepatocytes, adipocytes and skeletal muscle cells in obese nondiabetic fa/fa Zucker rats (ZFR), thereby improving insulin resistance.. We aimed first to identify Ex-4-induced changes in the transcriptome of skeletal muscle cells in ZFR.. Ontology analysis of differentially expressed genes (DEGs) in ZFR versus lean animals (LR) showed that the extracellular matrix (ECM) is the first most affected cellular compartment, followed by myofibrils and endoplasmic reticulum (ER). Interestingly, among 15 genes regulated in ZFR versus LR, 14 of them were inversely regulated by Ex-4, as further confirmed by RT-qPCR. Picro-Sirius red histological staining showed that decreased ECM fiber area in ZFR is partially restored by Ex-4. Ontology analysis of the myofibril compartment revealed that decreased muscle contractile function in ZFR is partially restored by Ex-4, as confirmed by Phalloidin histological staining that showed a partial restoration by Ex-4 of altered contractile apparatus in ZFR. Ontology analysis of ER DEGs in ZFR versus LR showed that some of them are related to the AMP-activated protein kinase (AMPK) signaling pathway. Phosphorylated AMPK levels were strongly increased in Ex-4-treated ZFR.. Altogether, our results suggest that GLP-1ra strongly restructure ECM and reinforce contractile capabilities in ZFR, while optimizing the cellular metabolism through AMPK.

Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Exenatide; Incretins; Insulin; Muscle, Skeletal; Obesity; Rats; Rats, Zucker; Transcriptome

Topics: Appetite; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity; Overweight; Receptors, Gastrointestinal Hormone

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Incretins; Obesity; Renal Insufficiency, Chronic

Considering the rapidly increasing prevalence of obesity worldwide, the number of weight control drugs is very few. Incretin-based therapies are currently being developed to achieve weight control, and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) are used in incretin-based therapies. This study aimed to investigate the cytotoxicity of exenatide, a GLP-1A, on 3T3-L1 adipocytes and the effect of exenatide on the expression of adipogenesis-related genes, insulin and glucose levels, and apoptosis. Cytotoxic activity of exenatide on 3T3-L1 adipocytes was determined by MTT method. Gene expression levels were determined by qPCR. Apoptosis studies were performed on the Muse Cell Analyzer. C1q/TNF-related protein-3 (CTRP3) expression levels were found to be higher in exenatide treated adipocyte cells than in control cells (p < 0.001). Adipocyte cells treated with exenatide were found to have lower PPAR-γ gene expression levels when compared to control adipocyte cells (p < 0.001). Intracellular insulin (p < 0.001) and glucose levels were higher in 3T3-L1 adipocytes treated with exenatide compared to control adipocyte cells. Total apoptosis increased approximately 1.5 times as a result of exenatide administration. The increase in CTRP3 gene expression, which is thought to be a new biomarker for obesity, and the decrease in PPAR-γ gene expression indicate that exenatide is a promising new pharmacotherapeutic agent in the treatment of obesity by regulating the expression of genes related to adipogenesis and lipogenesis and inducing apoptosis.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Alprostadil; Animals; Apoptosis; Cell Differentiation; Complement C1q; Exenatide; Gene Expression; Glucagon-Like Peptide-1 Receptor; Glucose; Incretins; Insulin; Mice; Obesity; PPAR gamma

Topics: Animals; Blood Glucose; Diet; Incretins; Mice; Mice, Obese; Niacin; Obesity; Palmitates; PPAR gamma; Sitagliptin Phosphate; Up-Regulation

Recent studies show that incretin hormone analogues effectively control blood glucose while producing major weight losses and reducing the risk of all-cause mortality, myocardial infarction, stroke and kidney function impairment. Furthermore, the risk of dementia and cognitive impairment is reduced. A monomolecular coagonist (tirzepatide) of receptors for both incretin hormones (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) produced HbA1c values below 5.7% in 50% of the treated patients and weight losses exceeding 20% in obese individuals. These new agents will radically change our approach to the treatment of T2DM and obesity alike.

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

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

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are innovative drugs that effectively reduce glycemic levels and overweight in patients with type 2 diabetes mellitus (T2DM). However, the criteria for predicting the hypoglycemic effect of this group of drugs have not been practically defined.. To assess the factors contributing to the achievement the glycemia normalization in patients with diabetes mellitus and obesity by adding to antihyperglycemic therapy (AT) a drug from the GLP-1 RA group liraglutide 3.0 mg per day.. A single-center, prospective, non-randomized study was provided. The objects of the study were patients with T2DM and obesity (n=22). Liraglutide 3.0 mg per day was added to the current AT of patients. Initially, the parameters of carbohydrate metabolism, hormones of the incretin system on an empty stomach and during the mixed-meal test, insulin resistance using the euglycemic hyperinsulinemic clamp test, and body composition were studied. After 9 months of therapy, all studies were repeated and a search for possible predictors of the carbohydrate metabolism normalization was made.. The body mass index of patients decreased from 42.4 [37.7; 45.0] to 35.9 [33.0; 40.9] kg/m2. Fasting blood glucose and glycated hemoglobin levels decreased from 9.02 [7.40; 11.37] mmol/L and 7.85 [7.43; 8.65]% up to 5.90 [5.12; 6.18] mmol/L and 6.40 [5.90; 6.60]%, respectively. 14 (63.6%) patients reached normoglycemia. Insulin resistance according to the clamp test did not change over the study. Basal concentrations of oxyntomodulin, glycentin and the area under the GLP-1, oxyntomodulin, glycentin curve significantly decreased 9 months after liraglutide administration. The prognostic marker of the achievement of normoglycemia during therapy with liraglutide 3.0 mg/day is the level of endogenous GLP-15.5 pmol/L before the appointment of arGPP-1 therapy.. The concentration of endogenous GLP-1 before the appointment of liraglutide therapy at a dose of 3.0 mg per day can be used for prediction the drug hypoglycemic effect and achieving normoglycemia possibility.. Актуальность. Агонисты рецепторов глюкагоноподобного пептида-1 (арГПП-1) являются инновационными препаратами, эффективно снижающими уровень гликемии и избыточный вес у пациентов с сахарным диабетом 2-го типа (СД 2). Однако практически не определены критерии, позволяющие прогнозировать сахароснижающий эффект этой группы препаратов. Цель. Оценить факторы, способствующие достижению нормализации гликемии у пациентов с СД 2 и ожирением при добавлении к сахароснижающей терапии (СТ) препарата из группы арГПП-1 лираглутида 3,0 мг/сут. Материалы и методы. Проведено одноцентровое проспективное нерандомизированное исследование. Объектами исследования выступили пациенты с СД 2 и ожирением (n=22). К текущей СТ пациентов был добавлен лираглутид 3,0 мг/сут. Исходно исследованы показатели углеводного обмена, гормонов инкретиновой системы натощак и в течение теста со смешанной пищей, инсулинорезистентности с помощью эугликемического гиперинсулинемического клэмп-теста, композитного состава тела. Через 9 мес терапии повторены все исследования и проведен поиск возможных предикторов нормализации углеводного обмена. Результаты. Индекс массы тела пациентов снизился с 42,4 [37,7; 45,0] до 35,9 [33,0; 40,9] кг/м2. Уровни глюкозы крови натощак и гликированного гемоглобина снизились с 9,02 [7,40; 11,37] ммоль/л и 7,85 [7,43; 8,65]% до 5,90 [5,12; 6,18] ммоль/л и 6,40 [5,90; 6,60]% соответственно. Нормогликемии достигли 14 (63,6%) пациентов. Инсулинорезистентность, согласно клэмп-тесту, не изменилась на протяжении 9 мес исследования. Базальные концентрации оксинтомодулина, глицентина и площади под кривой ГПП-1, оксинтомодулина, глицентина значимо снизились через 9 мес после назначения лираглутида. Прогностическим маркером достижения нормогликемии при терапии лираглутидом 3,0 мг/сут является уровень эндогенного ГПП-15,5 пмоль/л до назначения терапии арГПП-1. Заключение. Концентрация эндогенного ГПП-1 до назначения терапии лираглутидом в дозе 3,0 мг/сут может быть использована для прогнозирования сахароснижающего эффекта препарата и возможности достижения нормогликемии.

Topics: Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Obesity; Oxyntomodulin; Prognosis; Prospective Studies

Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (GLP-1/GIP co-agonist) have been shown to outperform each single peptide in the treatment of obesity and cardiometabolic disease in preclinical and clinical trials. By combining physiological treatment endpoints with plasma proteomic profiling (PPP), we aimed to identify biomarkers to advance non-invasive metabolic monitoring of compound treatment success and exploration of ulterior treatment effects on an individual basis.. We performed metabolic phenotyping along with PPP in body weight-matched male and female diet-induced obese (DIO) mice treated for 21 days with phosphate-buffered saline, single GIP and GLP-1 mono-agonists, or a GLP-1/GIP co-agonist.. GLP-1R/GIPR co-agonism improved obesity, glucose intolerance, non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia with superior efficacy in both male and female mice compared with mono-agonist treatments. PPP revealed broader changes of plasma proteins after GLP-1/GIP co-agonist compared with mono-agonist treatments in both sexes, including established and potential novel biomarkers for systemic inflammation, NAFLD and atherosclerosis. Subtle sex-specific differences have been observed in metabolic phenotyping and PPP.. We herein show that a recently developed unimolecular GLP-1/GIP co-agonist is more efficient in improving metabolic disease than either mono-agonist in both sexes. PPP led to the identification of a sex-independent protein panel with the potential to monitor non-invasively the treatment efficacies on metabolic function of this clinically advancing GLP-1/GIP co-agonist.

Topics: Animals; Diet; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Incretins; Male; Mice; Mice, Obese; Obesity; Proteome; Proteomics; Treatment Outcome

Periodontitis confers an increased risk of developing type 2 diabetes and, in patients with obesity, it might interfere with the incretin axis. The effect of periodontal treatment on glucoregulatory hormones remains unknown.. To evaluate the effect of periodontal treatment on incretin axis in obese and lean nondiabetic individuals.. King's College Dental Hospital and Institute, London, UK.. The metabolic profile of obese and normal-body-mass-index individuals affected by periodontitis was studied at baseline, 2, and 6 months after intensive periodontal treatment, by measuring plasma insulin, glucagon, glucagon-like peptide-1(GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) and markers of systemic inflammation and oxidative stress.. Circulating levels of incretins and inflammatory markers.. At baseline, periodontal parameters were worse for obese than nonobese; this was accompanied by higher levels of circulating high-sensitivity C-reactive protein (hs-CRP), insulin, and GLP-1. The response to periodontal treatment was less favorable in the obese group, without significant variations of hs-CRP or malondialdehyde. Glucoregulatory hormones changed differently after treatment: while insulin and glucagon did not vary at 2 and 6 months, GLP-1 and GIP significantly increased at 6 months in both groups. In particular, GLP-1 increased more rapidly in obese participants, while the increase of GIP followed similar trends across visits in both groups.. Nonsurgical treatment of periodontitis is associated with increased GLP-1 and GIP levels in nonobese and obese patients; changes in GLP-1 were more rapid in obese participants. This might have positive implications for the metabolic risk of these individuals.

Topics: Adult; Case-Control Studies; Cohort Studies; Female; Follow-Up Studies; Humans; Incretins; Male; Middle Aged; Obesity; Periodontitis; Thinness; United Kingdom

Topics: Anti-Obesity Agents; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Incretins; Obesity; Treatment Outcome; Weight Loss

Extended-release naltrexone/bupropion (NB) is indicated for chronic weight management. Incretin agents are recommended for patients with type 2 diabetes. This analysis looked at the add-on of NB to incretins to see if weight loss could occur in patients already stabilized on incretin agents.. This was a post-hoc analysis of NB vs. placebo (PL) among subjects with type 2 diabetes stable on an incretin agent prior to randomization in a double-blind, PL-controlled cardiovascular outcome trial (N = 1317).. Over 1 year, mean weight loss was significantly greater among NB patients vs. PL among those taking DPP-4i (mean absolute difference 4.6% [p < 0.0001]) and those taking GLP-1RAs (mean absolute difference 5.2%, p < 0.0001). Proportions of subjects achieving 5% weight loss were significantly greater for NB vs. PL at weeks 26 and 52 among those taking DPP-4is or GLP-1RAs. There were no significant differences in effectiveness observed between NB + DPP-4i and NB + GLP-1RA or between PL + DPP-4i and PL + GLP-1RA in any of the analyses. Serious adverse events were reported by 9.1% and 11.1% for PL + DPP-4i and PL + GLP-1RA, respectively, and 13.3% and 12.4% of NB + DPP-4i and NB + GLP-1RA, respectively.. NB appears to be effective in reducing weight in patients with T2DM and obesity/overweight who are taking DPP-4ihibitors or GLP-1RA. The SAE rates in all arms of this analysis were lower than have been reported in other cardiovascular outcome trials in type 2 diabetes.

Topics: Aged; Anti-Obesity Agents; Body Weight; Bupropion; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Naltrexone; Obesity; Randomized Controlled Trials as Topic; Weight Loss

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

In adults, the time-to-glucose-peak at or after 30 minutes during an oral glucose tolerance test (OGTT) identifies physiologically distinct groups with differences in insulin sensitivity, β-cell function and risk for type 2 diabetes. In obese non-diabetic adolescents, we investigated if the OGTT-time-to-glucose-peak also reflects incretin and free fatty acid (FFA) responses besides insulin sensitivity and β-cell function, measured by the clamp.. Obese adolescents (n = 278) were categorized according to their OGTT-time-to-glucose-peak by Early-peak (at 30 minutes) vs Late-peak (>30 minutes) groups. Body composition, visceral adipose tissue, oral disposition index and OGTT-area under the curve (AUC) were examined. A subset of 102 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and β-cell function relative to insulin sensitivity.. Compared with the Early-peak group, the Late-peak group had impaired β-cell function relative to insulin sensitivity, lower glucose-dependent insulinotropic polypeptide-AUC, and higher FFA-AUC despite higher insulin- and C-peptide-AUC. They also had lower hepatic and peripheral insulin sensitivity despite similar percent body fat and visceral adipose tissue, and had higher prevalence of impaired glucose tolerance (all P < .05).. In obese non-diabetic youth, those with a Late-peak vs an Early-peak glucose during an OGTT showed diminished β-cell function, blunted incretin secretion, and lower insulin sensitivity of glucose and FFA metabolism. It remains to be determined if Late-peak glucose predicts the future development of type 2 diabetes in these high-risk youth.

Topics: Adolescent; Biomarkers; Body Mass Index; Child; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Incretins; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Obesity; Risk Factors; Time Factors

Glucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and adiposity in the context of nutrient excess. Interrupting GIPR signaling also enhances the sensitivity of the receptor for the other incretin peptide, glucagon-like peptide 1 (GLP-1). The role of GLP-1 compensation in loss of GIPR signaling to protect against obesity has not been directly tested.. We blocked the GIPR and GLP-1R with specific antibodies, alone and in combination, in healthy and diet-induced obese (DIO) mice. The primary outcome measure of these interventions was the effect on body weight and composition.. Antagonism of either the GIPR or GLP-1R system reduced food intake and weight gain during high-fat feeding and enhanced sensitivity to the alternative incretin signaling system. Combined antagonism of both GIPR and GLP-1R produced additive effects to mitigate DIO. Acute pharmacological studies using GIPR and GLP-1R agonists demonstrated both peptides reduced food intake, which was prevented by co-administration of the respective antagonists.. Disruption of either axis of the incretin system protects against diet-induced obesity in mice. However, combined antagonism of both GIPR and GLP-1R produced additional protection against diet-induced obesity, suggesting additional factors beyond compensation by the complementary incretin axis. While antagonizing the GLP-1 system decreases weight gain, GLP-1R agonists are used clinically to target obesity. Hence, the phenotype arising from loss of function of GLP-1R does not implicate GLP-1 as an obesogenic hormone. By extension, caution is warranted in labeling GIP as an obesogenic hormone based on loss-of-function studies.

Topics: Animals; Anti-Obesity Agents; Diet, High-Fat; Incretins; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Weight Gain

Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl).. Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50-350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting.. We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1β, TGF-β1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably.. In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.

Topics: Animals; Coronary Artery Disease; Coronary Circulation; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hypertension; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Male; Microcirculation; Nitric Oxide; Obesity; Oxidative Stress; Rats, Zucker; Sodium Chloride, Dietary; Ventricular Remodeling

Pancreatic islets are heterogenous. To clarify the relationship between islet heterogeneity and incretin action in the islets, we studied gene expression and metabolic profiles of non-large and enlarged islets of the Zucker fatty diabetes mellitus rat, an obese diabetes model, as well as incretin-induced insulin secretion (IIIS) in these islets.. Pancreatic islets of control (fa/+) and fatty (fa/fa) rats at 8 and 12 weeks-of-age were isolated. The islets of fa/fa rats at 12 weeks-of-age were separated into non-large islets (≤200 μm in diameter) and enlarged islets (>300 μm in diameter). Morphological analyses, insulin secretion experiments, transcriptome analysis, metabolome analysis and oxygen consumption analysis were carried out on these islets.. The number of enlarged islets was increased with age in fatty rats, and IIIS was significantly reduced in the enlarged islets. Markers for β-cell differentiation were markedly decreased in the enlarged islets, but those for cell proliferation were increased. Glycolysis was enhanced in the enlarged islets, whereas the tricarboxylic acid cycle was suppressed. The oxygen consumption rate under glucose stimulation was reduced in the enlarged islets. Production of glutamate, a key signal for IIIS, was decreased in the enlarged islets.. The enlarged islets of Zucker fatty diabetes mellitus rats, which are defective for IIIS, show tumor cell-like metabolic features, including a dedifferentiated state, accelerated aerobic glycolysis and impaired mitochondrial function. The age-dependent increase in such islets could contribute to the pathophysiology of obese diabetes.

Topics: Animals; Gene Expression Profiling; Gene Expression Regulation; Incretins; Insulin Secretion; Islets of Langerhans; Male; Metabolome; Obesity; Pancreatic Neoplasms; Rats; Rats, Zucker

Methylglyoxal was shown to impair adipose tissue capillarization and insulin sensitivity in obese models. We hypothesized that glyoxalase-1 (GLO-1) activity could be diminished in the adipose tissue of type 2 diabetic obese patients. Moreover, we assessed whether such activity could be increased by GLP-1-based therapies in order to improve adipose tissue capillarization and insulin sensitivity. GLO-1 activity was assessed in visceral adipose tissue of a cohort of obese patients. The role of GLP-1 in modulating GLO-1 was assessed in type 2 diabetic GK rats submitted to sleeve gastrectomy or Liraglutide treatment, in the adipose tissue angiogenesis assay and in the HUVEC cell line. Glyoxalase-1 activity was decreased in visceral adipose tissue of pre-diabetic and diabetic obese patients, together with other markers of adipose tissue dysfunction and correlated with increased HbA1c levels. Decreased adipose tissue GLO-1 levels in GK rats were increased by sleeve gastrectomy and Liraglutide, being associated with overexpression of angiogenic and vasoactive factors, as well as insulin receptor phosphorylation (Tyr1161). Moreover, GLP-1 increased adipose tissue capillarization and HUVEC proliferation in a glyoxalase-dependent manner. Lower adipose tissue GLO-1 activity was observed in dysmetabolic patients, being a target for GLP-1 in improving adipose tissue capillarization and insulin sensitivity.

Topics: Adipose Tissue; Adult; Aged; Animals; Capillaries; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Gastrectomy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Human Umbilical Vein Endothelial Cells; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lactoylglutathione Lyase; Liraglutide; Male; Middle Aged; Neovascularization, Physiologic; Obesity; Rats, Wistar; Signal Transduction

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (

Topics: Adipocytes; Adipokines; Adult; Animals; Bariatric Surgery; Bile Acids and Salts; Cells, Cultured; Disease Models, Animal; Down-Regulation; Female; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Incretins; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Obesity; Tumor Necrosis Factors; Weight Loss

To study the relationship between the amount of surgery-induced gastric volume reduction and long-term weight loss and glucose tolerance.. Vertical sleeve gastrectomy (VSG) has recently surpassed gastric bypass to become the most popular surgical intervention to induce sustained weight loss. Besides inducing significant weight loss, VSG also improves glucose tolerance. Although no clear correlation has been observed between the size of the residual stomach and sustained weight loss, this begs the question whether less aggressive gastric volume reduction may provide sufficient efficacy when weight loss is not the major goal of the surgical intervention.. A series of strategies to reduce gastric volume were developed and tested in Long Evans male rats, namely: VSG, Fundal (F)-Resection, Gastric Sleeve Plication (GSP), Fundal-Plication, and Fundal-Constrained.. All surgical interventions resulted in a reduction of gastric volume relative to sham, but none of the interventions were as effective as the VSG. Gastric volume was linearly correlated to increased gastric emptying rate as well as increased GLP-1 response. Overall, cumulative food intake was the strongest correlate to weight loss and was logarithmically related to gastric volume. Regression modeling revealed a nonlinear inverse relation between body weight reduction and gastric volume, confirming that VSG is the only effective long-term weight loss strategy among the experimental operations tested.. The data suggest a minimum threshold volume of the residual stomach that is necessary to induce sustained weight loss. Although all gastric volume interventions increased the GLP-1 response, none of the interventions, except VSG, significantly improved glucose tolerance. In conclusion, if weight loss is the primary goal of surgical intervention, significant volume reduction is required, and this most likely requires excising gastric tissue.

Topics: Animals; Bariatric Surgery; Blood Glucose; Disease Models, Animal; Gastric Emptying; Glucagon-Like Peptide 1; Glucose Tolerance Test; Incretins; Male; Obesity; Organ Size; Rats; Rats, Long-Evans; Stomach; Weight Loss

Topics: Bariatric Surgery; Binge-Eating Disorder; Craniopharyngioma; Humans; Hypothalamic Diseases; Incretins; Liraglutide; Male; Neurosurgical Procedures; Obesity; Pituitary Neoplasms; Postoperative Complications; Satiety Response; Treatment Failure; Weight Gain; Young Adult

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Topics: Adiposity; Animals; Hypothalamus; Incretins; Leptin; Mice; Obesity; rap1 GTP-Binding Proteins; Receptors, Gastrointestinal Hormone; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein

Developing effective treatments for obesity and related metabolic disease remains a challenge. One logical strategy targets the appetite-regulating actions of gut hormones such as incretins. One of these incretins, glucose-dependent insulinotropic polypeptide (GIP), has garnered much attention as a potential target: however, whether it is beneficial to boost or block the action of GIP to promote weight loss remains an unresolved question. In this issue of the JCI, Kaneko and colleagues show that antagonizing GIP signaling in the CNS enhances the weight-reducing effects of leptin in rodents with diet-induced obesity. The authors posit that an increase in circulating intestinally derived GIP, as a consequence of overnutrition, acts in the brain to impair hypothalamic leptin action, resulting in increased food intake and body weight gain. This research advances the idea that multiple GIP signaling pathways and mechanisms exist in the obese state and offers intriguing new insights into the antiobesogenic consequences of antagonizing brain GIP action.

Topics: Gastric Inhibitory Polypeptide; Humans; Incretins; Leptin; Obesity; Weight Loss

Topics: Adult; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Obesity; Polycystic Ovary Syndrome; Prediabetic State

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.

Topics: Adaptor Proteins, Signal Transducing; Animals; Binding, Competitive; Cytokine Receptor gp130; Cytokines; Diabetes Mellitus, Type 2; Drug Design; Fatty Liver; Glucose Tolerance Test; Humans; Hyperglycemia; Immunoglobulin G; Incretins; Interleukin-6; Male; Mice; Muscle, Skeletal; Obesity; Pancreas; Phosphoproteins; Protein Engineering; Receptors, Interleukin-6; Recombinant Fusion Proteins; Signal Transduction; Transcription Factors; Weight Gain; YAP-Signaling Proteins

Dipeptidyl peptidase-4 (DPP-4) controls glucose homeostasis through enzymatic termination of incretin action. We report that plasma DPP-4 activity correlates with body weight and fat mass, but not glucose control, in mice. Genetic disruption of adipocyte Dpp4 expression reduced plasma DPP-4 activity in older mice but did not perturb incretin levels or glucose homeostasis. Knockdown of hepatocyte Dpp4 completely abrogated the obesity-associated increase in plasma DPP-4 activity, reduced liver cytokine expression, and partially attenuated inflammation in adipose tissue without changes in incretin levels or glucose homeostasis. In contrast, circulating levels of soluble DPP4 (sDPP4) were dissociated from inflammation in mice with endothelial-selective or global genetic inactivation of Dpp4. Remarkably, inhibition of DPP-4 enzymatic activity upregulated circulating levels of sDPP4 originating from endothelial or hematopoietic cells without inducing systemic or localized inflammation. Collectively, these findings reveal unexpected complexity in regulation of soluble versus enzymatic DPP-4 and control of inflammation and glucose homeostasis.

Topics: 3T3-L1 Cells; Animals; Cytokines; Dipeptidyl Peptidase 4; Glucose; Hepatocytes; Incretins; Inflammation; Mice; Mice, Inbred C57BL; Obesity

The influential role of incretin hormones on glucose metabolism in patients with a history of Roux-en-Y gastric bypass (RYGB) has been investigated thoroughly, but there has been little examination of the effect of incretins and ectopic lipids on altered glucose profiles, especially severe hypoglycemia in pregnant women with RYGB.. In this prospective clinical study, an oral glucose tolerance test (OGTT), an intravenous glucose tolerance test (IVGTT), and continuous glucose monitoring (CGM) were conducted in 25 women with RYGB during pregnancy, 19 of normal weight (NW) and 19 with obesity (OB) between the 24th and the 28th weeks of pregnancy, and 3 to 6 months post-partum. Post-partum, the ectopic lipid content in the liver, heart, and skeletal muscle was analyzed using. RYGB patients presented with major fluctuations in glucose profiles, including a high occurrence of postprandial hyperglycemic spikes and hypoglycemic events during the day, as well as a high risk of hypoglycemic periods during the night (2.9 ± 1.1% vs. 0.1 ± 0.2% in the OB and vs. 0.8 ± 0.6% in the NW groups, p < 0.001). During the extended OGTT, RYGB patients presented with exaggerated expression of GLP-1, which was the main driver of the exaggerated risk of postprandial hypoglycemia in a time-lagged correlation analysis. Basal and dynamic GLP-1 levels were not related to insulin sensitivity, insulin secretion, or beta cell function and did not differ between pregnant women with and without GDM. A lower amount of liver fat (2.34 ± 5.22% vs.5.68 ± 4.42%, p = 0.015), which was positively related to insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR: rho = 0.61, p = 0.002) and beta-cell function (insulinogenic index: rho = 0.65, p = 0.001), was observed in the RYGB group after delivery in comparison to the OB group.. GLP-1 is mainly involved in the regulation of postprandial glucose metabolism and therefore especially in the development of postprandial hypoglycemia in pregnant RYGB patients, who are characterized by major alterations in glucose profiles, and thus in long-term regulation, multiple organ-related mechanisms, such as the lipid content in the liver, must be involved.

Topics: Adult; Anastomosis, Roux-en-Y; Blood Glucose; Diabetes, Gestational; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Incretins; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Lipids; Obesity; Pregnancy

Polycystic ovary syndrome (PCOS) is associated with reduced quality of life (QoL), though the role of associated obesity is unclear. In this study we examined the effects of six months treatment with liraglutide, 1.8 mg od, on obesity, depression and QoL in young women with PCOS and obesity compared to age- and weight-matched controls. In a cross-sectional study, 36 women were recruited (19 PCOS, 17 controls), age 33.9 ± 6.7 vs. 33.5 ± 7.1 yr, and weight 102.1 ± 17.1 vs. 100.4 ± 15.1 kg, respectively. PCOS was diagnosed according to the Rotterdam criteria. Depression was measured using the Centre for Epidemiologic Studies Depression Scale (CES-D). QoL was measured using the World Health Organization QoL questionnaire (WHOQOL-BREF). At baseline there was no difference in QoL or CES-D scores between the two groups. At six months, weight was reduced by 3.0 ± 4.2 kg, p = .01, in the PCOS group and 3.8 ± 3.4 kg, p = .001, in controls. Psychological health improved in the PCOS group (percentage change 11.3%, p < .02). Combining the two groups revealed significant improvement (p < .05) in physical (82.6 ± 11.2 vs. 78.9 ± 13.6), psychological (62.4 ± 16.5 vs. 57.5 ± 16.4) and social health (76.6 ± 15.3 vs. 71 ± 16.8) components of the WHOQOL-BREF at six months. Weight loss is associated with an improvement in QoL; and when matched for age and obesity, PCOS was not independently associated with reduced QoL or depression.

Topics: Adult; Body Weight; Case-Control Studies; Cross-Sectional Studies; Depression; Female; Humans; Incretins; Liraglutide; Obesity; Polycystic Ovary Syndrome; Quality of Life; Weight Loss

The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been suggested to play a role in bone metabolism. Exogenous administration of GIP inhibits bone resorption, but the effect of GLP-1 is less clear. Furthermore, the combined effect of exogenous GIP and GLP-1 on bone metabolism is unknown.. To investigate the effect of separate and combined infusions of the incretin hormones GIP and GLP-1 on bone resorption and formation.. Randomized, double-blinded, placebo-controlled, crossover study including five study days.. Seventeen overweight/obese men.. On the first study day, a 50-g oral glucose tolerance test (OGTT) was performed. On the next four study days, isoglycemic IV glucose infusions (IIGI), mimicking the glucose excursions from the OGTT, were performed with concomitant infusions of GIP (4 pmol/kg/min), GLP-1 (1 pmol/kg/min), GIP+GLP-1 (4 and 1 pmol/kg/min, respectively), or placebo, respectively.. Changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX) and in bone formation as assessed by procollagen type 1 N-terminal propeptide (P1NP) concentrations.. During the OGTT, CTX was significantly lowered by 54 ± 13% from baseline (mean ± SD) compared with 28 ± 12% during IIGI + saline (P < 0.0001). During IIGI+GLP-1 and IIGI+GIP, CTX was lowered by 65 ± 16% and 74 ± 9%, respectively, from baseline, whereas IGII+GIP+GLP-1 lowered CTX by 84 ± 4% from baseline. P1NP levels were unaffected by the interventions.. Our data suggest that GLP-1, like GIP, may be involved in regulation of bone resorption and that GIP and GLP-1 together have partially additive inhibitory effects.

Topics: Adult; Bone and Bones; Bone Resorption; Collagen Type I; Cross-Over Studies; Double-Blind Method; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Male; Middle Aged; Obesity; Osteogenesis; Overweight; Peptide Fragments; Peptides; Procollagen; Random Allocation

The benefits of IT surgery are based on incretin effects. In this study we show the influence of high fat diet (HFD) used both before and after surgery, on ileal transposition (IT) effects.. Forty-eight male rats were assigned to two groups: HFD and control diet (CD) fed rats. After eight weeks, HFD and CD fed rats were randomly assigned to two types of surgery: IT and SHAM, then for 50% of animals of each group the diet was changed, whereas the other 50% received the same type of diet. Eight weeks after surgery the incretin level, glucose tolerance as well as body mass and insulin level were assessed.. GLP-1 plasma concentration was significantly higher in the IT operated CD/CD group compared to fasting state and did not differ significantly from the SHAM operated CD/CD animals. IT influenced the glucose stimulated PYY plasma level when compared with SHAM operated animals in the CD/HFD group, where the PYY plasma level was higher than in the SHAM operated animals. The effect of IT as well as of pre and postoperative diet on GIP plasma levels were insignificant. The IT group members maintained on the CD were characterised by a lower fasting glucose level, both pre and postoperatively, compared with the SHAM operated animals. The effect of IT on the fasting glucose level in groups preoperatively maintained on an HFD was insignificant.. IT surgery itself seems to have rather limited incretin effects in rats, whose obesity is the result of HFD.

Topics: Animals; Dietary Fats; Glucose Intolerance; Ileum; Incretins; Male; Obesity; Rats; Rats, Sprague-Dawley

It is difficult to know if the cause for obesity is the type of sweetener, high fat (HF) content, or the combination of sweetener and fat. The purpose of the present work was to study different types of sweeteners; in particular, steviol glycosides (SG), glucose, fructose, sucrose, brown sugar, honey, SG + sucrose (SV), and sucralose on the functionality of the adipocyte. Male Wistar rats were fed for four months with different sweeteners or sweetener with HF added. Taste receptors T1R2 and T1R3 were differentially expressed in the tongue and intestine by sweeteners and HF. The combination of fat and sweetener showed an additive effect on circulating levels of GIP and GLP-1 except for honey, SG, and brown sugar. In adipose tissue, sucrose and sucralose stimulated TLR4, and c-Jun N-terminal (JNK). The combination of HF with sweeteners increased NFκB, with the exception of SG and honey. Honey kept the insulin signaling pathway active and the smallest adipocytes in white (WAT) and brown (BAT) adipose tissue and the highest expression of adiponectin, PPARγ, and UCP-1 in BAT. The addition of HF reduced mitochondrial branched-chain amino transferase (BCAT2) branched-chain keto acid dehydrogenase E1 (BCKDH) and increased branched chain amino acids (BCAA) levels by sucrose and sucralose. Our data suggests that the consumption of particular honey maintained functional adipocytes despite the consumption of a HF diet.

Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Adiponectin; Adipose Tissue; Animals; Diet, High-Fat; Dietary Fats; Dietary Sugars; Honey; Incretins; Inflammation; Insulin; Male; Membrane Transport Proteins; Mitochondrial Proteins; Monocarboxylic Acid Transporters; NF-kappa B; Obesity; PPAR gamma; Rats, Wistar; Solute Carrier Proteins; Stevia; Sucrose; Sweetening Agents; Taste; Taste Buds; Toll-Like Receptor 4; Transaminases; Uncoupling Protein 1

Topics: Animal Feed; Animals; Copepoda; Disease Models, Animal; Energy Metabolism; Exenatide; Fatty Acids; Female; Glucose; Incretins; Isolated Heart Preparation; Mice, Inbred C57BL; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Obesity; Oils; Recovery of Function; Ventricular Function, Left; Ventricular Pressure

To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide).. The acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. The long-term effects of ZP4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice.. ZP4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4 weeks' dosing with ZP4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP-1 agonist.. ZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity.

Topics: Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Drug Design; Drug Therapy, Combination; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Half-Life; HEK293 Cells; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Rats, Sprague-Dawley; Receptors, Gastrointestinal Hormone; Receptors, Glucagon; Recombinant Proteins; Weight Loss

Postprandial glucose-induced insulin secretion from the islets of Langerhans is facilitated by glucagon-like peptide-1 (GLP-1)-a metabolic hormone with insulinotropic properties. Among the variety of effects it mediates, GLP-1 induces delta cell secretion of somatostatin, inhibits alpha cell release of glucagon, reduces gastric emptying, and slows food intake. These events collectively contribute to weight loss over time. During type 2 diabetes (T2DM), however, the incretin response to glucose is reduced and accompanied by a moderate reduction in GLP-1 secretion. To compensate for the reduced incretin effect, a human immunodeficiency virus-based lentiviral vector was generated to deliver DNA encoding human GLP-1 (LentiGLP-1), and the anti-diabetic efficacy of LentiGLP-1 was tested in a high-fat diet/streptozotocin-induced model of T2DM. Therapeutic administration of LentiGLP-1 reduced blood glucose levels in obese diabetic Sprague Dawley rats, along with improving insulin sensitivity and glucose tolerance. Normoglycemia was correlated with increased blood GLP-1 and pancreatic beta cell regeneration in LentiGLP-1-treated rats. Plasma triglyceride levels were also normalized after LentiGLP-1 injection. Collectively, these data suggest the clinical potential of GLP-1 gene transfer therapy for the treatment of T2DM.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Genetic Therapy; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Islets of Langerhans; Lentivirus; Obesity; Rats

Topics: Alcohol Deterrents; Appetite Depressants; Benzazepines; Cohort Studies; Drug Therapy; Humans; Incretins; Liraglutide; Military Personnel; Naltrexone; Obesity; Phentermine; Retrospective Studies

Topics: Animals; Bile Acids and Salts; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Duodenoscopy; Duodenum; Energy Metabolism; Gastrointestinal Microbiome; Humans; Incretins; Intestinal Absorption; Intestinal Mucosa; Obesity

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

Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation; however, little is known of these effects in humans. This study aimed to 1) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl- sn-glycerol (2-AG), and OEA in humans; and 2) examine relationships to intestinal permeability, inflammation markers, and incretin hormone secretion. Twenty lean, 18 overweight, and 19 obese participants underwent intraduodenal Intralipid infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumor necrosis factor-α (TNFα), glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and Toll-like receptor 4 (TLR4) (by RT-PCR) were assessed. Fasting plasma AEA was increased in obese compared with lean and overweight patients ( P < 0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese compared with lean ( P < 0.05), and these levels related negatively to plasma AEA ( P < 0.05). The iAUC for AEA was positively related to iAUC GIP ( r = 0.384, P = 0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP compared with lean and overweight subjects. The relationships between plasma AEA with duodenal ZO-1, IAP, and GIP suggest that altered endocannabinoid signaling may contribute to changes in intestinal permeability, inflammation, and incretin release in human obesity.

Topics: Adult; Alkaline Phosphatase; Arachidonic Acids; Dietary Fats; Duodenum; Endocannabinoids; Female; Gastric Inhibitory Polypeptide; Gene Expression; Glucagon-Like Peptide 1; Glycerides; GPI-Linked Proteins; Humans; Incretins; Inflammation; Male; Obesity; Occludin; Oleic Acids; Overweight; Permeability; Polyunsaturated Alkamides; Thinness; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Zonula Occludens-1 Protein

As incretins are known to play an important role in type 2 diabetics (T2D) improvement observed after Roux-en-Y gastric bypass (RYGB), our aim was to assess whether increasing the length of RYGB biliopancreatic limb in T2D would modify the incretin staining cell density found after the gastric outlet. Small intestine biopsies (n = 38) were harvested during RYGB at two different distances from the duodenal angle; either 60-90 cm (n = 28), from non-diabetic (n = 18) patients, and T2D (n = 10), or 200 cm (n = 10) from T2D. GIP and GLP-1 staining cells were identified by immunohistochemistry and GLP-1/GIP co-staining cells by immunofluorescence. Incretin staining cell density at the proximal small intestine of T2D and non-diabetic individuals was similar. At 200 cm, T2D patients depicted a significantly lower GIP staining cell density (0.181 ± 0.016 vs 0.266 ± 0.033, P = 0.038) with a similar GLP-1 staining cell density when compared to the proximal gut. GIP/GLP-1 co-staining cells was similar in all studied groups. In T2D patients, the incretin staining cells density in the distal intestine is significantly different from the proximal gut. Thus, a longer RYGB biliopancreatic limb produces a distinctive incretin cell pattern at the gastro-enteric anastomosis that can result in different endocrine profiles.

Topics: Adult; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Incretins; Intestine, Small; Male; Obesity

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; CHO Cells; Cricetulus; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Endocannabinoids; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Glycolysis; Incretins; Male; Mice, Inbred C57BL; Obesity; Oleic Acids; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Weight Loss

β-Cell-β-cell interactions are required for normal regulation of insulin secretion. We previously found that formation of spheroid clusters (called K20-SC) from MIN6-K20 clonal β-cells lacking incretin-induced insulin secretion (IIIS) under monolayer culture (called K20-MC) drastically induced incretin responsiveness. Here we investigated the mechanism by which an incretin-unresponsive state transforms to an incretin-responsive state using K20-SC as a model. Glutamate production by glucose through the malate-aspartate shuttle and cAMP signaling, both of which are critical for IIIS, were enhanced in K20-SC. SC formed from β-cells deficient for aspartate aminotransferase 1, a critical enzyme in the malate-aspartate shuttle, exhibited reduced IIIS. Expression of the sodium-coupled neutral amino acid transporter 5 (SNAT5), which is involved in glutamine transport, was downregulated in K20-SC and pancreatic islets of normal mice but was upregulated in K20-MC and islets of rodent models of obesity and diabetes, both of which exhibit impaired IIIS. Inhibition of SNAT5 significantly increased cellular glutamate content and improved IIIS in islets of these models and in K20-MC. These results suggest that suppression of SNAT5 activity, which results in increased glutamate production, and enhancement of cAMP signaling endows incretin-unresponsive β-cells with incretin responsiveness.

Topics: Amino Acid Transport Systems, Neutral; Animals; Anti-Obesity Agents; Cell Communication; Cell Line; Cells, Cultured; Clone Cells; Diabetes Mellitus, Type 2; Drug Resistance; Gene Expression Regulation; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Islets of Langerhans; Male; Membrane Transport Modulators; Mice, Inbred Strains; Microscopy, Electron, Transmission; Models, Biological; Obesity; RNA Interference; Spheroids, Cellular; Tissue Culture Techniques

Considering the possible role of triglycerides (TG), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the regulation of appetite, this study aimed to compare high fat meal-induced response of GIP and GLP-1, appetite scores and ad libitum energy intake in women with obesity, according to postprandial increment in triglyceridemia (∆TG).  Methods: Thirty-three no-diabetic women (BMI = 35.0 ± 3.2 kg.m-2) were divided into two groups: Group with ∆TG ≤ median were called "Low TG change -LTG" and ∆TG > median, "High TG change - HTG". Plasma concentrations of GIP, GLP-1 and appetite sensations were measured prior to, and every 30 min for 180 min after ingestion of a high-fat breakfast. An ad libitum lunch was served 3 h after the test meal.. The AUC incrementalGIP were significant lower in HTG vs. LTG group (p = 0.03). The same was observed for GIP levels at 150 min (p = 0.03) and at 180 min (p < 0.01). Satiety was lower in HTG at 120 min (p = 0.03) and 150 min (p < 0.01). The AUC totalGLP1 were similar between groups and there were no between-group differences for the GLP-1 at each time point. Ad libitum food intake were also similar between groups.. The HTG group exhibited differences in satiety scores and lower postprandial secretion of GIP, however with no impact on ad libitum food intake in short term.

Topics: Adult; Appetite; Body Mass Index; Diet, High-Fat; Dietary Fats; Energy Intake; Female; Humans; Incretins; Middle Aged; Obesity; Postprandial Period; Satiety Response; Triglycerides; Young Adult

Obesity is a serious, chronic, relapsing disease of energy regulation, with strong genetic and early-life environmental determinants. Pharmacotherapy can be a useful adjunct to lifestyle intervention in effecting and maintaining clinically meaningful weight loss.. The aim of this article is to discuss the role of pharmacotherapy in obesity management. The efficacy, side effects and contraindications of available weight-loss medications are reviewed.. Long-term pharmacotherapy options, which can be effective in providing moderate weight loss, are available to treat obesity. Pharma-cotherapy should be considered an adjunct to lifestyle intervention in those with a body mass index (BMI) >30 kg/m30 kg/m2, or in those with a BMI of 27-30 kg/m2 and obesity-related complications. Safety and efficacy should be monitored closely on commencement, and the medication should be discontinued if there are safety or tolerability issues, or if.

Topics: Anti-Obesity Agents; Appetite Depressants; Body Mass Index; Drug Therapy; Drug Therapy, Combination; Fructose; Humans; Incretins; Lactones; Liraglutide; Obesity; Orlistat; Phentermine; Topiramate

The global increase of obesity parallels the obesity-related glomerulopathy (ORG) epidemic. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists were well recognized to attenuate renal injury independent of glucose control in diabetic nephropathy. There are limited studies focusing on their effects on ORG. We explored the effects of incretin-based therapies on early ORG and the inflammatory responses involved mainly concentrated on mast cell (MC) and macrophage (M) infiltration and local pro-inflammatory factors.. ORG rat models were induced by high-fat diet and then divided into ORG vehicle, vildagliptin (3 mg/kg/day, qd) and liraglutide (200 μg/kg, bid) treated groups. After 8 weeks of treatments, albuminuria, glomerular histology, renal inflammatory cell infiltration, and pro-inflammatory factors were analyzed.. Early ORG model was demonstrated by albuminuria, glomerulomegaly, foot process fusion, and mesangial and endothelial mild proliferation. Incretin-based therapies limited body weight gain and improved insulin sensitivity. ORG was alleviated, manifested by decreased average glomerular area, attenuated mesangial and endothelial cell proliferation, and revived cell-to-cell propagation of podocytes, which contributed to reduced albuminuria. Compared with ORG vehicle, MC and M1 macrophage (pro-inflammatory) infiltration and M1/M2 ratio were significantly decreased; M2 macrophage (anti-inflammatory) was not significantly increased after incretin-based treatments. Tumor necrosis factor-α (TNF-α) and IL-6 in renal cortex were significantly downregulated, while transforming growth factor-β1 (TGF-β1) remained unchanged.. Incretin-based treatments could alleviate high-fat diet-induced ORG partly through the systemic insulin sensitivity improvement and the attenuated local inflammation, mainly by the decrease of MC and M1 macrophage infiltration and reduction of TNF-α and IL-6.

Topics: Adamantane; Albuminuria; Animals; Creatinine; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose Tolerance Test; Incretins; Inflammation; Interleukin-6; Kidney Diseases; Kidney Glomerulus; Liraglutide; Macrophages; Male; Mast Cells; Nitriles; Obesity; Pyrrolidines; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vildagliptin

The increasing prevalence of obesity and diabetes is an urgent worldwide health challenge. Now in Cell Stem Cell, Yue et al. (2017) report a proof-of-concept study using genetically engineered skin transplants that produce the incretin GLP-1 to prevent diet-induced obesity, suggesting a powerful approach for treating metabolic disorders.

Topics: Diabetes Mellitus, Type 2; Diet; Humans; Incretins; Obesity; Stem Cells

The glucose-induced secretion of incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), is dependent on luminal glucose levels and transport of glucose via the sodium-glucose transporter 1 (SGLT1) in the small intestine. Because GLP-1 and GIP function in decreasing and increasing the body weight, respectively, we aimed to analyze the effect of transient inhibition of SGLT1 by canagliflozin on incretin secretion in an obese rat model. Male Sprague-Dawley rats were maintained on a high-fat high-sucrose diet for 6-7 weeks, and plasma GLP-1 and GIP levels were measured during an oral glucose tolerance test (OGTT). In addition, GLP-1 secretion was examined in a murine GLP-1 producing enteroendocrine cell line, GLUTag. Concomitant administration of 10 mg/kg canagliflozin with glucose loading suppressed glucose excursion, increased total GLP-1 levels, and reduced total GIP levels in systemic circulation, as revealed in the OGTT. Total and active GLP-1 levels were increased in portal blood, whereas total and active GIP levels tended to be decreased 15 min after the administration of canagliflozin with glucose. Canagliflozin (at 0.1-30 μM) did not directly affect release of GLP-1 in vitro. These results suggest that the oral administration of canagliflozin suppresses GIP secretion via the inhibition of SGLT1 in the upper part of the intestine and enhances GLP-1 secretion by increasing the glucose delivery to the lower part of the small intestine in an obese rodent model.

Topics: Animals; Blood Glucose; Canagliflozin; Cell Line; Diet, High-Fat; Dietary Carbohydrates; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Hypoglycemic Agents; Incretins; Insulin; Male; Obesity; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 1; Sucrose

Topics: Administration, Oral; Adult; Computer Simulation; Down-Regulation; Female; Glucose; Humans; Hypoglycemia; Incretins; Insulin Resistance; Male; Middle Aged; Obesity; Weight Loss

Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.

Topics: Animals; Body Weight; Dexamethasone; Energy Metabolism; Glucagon-Like Peptide 1; Glucocorticoids; Glucose; HEK293 Cells; Humans; Hypothalamus; Incretins; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

Topics: Anti-Obesity Agents; Glucocorticoids; Humans; Incretins; Obesity

Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance.. By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a high-fat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes.. Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.

Topics: Animals; Biomarkers; Blood Glucose; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Exenatide; Fatty Acid Synthase, Type I; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide 1; Hepatocytes; Hyperlipidemias; Incretins; Insulin; Insulin Resistance; Intestinal Mucosa; Intestines; Lipoproteins, VLDL; Liver; Male; Mice, Inbred C57BL; Obesity; Peptides; RNA, Messenger; Signal Transduction; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Time Factors; Triglycerides; Up-Regulation; Vagotomy; Vagus Nerve; Venoms

To study the immediate effects of Roux-en-Y gastric bypass (RYGB) on glucose homeostasis, insulin, and incretin responses to mixed-meal tests compared with the effects of calorie restriction (CR).. University-affiliated bariatric surgery clinic.. RYGB induces remission of type 2 diabetes (T2D) long before significant weight loss occurs. The time course and underlying mechanisms of this remission remain enigmatic. A prevailing theory is that secretory patterns of incretin hormones are altered due to rearrangement of the gastrointestinal tract. To what extent reduced calorie intake contributes to the remission of T2D is unknown.. Nine normoglycemic patients and 10 T2D patients were subjected to mixed-meal tests (MMT) 4 weeks before surgery before initiation of a very low calorie diet regimen (MMT. CR lowered insulin in T2D patients, whereas glucose, GIP, and GLP-1 were unaffected. RYGB immediately increased plasma insulin and GIP. The GLP-1 response was delayed compared with the GIP response. T2D patients exhibited lower insulin responses after RYGB compared with normoglycemic patients. GIP responses were similar in both groups at all occasions, whereas T2D patients displayed markedly elevated GLP-1 responses 6 weeks after RYGB. Glucose was unaffected by CR and RYGB in both groups. Insulin sensitivity was unaffected by CR but improved with RYGB.. RYGB exerts powerful and immediate effects on insulin and incretin responses to food, independently of changes caused by CR.

Topics: Adult; Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulins; Meals; Obesity

The superior effect of Roux-en-Y gastric bypass (RYGB) on glucose control compared with laparoscopic adjustable gastric banding (LAGB) is confounded by the greater weight loss after RYGB. We therefore examined the effect of these two surgeries on metabolic parameters matched on small and large amounts of weight loss.. Severely obese individuals with type 2 diabetes were tested for glucose metabolism, β-cell function, and insulin sensitivity after oral and intravenous glucose stimuli, before and 1 year after RYGB and LAGB, and at 10% and 20% weight loss after each surgery.. RYGB resulted in greater glucagon-like peptide 1 release and incretin effect, compared with LAGB, at any level of weight loss. RYGB decreased glucose levels (120 min and area under the curve for glucose) more than LAGB at 10% weight loss. However, the improvement in glucose metabolism, the rate of diabetes remission and use of diabetes medications, insulin sensitivity, and β-cell function were similar after the two types of surgery after 20% equivalent weight loss.. Although RYGB retained its unique effect on incretins, the superiority of the effect of RYGB over that of LAGB on glucose metabolism, which is apparent after 10% weight loss, was attenuated after larger weight loss.

Topics: Adult; Bariatric Surgery; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin Resistance; Longitudinal Studies; Male; Middle Aged; Obesity; Postoperative Period; Prospective Studies; Sweetening Agents; Weight Loss

The role of incretins in type 2 diabetes is controversial. This study investigated the association between incretin levels in obese Korean children and adolescents newly diagnosed with type 2 diabetes.. We performed a 2-hr oral glucose tolerance test (OGTT) in obese children and adolescents with type 2 diabetes and with normal glucose tolerance.. Twelve obese children and adolescents with newly diagnosed type 2 diabetes (DM group) and 12 obese age-matched subjects without type 2 diabetes (NDM group) were included.. An OGTT was conducted and insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were measured during the OGTT.. The mean age of the patients was 13·8 ± 2·0 years, and the mean body mass index (BMI) Z-score was 2·1 ± 0·5. The groups were comparable in age, sex, BMI Z-score and waist:hip ratio. The DM group had significantly lower homeostasis model assessment of β and insulinogenic index values (P < 0·001). The homeostasis model assessment of insulin resistance index was not different between the two groups. Insulin and C-peptide secretions were significantly lower in the DM group than in the NDM group (P < 0·001). Total GLP-1 secretion was significantly higher in the DM group while intact GLP-1 and GIP secretion values were not significantly different between the two groups.. Impaired insulin secretion might be important in the pathogenesis of type 2 diabetes in obese Korean children and adolescents, however, which may not be attributed to incretin secretion.

Topics: Adolescent; Analysis of Variance; Asian People; Blood Glucose; Body Mass Index; C-Peptide; Case-Control Studies; Child; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Male; Obesity; Republic of Korea

Glucagon-like peptide-1 receptor agonists may have a role in modulation of cardiac fibrosis. Our study aimed to determine the effect of the glucagon-like peptide-1 receptor agonist liraglutide in obesity, hypertension and age-induced murine models of cardiac fibrosis and identify associated molecular mechanisms.. C57Bl/6J mice on a high-fat diet and C57Bl/6J mice on a normal chow diet treated with angiotensin II were used to induce obesity and hypertension-mediated cardiac fibrosis, respectively. C57Bl/6J mice 20 months old were used to study age-induced cardiac fibrosis. Liraglutide treatment of 30 µg/kg/day-300 µg/kg s.c. twice daily was administered for 4 weeks.. Liraglutide treatment attenuated obesity, hypertension and age-induced increases in interstitial cardiac fibrosis and expression of inflammatory and oxidative stress markers.. These observations identify a potential role for liraglutide in the prevention of cardiac fibrosis and identify molecular mechanisms associated with these effects.

Topics: Aging; Angiotensin II; Animals; Aorta; Blood Pressure; Body Weight; Chemokine CCL2; Diet, High-Fat; Disease Models, Animal; Endothelium, Vascular; Fibrosis; Glucagon-Like Peptide-1 Receptor; Heart; Heart Diseases; Hypertension; I-kappa B Proteins; Immunohistochemistry; Incretins; Inflammation; Interleukin-10; Liraglutide; Macrophages; Male; Mice; Mice, Inbred C57BL; Myocardium; NF-kappa B p50 Subunit; Obesity; Oxidative Stress; Real-Time Polymerase Chain Reaction; Vasoconstrictor Agents; Vimentin

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) added to insulin in type 2 diabetes patients have shown to lower body weight, improve glycaemic control and reduce total daily insulin dose in short term studies, although the individual response greatly varies.. To evaluate GLP-1 RA treatment on body weight, glycaemic control and total daily insulin dose in obese, insulin-using type 2 diabetes patients after 2 years follow-up in a real life setting and to explore a possible relation with eating behaviour.. The Martini Hospital and the University Medical Center in Groningen in the Netherlands.. Eligible patients were at least 18 years of age, were on insulin therapy and obese (BMI > 30 kg/m(2)), started GLP-1 RA treatment. At baseline eating behaviour was classified according to the validated Dutch Eating Behaviour Questionnaire. A 2 years follow-up was performed. Main outcome measures Body weight, HbA1c and total daily insulin dose.. 151 Patients started with exenatide or liraglutide. 120 patients completed the 2 years follow-up. From baseline to 2 years, body weight (mean ± SD) changed from 117.9 ± 22.1 to 107.9 ± 22.9 kg (P < 0.0001), HbA1c (median, IQR) changed from 7.9 (7.2-8.9) to 7.6 (6.9-8.3) % [63 (55-74) to 60 (52-67) mmol/mol] (P < 0.0001), total daily insulin dose changed from 90 (56-150) to 60 (0-100) Units/day (P < 0.0001). Weight change differed between eating behaviour groups (P < 0.001) in which external eating behaviour (n = 17) resulted in the smallest decline (-3.1 %) and restrained (n = 41) in the greatest (-10.3 %) in comparison with emotional (n = 37, -8.5 %) and indifferent (n = 25, -9.6 %) eating behaviours.. Two year of GLP-1 RA treatment resulted in a sustained reduction of weight, HbA1c and total daily insulin dose in obese, insulin-using type 2 diabetes patients in a real life setting. Largest weight loss was achieved in patients with a predominant restraint eating pattern while a predominant external eating pattern resulted in the smallest weight reduction.

Topics: Aged; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Feeding Behavior; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Male; Middle Aged; Netherlands; Obesity; Peptides; Prospective Studies; Surveys and Questionnaires; Time Factors; Treatment Outcome; Venoms; Weight Loss

The aim of the work was to compare the hormonal and the metabolic mechanisms involved in weight loss and remission of T2DM one year after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) in morbidly obese type 2 diabetic (T2DM) patients. Insulin sensitivity, insulin secretion, and the gastrointestinal (GI) hormone response to a mixed meal test (MMT) were evaluated before and one year after BS (14 RYGB and 19 VSG). RYGB and VSG groups had similar characteristics at baseline. Weight loss at one year was similar in the 2 groups (ΔBMI%: - 32±10 and - 30±7%, p=0.546). Insulin sensitivity and insulin secretion improved similarly after either procedures with a similar rate in T2DM remission (86% in RYGB and 76% in VSG). Meal-stimulated GLP-1 levels increased after both procedures reaching significantly higher levels after RYGB (p=0.0001). GIP response to MMT decreased to a similar extent after the 2 interventions (p=0.977). Both fasting and post-meal ghrelin concentrations were markedly suppressed after VSG and significantly lower than RYGB (p=0.013 to p=0.035). The improvement of insulin sensitivity and beta-cell function was significantly associated with weight loss (p=0.014 to p=0.035), while no relation was found with the changes in GI hormones. In conclusion, in morbidly obese T2DM patients, RYGB and VSG result in similar improvements of the glucose status in the face of different GI hormonal pattern. Weight loss is the key determinant of diabetes remission one year after surgery.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastrectomy; Gastric Bypass; Glucose Tolerance Test; Homeostasis; Hormones; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Obesity; Prospective Studies; Weight Loss

The incretin effect reflects the actions of enteral stimuli to promote prandial insulin secretion. Impairment of this measure has been proposed as an early marker of β-cell dysfunction and described in T2D, IGT, and even obesity without IGT. We sought to determine the effects of obesity and diabetes on the incretin effect in young subjects with short exposures to metabolic abnormalities and a few other confounding medical conditions. Subjects with T2D (n = 10; 18.0 ± 0.4 yr) or NGT, either obese (n = 11; 17.7 ± 0.4 yr) or lean (n = 8; 26.5 ± 2.3 yr), had OGTT and iso-iv. The incretin effect was calculated as the difference in insulin secretion during these tests and was decreased ∼50% in both the NGT-Ob and T2D subjects relative to the NGT-Ln group. The T2D group had impaired glucose tolerance and insulin secretion during the OGTT, whereas the lean and obese NGT subjects had comparable glucose excursions and β-cell function. During the iso-iv test, the NGT-Ob subjects had significantly greater insulin secretion than the NGT-Ln and T2D groups. These findings demonstrate that in young subjects with early, well-controlled T2D the incretin effect is reduced, similar to what has been described in diabetic adults. The lower incretin effect calculated for the obese subjects with NGT is driven by a disproportionately greater insulin response to iv glucose and does not affect postprandial glucose regulation. These findings confirm that the incretin effect is an early marker of impaired insulin secretion in persons with abnormal glucose tolerance but suggest that in obese subjects with NGT the incretin effect calculation can be confounded by exaggerated insulin secretion to iv glucose.

Topics: Adolescent; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male; Obesity; Young Adult

More than 20 years ago, Pories et al. published a seminal article, "Who Would Have Thought It? An Operation Proves to Be the Most Effective Therapy for Adult-Onset Diabetes Mellitus." This was based on their observation that bariatric surgery rapidly normalized blood glucose levels in obese people with type 2 diabetes mellitus (T2DM), and 10 years later, almost 90% remained diabetes free. Pories et al. suggested that caloric restriction played a key role and that the relative contributions of proximal intestinal nutrient exclusion, rapid distal gut nutrient delivery, and the role of gut hormones required further investigation. These findings of T2DM improvement/remission after bariatric surgery have been widely replicated, together with the observation that bariatric surgery prevents or delays incident T2DM. Over the ensuing two decades, important glucoregulatory roles of the gastrointestinal (GI) tract have been firmly established. However, the physiological and molecular mechanisms underlying the beneficial glycemic effects of bariatric surgery remain incompletely understood. In addition to the mechanisms proposed by Pories et al., changes in bile acid metabolism, GI tract nutrient sensing and glucose utilization, incretins, possible anti-incretin(s), and the intestinal microbiome are implicated. These changes, acting through peripheral and/or central pathways, lead to reduced hepatic glucose production, increased tissue glucose uptake, improved insulin sensitivity, and enhanced β-cell function. A constellation of factors, rather than a single overarching mechanism, likely mediate postoperative glycemic improvement, with the contributing factors varying according to the surgical procedure. Thus, different bariatric/metabolic procedures provide us with experimental tools to probe GI tract physiology. Embracing this approach through the application of detailed phenotyping, genomics, metabolomics, and gut microbiome studies will enhance our understanding of metabolic regulation and help identify novel therapeutic targets.

Topics: Bariatric Surgery; Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Energy Metabolism; Gastrointestinal Hormones; Gastrointestinal Tract; Glucose; Humans; Incretins; Insulin Resistance; Obesity; Remission Induction; Signal Transduction; Weight Loss

Gastrointestinal hormones, such as glucagon-like peptide (GLP-1), have been hypothesized to play a role in the pathogenesis of obesity-related complications. However, few data are available in youth. The objective of this study was to investigate the GLP-1 response to oral glucose load in obese pre-pubertal children and its relationship with insulin secretion.. Ten pre-pubertal obese children [five boys; 10.5±1.6 years; body mass index-standard deviation score (BMI-SDS): 2.2±0.5] and 10 controls (eight boys; 9.9±1.2 years; BMI-SDS: -0.7±0.5) underwent a modified oral glucose tolerance test (OGTT) to evaluate post-load glucose, insulin and GLP-1 responses. Insulin sensitivity [homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and secretion [HOMA-beta, insulinogenic index (IGI)] indexes, area under the curve (AUC) for glucose, insulin and GLP-1 were calculated.. In obese children GLP-1 AUC values were higher and correlated with BMI-SDS (r=0.45; p=0.04), HOMA-IR (r=0.53; p=0.01) and fasting glucose (r=0.68; p=0.001).. Obese children showed an increased GLP-1 response to oral glucose. These changes might likely represent a compensatory mechanism to avoid post-prandial hyperglycemia and allow a normal glucose tolerance.

Topics: Biomarkers; Case-Control Studies; Child; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Incretins; Male; Obesity; Prognosis; Puberty

Topics: Humans; Incretins; Insulin; Insulin Resistance; Obesity; Sleep Apnea, Obstructive

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin(9-39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.

Topics: Adult; Blood Glucose; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Life Style; Male; Middle Aged; Obesity

To investigate the behavioural and intracellular mechanisms by which the glucagon like peptide-1 (GLP-1) receptor agonist, liraglutide, and leptin in combination enhance the food intake inhibitory and weight loss effects of either treatment alone.. We examined the effects of liraglutide (a long-acting GLP-1 analogue) and leptin co-treatment, delivered in low or moderate doses subcutaneously (s.c.) or to the third ventricle, respectively, on cumulative intake, meal patterns and hypothalamic expression of intracellular signalling proteins [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and protein tyrosine phosphatase-1B (PTP1B)] in lean rats.. A low-dose combination of liraglutide (25 µg/kg) and leptin (0.75 µg) additively reduced cumulative food intake and body weight, a result mediated predominantly through a significant reduction in meal frequency that was not present with either drug alone. Liraglutide treatment alone also reduced meal size; an effect not enhanced with leptin co-administration. Moderate doses of liraglutide (75 µg/kg) and leptin (4 µg), examined separately, each reduced meal frequency, cumulative food intake and body weight; only liraglutide reduced meal size. In combination these doses did not further enhance the anorexigenic effects of either treatment alone. Ex vivo immunoblot analysis showed elevated pSTAT3 in the hypothalamic tissue after liraglutide-leptin co-treatment, an effect which was greater than that of leptin treatment alone. In addition, s.c. liraglutide reduced the expression of PTP1B (a negative regulator of leptin receptor signalling), revealing a potential mechanism for the enhanced pSTAT3 response after liraglutide-leptin co-administration.. Collectively, these results show novel behavioural and molecular mechanisms underlying the additive reduction in food intake and body weight after liraglutide-leptin combination treatment.

Topics: Animals; Appetite Depressants; Body Weight; Drug Therapy, Combination; Eating; Glucagon-Like Peptide 1; Hypothalamus; Incretins; Leptin; Liraglutide; Male; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Weight Loss

The microbial community populating the human digestive tract has been linked to the development of obesity, diabetes and liver diseases. Proposed mechanisms on how the gut microbiota could contribute to obesity and metabolic diseases include: (1) improved energy extraction from diet by the conversion of dietary fibre to SCFA; (2) increased intestinal permeability for bacterial lipopolysaccharides (LPS) in response to the consumption of high-fat diets resulting in an elevated systemic LPS level and low-grade inflammation. Animal studies indicate differences in the physiologic effects of fermentable and non-fermentable dietary fibres as well as differences in long- and short-term effects of fermentable dietary fibre. The human intestinal microbiome is enriched in genes involved in the degradation of indigestible polysaccharides. The extent to which dietary fibres are fermented and in which molar ratio SCFA are formed depends on their physicochemical properties and on the individual microbiome. Acetate and propionate play an important role in lipid and glucose metabolism. Acetate serves as a substrate for de novo lipogenesis in liver, whereas propionate can be utilised for gluconeogenesis. The conversion of fermentable dietary fibre to SCFA provides additional energy to the host which could promote obesity. However, epidemiologic studies indicate that diets rich in fibre rather prevent than promote obesity development. This may be due to the fact that SCFA are also ligands of free fatty acid receptors (FFAR). Activation of FFAR leads to an increased expression and secretion of enteroendocrine hormones such as glucagon-like-peptide 1 or peptide YY which cause satiety. In conclusion, the role of SCFA in host energy balance needs to be re-evaluated.

Topics: Animals; Dietary Fiber; Energy Metabolism; Fatty Acids, Volatile; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Inflammation; Intestinal Mucosa; Intestines; Lipid Metabolism; Lipopolysaccharides; Obesity; Peptide YY; Permeability; Satiation

26RFa is a hypothalamic neuropeptide that promotes food intake. 26RFa is upregulated in obese animal models, and its orexigenic activity is accentuated in rodents fed a high-fat diet, suggesting that this neuropeptide might play a role in the development and maintenance of the obese status. As obesity is frequently associated with type 2 diabetes, we investigated whether 26RFa may be involved in the regulation of glucose homeostasis. In the current study, we show a moderate positive correlation between plasma 26RFa levels and plasma insulin in patients with diabetes. Plasma 26RFa concentration also increases in response to an oral glucose tolerance test. In addition, we found that 26RFa and its receptor GPR103 are present in human pancreatic β-cells as well as in the gut. In mice, 26RFa attenuates the hyperglycemia induced by a glucose load, potentiates insulin sensitivity, and increases plasma insulin concentrations. Consistent with these data, 26RFa stimulates insulin production by MIN6 insulinoma cells. Finally, we show, using in vivo and in vitro approaches, that a glucose load induces a massive secretion of 26RFa by the small intestine. Altogether, the present data indicate that 26RFa acts as an incretin to regulate glucose homeostasis.

Topics: Animals; Cell Line, Tumor; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Glucose Tolerance Test; Homeostasis; Humans; Hypothalamus; Incretins; Insulin; Insulin-Secreting Cells; Mice; Neuropeptides; Obesity

Topics: Adult; Dose-Response Relationship, Drug; Humans; Incretins; Injections, Subcutaneous; Liraglutide; Obesity; Weight Loss

Male obesity has been linked to subfecundity. This study is to investigate the effects of GLP-1 receptor (GLP-1R) agonist exenatide on sperm quality in high-fat diet (HFD)-induced obese mice.. After 12 weeks of chow diet (CD) or HFD challenge, mice on HFD were allocated to either saline or exenatide (24 nmol/kg/day) interventions for 8 weeks. Sperm quality and the inflammatory profile of testis were compared among three groups.. Obesity reduced the quality of sperm and changed the inflammatory profile characterized by increased mRNA expression levels of TNF-α, MCP-1, and F4/80 in testis. Exenatide intervention reduced the expression of pro-inflammatory cytokines and improved the quality of sperm.. HFD-induced obesity leads to the impairment of sperm quality and increased inflammation of testis in mice, and the abnormal physiology can be attenuated by exenatide treatment. Exenatide treatment may bring additional profits to obese and diabetes men by improving sperm function.

Topics: Animals; Cytokines; Diet, High-Fat; Exenatide; Glucagon-Like Peptide-1 Receptor; Incretins; Inflammation; Male; Mice; Obesity; Peptides; Spermatozoa; Testis; Venoms

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), enhance postprandial insulin secretion, promote adipogenesis, and regulate gastrointestinal motility and food intake. To date, a consensus on how the incretin response is altered in obesity is lacking. We investigated the effects of chronic high-fat (HF) feeding on incretin secretion in the lymph fistula rat model. Male Sprague-Dawley rats (8 wk) were provided a semipurified AIN93M HF or low-fat (LF) diet ad libitum for 3 or 13 wk; a HF pair-fed (HF-PF) group was included as a control during the 3-wk feeding trial. Energy intake, body weight, and body composition were regularly monitored. At the culmination of the feeding period, an intestinal lymphatic duct cannula and duodenal infusion tube were installed. All animals were challenged with a 3-ml Ensure bolus (3.125 kcal/animal) to measure lymphatic incretin secretion. Despite a significantly higher energy intake, both the 3-wk and 13-wk HF-fed animals did not have an increase in body weight and only a slight increase in body fat compared with LF-fed rats. Following the duodenal Ensure challenge, the 3-wk and 13-wk HF-fed rats had significantly greater lymphatic GIP and GLP-1 secretion than the LF-fed animals. Additionally, the HF-PF group displayed a secretion profile similar to the HF-fed animals for GIP but a similar pattern to the LF-fed animals for GLP-1. The HF-PF data suggest that the increased GIP secretion is driven by the greater percentage of fat intake, whereas the increased GLP-1 secretion is driven by the excess caloric intake.

Topics: Adipogenesis; Animals; Body Composition; Body Weight; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Gastric Inhibitory Polypeptide; Gastrointestinal Motility; Glucagon-Like Peptide 1; Incretins; Insulin; Insulin Secretion; Male; Obesity; Postprandial Period; Rats; Rats, Sprague-Dawley

The aim of this retrospective observational study was to evaluate whether adding liraglutide to lifestyle changes, metformin (Met) and testosterone replacement therapy (TRT), by means of improving weight and glycaemic control, could boost erectile function in type 2 diabetic obese men with overt hypogonadism and erectile dysfunction (ED) in a 'real-life setting'. Forty-three obese, diabetic and hypogonadal men (aged 45-59 years) were evaluated because of complaining about the recent onset of ED. They were subdivided into two groups according to whether hypogonadism occurred after puberty (G1; n = 30: 25 with dysfunctional hypogonadism and 5 with acquired hypogonadotropic hypogonadism) or before puberty (G2; n = 13: 10 with Klinefelter's syndrome and 3 with idiopathic hypogonadotropic hypogonadism). Both G1 and G2 patients were given a combination of testosterone (T) [testosterone undecanoate (TU) 1000 mg/every 12 weeks] and Met (2000-3000 mg/day) for 1 year. In the poor responders (N) to this therapy in terms of glycaemic target (G1N: n = 16; G2N: n = 10), liraglutide (L) (1.2 μg/day) was added for a second year, while the good responders (Y) to T + Met (G1Y: 14/30 and G2Y: 3/13) continued this two drugs regimen therapy for another year. All patients were asked to fill in the International Index of Erectile Function (IIEF 15) questionnaire before starting TU plus Met (T1) and after 12 months (T2) and 24 months (T3) of treatment. Patients underwent a clinical examination and a determination of serum sex hormone binding globulin (SHBG), total testosterone (T) and glycosylated haemoglobin (HbA1c) at T1, T2 and T3. At T2, each patient obtained an improvement of ED (p < 0.01) and of the metabolic parameters without reaching, however, the glycaemic goals [HbA1c = >7.5% (>58 mmol/mol)], while T turned out to be within the range of young men. L added to TU and Met regimen in G1N and G2N allowed these patients to reach not only the glycaemic target [HbA1c = <7.5% (<58 nmol/mol)] and a significant reduction in body weight (p < 0.01), but also a further increase in SHBG (p < 0.05) and T (p < 0.01) plasma levels as well as a significant increment of IIEF score (T3). Conversely, at T3 G1Y and G2Y, who received the combined therapy with TRT and Met for the second year, showed a partial failure of that treatment given that there was no improvement of the IIEF score and they showed a significant rise in serum HbA1c (p < 0.05) and weight (p < 0.04) compared with the asses

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Erectile Dysfunction; Glycated Hemoglobin; Hormone Replacement Therapy; Humans; Hypoglycemic Agents; Hypogonadism; Incretins; Liraglutide; Male; Metformin; Middle Aged; Obesity; Penile Erection; Retrospective Studies; Risk Reduction Behavior; Testosterone; Time Factors; Treatment Outcome; Weight Loss

Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794.. AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala(2) ]GIP(1-42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F β-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu(14) ] exenatide. Human GIP or [d-Ala(2) ]GIP(1-42) were used for comparison.. AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala(2) ]GIP(1-42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala(2) ]GIP(1-42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174.. These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Chemistry, Pharmaceutical; Diabetes Mellitus, Experimental; Female; Gastric Inhibitory Polypeptide; Hypoglycemic Agents; Incretins; Male; Mice; Mice, Obese; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker

The aim of the present study was to assess the effect of dietary macronutrients on postprandial incretin responses and satiety and hunger sensation in obese and normal-weight women. A total of eleven obese and nine normal-weight women were recruited for the assessment of plasma concentrations of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and insulin and the sensation of satiety and hunger using a visual analogue scale before and during a 6 h period after administration of three different macronutrient test meals. The AUCtotal GLP-1 and AUCtotal GIP values were decreased in obese women after the consumption of a fatty meal and all the test meals, respectively. However, the AUCtotal insulin value after a carbohydrate meal was greater in the obese group. The AUCtotal satiety value was decreased only after the intake of the protein meal in obese women when compared with normal-weight women. After the consumption of the fatty meal, a significant positive correlation between maximum satiety sensation and the AUCtotal GLP-1 value in the obese group and that between minimum hunger sensation and the AUCtotal GLP-1 value in the normal-weight group were observed. In conclusion, the findings of the present study suggest that: (1) satiety sensation after consumption of carbohydrate and protein meals in the obese group is related to the postprandial insulin response, while after consumption of a fatty meal, it is related to the postprandial GLP-1 release; (2) the postprandial GIP response does not influence the sensation of satiety and hunger; (3) the reduced GLP-1 release after the intake of a fatty meal in obese individuals may explain impaired satiety sensation; (4) the impaired postprandial GIP response is not related to the consumption of macronutrients and may be the early indicator of incretin axis dysfunction in obese women.

Topics: Adolescent; Adult; Area Under Curve; Diet; Female; Food Analysis; Humans; Incretins; Obesity; Satiety Response; Young Adult

Currently, the most effective treatment for obesity is bariatric surgery. Gastroduodenal bypass surgery produces sustained weight loss and improves glycemic control and insulin sensitivity. Previous studies have shown that sleeve gastrectomy (SG) produces similar results and implicate changes in incretin hormone release in these effects.. Male Sprague-Dawley rats were divided into four groups; lean control (lean), diet-induced obesity (DIO), DIO animals that had undergone SG (SG), and DIO animals that had undergone a sham operation (sham).. After a 2-week recovery period, the incretin response to a standard test meal was measured. Blood sampling was performed in free-moving rats at various time points using chronic vascular access to the right jugular vein. There was a significant increase in the bodyweight of DIO animals fed a high-fat/high-sugar diet compared with the lean animals, which was reversed by SG. DIO caused an impairment of the GLP-1 response to a standard test meal, but not the GIP response. SG resulted in a dramatic increase in the GLP-1 response to a standard test meal but had no effect on the GIP response.. A rapid rise in blood sugar was observed in the SG group following a standard test meal that was followed by reactive hypoglycemia. SG dramatically increases the GLP-1 response to a standard test meal but has no effect on GIP in a rat model of DIO.

Topics: Animals; Blood Glucose; Diet; Disease Models, Animal; Gastrectomy; Glucagon-Like Peptide 1; Incretins; Male; Obesity; Rats; Rats, Sprague-Dawley

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults.

Topics: Adult; Blood Glucose; Body Weight; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Obesity; Peptide Fragments

To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with type 2 diabetes.. A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year of insulin independency (group A) were age-matched pairwise to people with type 2 diabetes (group B) and to six people with type 2 diabetes of similar age and BMI (group C). β-Cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic-euglycemic clamp) and metabolic response during a mixed meal were studied.. Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C) and could be explained by BMI alone in a multivariate analysis. Neither insulin pulsatility, incretin secretion nor insulin sensitivity differed among the groups.. We found no evidence that LADA and type 2 diabetes were distinct disease entities beyond the differences explained by BMI.

Topics: Adult; Age of Onset; Autoantibodies; Autoimmune Diseases; Blood Glucose; Body Mass Index; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Glutamate Decarboxylase; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Matched-Pair Analysis; Obesity; Overweight; Postprandial Period

Arguably the most fundamental physiological systems for all eukaryotic life are those governing energy balance. Without sufficient energy, an individual is unable to survive and reproduce. Thus, an ever-growing appreciation is that mammalian physiology developed a redundant set of neuroendocrine signals that regulate energy intake and expenditure, which maintains sufficient circulating energy, predominantly in the form of glucose, to ensure that energy needs are met throughout the body. This orchestrated control requires cross talk between the gastrointestinal tract, which senses the incoming meal; the pancreas, which produces glycemic counterregulatory hormones; and the brain, which controls autonomic and behavioral processes regulating energy balance. Therefore, this review highlights the physiological, pharmacological, and pathophysiological effects of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide, as well as the pancreatic hormone amylin, on energy balance and glycemic control.

Topics: Animals; Appetite Regulation; Blood Glucose; Brain; Diabetes Mellitus, Type 2; Gastrointestinal Tract; Humans; Incretins; Islet Amyloid Polypeptide; Models, Biological; Neurons; Neurosecretion; Obesity; Pancreas; Vagus Nerve

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.

Topics: Adolescent; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Male; Obesity; Prediabetic State

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

Topics: Animals; Blood Glucose; Carbohydrate Metabolism, Inborn Errors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Eating; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Homeostasis; Humans; Hyperglycemia; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Malabsorption Syndromes; Mice; Mice, Knockout; Models, Biological; Obesity; Receptors, Glucagon

The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short-lived biological actions.. This study has examined metabolic actions of exendin-4, GIP[mPEG] and a novel CCK-8 analogue, (pGlu-Gln)-CCK-8 as enzymatically stable forms of GLP-1, GIP and CCK, respectively.. All peptides significantly (p < 0.01-p < 0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP-1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with exendin-4 or GIP[mPEG] in high fat-fed mice significantly decreased accumulated food intake (p < 0.05-p < 0.01), body weight gain (p < 0.05-p < 0.01) and improved (p < 0.05) insulin sensitivity in high fat-fed mice. However, there was no evidence for superior effects compared to (pGlu-Gln)-CCK-8 alone. Combined treatment of (pGlu-Gln)-CCK-8 and exendin-4 resulted in significantly (p < 0.05) lowered circulating glucose levels and improved (p < 0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu-Gln)-CCK-8, or combined with exendin-4, significantly (p < 0.05) lowered blood glucose levels 24 h post injection in untreated high fat-fed mice.. This study highlights the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.

Topics: Animals; Anti-Obesity Agents; Appetite Regulation; Cell Line; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Therapy, Combination; Exenatide; Gastric Inhibitory Polypeptide; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred Strains; Obesity; Peptides; Rats; Sincalide; Time Factors; Venoms

To characterize the magnitude and variance of the change of glucose and glucagon-like peptide-1 (GLP-1) concentrations, and to identify determinants of glucose control up to 2 years after gastric bypass (GBP).. Glucose and GLP-1 concentrations were measured during an oral glucose challenge before and 1, 12, and 24 months after GBP in 15 severely obese patients with type 2 diabetes.. Glucose area under the curve from 0 to 180 min (AUC(0-180)) started decreasing in magnitude (P < 0.05) 1 month after surgery. GLP-1 AUC(0-180) increased in magnitude 1 month after GBP (P < 0.05), with increased variance only after 1 year (P(σ)(2) ≤ 0.001). GLP-1 AUC(0-180) was positively associated with insulin AUC(0-180) (P = 0.025).. The increase in variance of GLP-1 at 1 and 2 years after GBP suggests mechanisms other than proximal gut bypass to explain the enhancement of GLP-1 secretion. The association between GLP-1 and insulin concentrations supports the idea that the incretins are involved in glucose control after GBP.

Topics: Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Male; Middle Aged; Obesity

People with type 2 diabetes mellitus (T2DM) are characterized by reduced incretin effect and inappropriate glucagon levels. We evaluated α and β-cell responses to oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion (IIGI) in lean and obese persons with T2DM or normal glucose tolerance (NGT) to elucidate the impact of obesity on the incretin effect and incretin hormone and glucagon responses.. Four hour 50-g OGTT and IIGI were performed in (i) Eight obese patients with T2DM [mean body mass index (BMI): 37 (range: 35-41) kg/m(2)]; (ii) Eight obese subjects with NGT [BMI: 33 (35-38) kg/m(2)]; (iii) Eight lean patients with T2DM [BMI: 24 (22-25) kg/m(2)]; and (iv) Eight lean healthy subjects [BMI: 23 (20-25) kg/m(2)].. The incretin effect was significantly (p < 0.05) reduced in patients with T2DM {obese: 7 ± 7% [mean ± standard error of the mean (SEM)]; lean: 29 ± 8%; p = 0.06)} and was lower in obese subjects (41 ± 4%) than in lean subjects with NGT (53 ± 4%; p < 0.05). Obese subjects with NGT were also characterized by elevated fasting plasma glucagon levels, but the inappropriate glucagon responses to OGTT found in the T2DM patients were not evident in these subjects.. Our findings suggest that reduced incretin effect and fasting hyperglucagonaemia constitute very early steps in the pathophysiology of T2DM detectable even in obese people who despite their insulin-resistant state have NGT.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Obesity

The early improvement of glucose control taking place shortly after gastric bypass surgery in obese diabetic patients has long been mysterious. A recent study in mice has highlighted some specific mechanisms underlying this phenomenon. The specificity of gastric bypass in obese diabetic mice relates to major changes in the sensations of hunger and to rapid improvement of glucose parameters. The induction of intestinal gluconeogenesis plays a major role in diminishing hunger, and in restoring insulin sensitivity of endogenous glucose production. In parallel, the restoration of the secretion of glucagon-like peptide 1 and insulin plays a key additional role, in this context of recovered insulin sensitivity, to improve postprandial glucose tolerance. Therefore, a synergy between an incretin effect and intestinal gluconeogenesis is a key feature accounting for the rapid improvement of glucose control in obese diabetic patients after bypass surgery.

Topics: Animals; Blood Glucose; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastroplasty; Glucagon-Like Peptide 1; Gluconeogenesis; Incretins; Insulin Resistance; Mice; Mice, Obese; Obesity

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Male; Obesity; Prevalence

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) improve markers of cognitive function in obesity-diabetes, however, both are rapidly degraded to their major metabolites, GLP-1(9-36)amide and GIP(3-42), respectively. Therefore, the present study investigated effects of GLP-1(9-36)amide and GIP(3-42) on locomotor activity, cognitive function and hippocampal synaptic plasticity in mice with diet-induced obesity and insulin resistance. High-fat fed Swiss TO mice treated with GLP-1(9-36)amide, GIP(3-42) or exendin(9-39)amide (twice-daily for 60 days) did not exhibit any changes in bodyweight, non-fasting plasma glucose and plasma insulin concentrations or glucose tolerance compared with high-fat saline controls. Similarly, locomotor and feeding activity, O(2) consumption, CO(2) production, respiratory exchange ratio and energy expenditure were not altered by chronic treatment with incretin metabolites. Administration of the truncated metabolites did not alter general behavior in an open field test or learning and memory ability as recorded during an object recognition test. High-fat mice exhibited a significant impairment in hippocampal long-term potentiation (LTP) which was not affected by treatment with incretin metabolites. These data indicate that incretin metabolites do not influence locomotor activity, cognitive function and hippocampal synaptic plasticity when administered at pharmacological doses to mice fed a high-fat diet.

Topics: Animals; Behavior, Animal; Cognition; Diet, High-Fat; Feeding Behavior; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Hippocampus; Incretins; Long-Term Potentiation; Male; Mice; Motor Activity; Neuronal Plasticity; Obesity; Oxygen Consumption; Peptide Fragments; Peptides; Synapses

Consensus exists that several bariatric surgery procedures produce a rapid improvement of glucose homeostasis in obese diabetic patients, improvement apparently uncorrelated with the degree of eventual weight loss after surgery. Several hypotheses have been suggested to account for these results: among these, the anti-incretin, the ghrelin and the lower-intestinal dumping hypotheses have been discussed in the literature. Since no clear-cut experimental results are so far available to confirm or disprove any of these hypotheses, in the present work a mathematical model of the glucose-insulin-incretin system has been built, capable of expressing these three postulated mechanisms. The model has been populated with critically evaluated parameter values from the literature, and simulations under the three scenarios have been compared.. The modeling results seem to indicate that the suppression of ghrelin release is unlikely to determine major changes in short-term glucose control. The possible existence of an anti-incretin hormone would be supported if an experimental increase of GIP concentrations were evident post-surgery. Given that, on the contrary, collected evidence suggests that GIP concentrations decrease post-surgery, the lower-intestinal dumping hypothesis would seem to describe the mechanism most likely to produce the observed normalization of Type 2 Diabetes Mellitus (T2DM) after bariatric surgery.. The proposed model can help discriminate among competing hypotheses in a context where definitive data are not available and mechanisms are still not clear.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Intestines; Mathematical Concepts; Models, Biological; Obesity; Treatment Outcome

There is a worsening high prevalence of global obesity. Special attention has been paid to the gut-endocrine system, represented by the regulators of appetite. In particular, it has been suggested that ghrelin ("hunger" peptide), and obestatin and glucagon-like peptide-1 (GLP-1) ("satiety" peptides) could play important roles in the pathogenesis of obesity.. The aims of this study were to compare fasting plasma ghrelin, obestatin, and GLP-1 levels between obese and nonobese prepubertal children, and to assess their relations with fatness indexes and insulin resistance (IR).. Fifty-two prepubertal obese children and 22 controls were enrolled. Fasting levels of gastrointestinal hormones (ghrelin, obestatin, and GLP-1), glucose, and insulin were evaluated. IR was assessed using the homeostasis model assessment of IR (HOMA-IR) index. Analysis was performed by Mann-Whitney U-test, Kruskal-Wallis test, and Spearman's correlation.. Obese prepubertal children and normal-weight controls had similar age distribution. Obese children were more insulin resistant when compared to controls (HOMA-IR: p < 0.01 ). GLP-1 levels were significantly lower in obese children than in controls (p < 0.01). Obestatin was significantly higher in obese than normal-weight children (p < 0.01), while ghrelin was not different. There was a negative correlation between GLP-1 and standard deviation score-body mass index (r = -0.36, p = 0.009) and between GLP-1 and waist circumference (r = -0.45, p = 0.001), while no association was observed with HOMA-IR.. GLP-1 levels have been shown to be correlated with adiposity indexes, but not with HOMA-IR, suggesting that this hormone could play an important role in the early development of obesity.

Topics: Adiposity; Blood Glucose; Body Mass Index; Case-Control Studies; Child; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Leptin; Male; Obesity; Waist Circumference

Given the scarcity of donors, moderately fatty livers (FLs) are currently being considered as possible grafts for orthotopic liver transplantation (OLT), notwithstanding their poor tolerance to conventional cold preservation. The behaviour of parenchymal and sinusoidal liver cells during transplantation is being studied worldwide. Much less attention has been paid to the biliary tree, although this is considered the Achille's heel even of normal liver transplantation. To evaluate the response of the biliary compartment of FLs to the various phases of OLT reliable markers are necessary. Previously we demonstrated that Alkaline Phosphatase was scarcely active in bile canaliculi of FLs and thus ruled it out as a marker. As an alternative, dipeptidylpeptidase-IV (DPP-IV), was investigated. This ecto-peptidase plays an important role in glucose metabolism, rapidly inactivating insulin secreting hormones (incretins) that are important regulators of glucose metabolism. DPP-IV inhibitors are indeed used to treat Type II diabetes. Neuropeptides regulating bile transport and composition are further important substrates of DPP-IV in the enterohepatic axis. DPP-IV activity was investigated with an azo-coupling method in the liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. Protein expression was studied by immunofluorescence with the monoclonal antibody (clone 5E8). In Wistar rat liver, DPP-IV activity and expression were high in the whole biliary tree, and moderate in sinusoid endothelial cells, in agreement with the literature. Main substrates of DPP-IV in hepatocytes and cholangiocytes could be incretins GLP-1 and GIP, and neuropeptides such as vasoactive intestinal peptide (VIP) and substance P, suggesting that these substances are inactivated or modified through the biliary route. In lean Zucker rat liver the enzyme reaction and protein expression patterns were similar to those of Wistar rat. In obese rat liver the patterns of DPP-IV activity and expression in hepatocytes reflected the morphological alterations induced by steatosis as lipid-rich hepatocytes had scarce activity, located either in deformed bile canaliculi or in the sinusoidal and lateral domains of the plasma membrane. These findings suggest that bile canaliculi in steatotic cells have an impaired capacity to inactivate incretins and neuropeptides. Incretin and/or neuropeptide deregulation is indeed thought to play important roles in obesity and insul

Topics: Animals; Dipeptidyl Peptidase 4; Fatty Liver; Fluorescent Antibody Technique; Gene Expression Regulation, Enzymologic; Incretins; Liver; Male; Neuropeptides; Obesity; Rats; Rats, Wistar; Rats, Zucker

The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys(37)Myr) (N-acetylGIP with myristic acid conjugated at Lys(37)), a simple combination of both peptides and a Lira-AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys(37)Myr)] were incubated with DPP-IV (dipeptidyl peptidase-IV) to assess peptide stability, and BRIN-BD11 cells were used to evaluate cAMP production and insulin secretion. Acute glucose-lowering and insulinotropic actions were evaluated in Swiss TO mice. Subchronic studies on glucose homoeostasis, insulin secretion, food intake and bodyweight were evaluated in ob/ob mice. Liraglutide, N-AcGIP(Lys(37)Myr), a simple combination of both peptides and the Lira-AcGIP preparation demonstrated improved DPP-IV resistance (P<0.001), while stimulating cAMP production and insulin secretion (1.4-2-fold; P<0.001). The Lira-AcGIP preparation was more potent at lowering plasma glucose (20-51% reduction; P<0.05-P<0.001) and stimulating insulin secretion (1.5-1.8-fold; P<0.05-P<0.001) compared with Liraglutide and N-AcGIP(Lys(37)Myr) or a simple peptide combination. Daily administration of the Lira-AcGIP preparation to ob/ob mice lowered bodyweight (7-9%; P<0.05), food intake (23%; P<0.05) and plasma glucose (46% reduction; P<0.001), while increasing plasma insulin (1.5-1.6-fold; P<0.001). The Lira-AcGIP preparation enhanced glucose tolerance, insulin response to glucose and insulin content (P<0.05-P<0.001). These findings demonstrate that a combined preparation of the acylated GLP-1 and GIP peptides Liraglutide and N-AcGIP(Lys(37)Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Incretins; Insulin; Insulin-Secreting Cells; Liraglutide; Male; Mice; Mice, Obese; Models, Biological; Obesity

Protein elicits a stronger early (30 min) glucose-dependent insulinotropic polypeptide (GIP) response than fat ingestion in lean individuals, with no difference in glucagon-like peptide-1 (GLP-1). We assessed the incretin hormone response to protein versus fat ingestion in obesity. Equicaloric (8 kcal/kg) fat (olive oil) or protein (whey protein) was ingested by non-diabetic obese male volunteers [body mass index (BMI) >30 kg/m(2) ; n = 12] and plasma GIP and GLP-1 were determined. We found no difference in the early GIP or GLP-1 responses to fat versus protein. However, the total 300-min GIP response was greater after fat than after protein ingestion (20.3 ± 3.9 vs. 10.0 ± 2.8 nmol/l × min; p = 0.026), whereas the 300-min GLP-1 responses were the same. Thus, in obesity, protein and fat ingestion elicit similar early (30 min) incretin hormone responses, whereas 300-min GIP secretion is more pronounced after fat than protein ingestion.

Topics: Adult; Dietary Fats; Dietary Proteins; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Male; Obesity

Insulin resistance is considered to play an important role in the pathogenesis of polycystic ovary syndrome (PCOS) and in the progression to type 2 diabetes. Recent reports concentrate on a possible relationship between incretin secretion and beta-cell function in PCOS. The aim of the present study is to investigate the incretin effect in obese and lean women with PCOS.. Twenty women with PCOS and ten age-matched healthy women were recruited in the study. The oral glucose tolerance test (OGTT) and isoglycemic test were carried out on each participant after an overnight fast at 2-weeks interval. Plasma levels of insulin, glucose, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) were assayed.. Obese women with PCOS demonstrated lower GIP concentrations (area under the curve [AUC]) in response to OGTT compared to the control group. The incretin effect was found significantly augmented in the obese women with PCOS compared to controls. This finding remained robust in the subgroup analysis including only body mass index (BMI)-matched healthy women.. Increased insulinotropic effect could counteract the blunted GIP response to OGTT in obese women with PCOS. It is suggested that the pathology of PCOS may also include impaired activity of the enteroinsular axis.

Topics: Adult; Analysis of Variance; Area Under Curve; Body Mass Index; Case-Control Studies; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Greece; Humans; Incretins; Insulin; Obesity; Pilot Projects; Polycystic Ovary Syndrome; Thinness; Young Adult

Incretin secretion and effect on insulin secretion are not fully understood in patients with type 2 diabetes. We investigated incretin and insulin secretion after meal intake in obese and non-obese Japanese patients with type 2 diabetes compared to non-diabetic subjects. Nine patients with type 2 diabetes and 5 non-diabetic subjects were recruited for this study. Five diabetic patients were obese (BMI > or = 25) and 4 patients were non-obese (BMI < 25). In response to a mixed meal test, the levels of immunoreactive insulin during 15-90 min and C-peptide during 0-180 min in non-obese patients were significantly lower than those in obese patients. Total GLP-1 and active GIP levels showed no significant difference between obese and non-obese patients throughout the meal tolerance test. In addition, there were no significant differences between diabetic patients and non-diabetic subjects. In conclusion, incretin secretion does not differ between Japanese obese and non-obese patients with type 2 diabetes and non-diabetic subjects.

Topics: Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Middle Aged; Obesity

Topics: Anti-Obesity Agents; Female; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Male; Nausea; Obesity; Treatment Outcome; Vomiting; Weight Loss

Topics: Anti-Obesity Agents; Comorbidity; Female; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Male; Metabolic Syndrome; Obesity; Treatment Outcome; Weight Loss

The prevalence of type 2 diabetes mellitus has reached epidemic proportions. Current treatment options for patients with diabetes include lifestyle modifications (eg, diet and exercise) along with pharmacotherapy (eg, oral antidiabetic drugs [OADs], incretin-based therapies, and insulin). Despite the availability of effective and safe treatments, many patients do not achieve recommended glycemic targets, thereby increasing their risk of long-term complications. Given the progressive nature of diabetes and the need for extensive patient management, it is important that physicians and patients develop a partnership to achieve therapeutic goals. At diagnosis, the diabetes care team, led by the patient, should evaluate all aspects of management, including appropriate treatment options that are suited to the patient's quality of life, convenience, and therapeutic goals. Treatment should also consider the patient's comorbidities, including hypertension and obesity. Management of early type 2 diabetes should include OADs and incretin-based therapies, and preference should be given to agents that do not cause either hypoglycemia or weight gain. A basal insulin should be initiated if glycemic control is not achieved with >or= 1 agents or if presenting glucose control is poor. Irrespective of pharmacotherapy, all patients should be encouraged to maintain a healthy diet and exercise regimen. Patients also need to become active participants in disease management by monitoring blood glucose, complying with medication, adhering to lifestyle modifications, and setting weight loss goals when appropriate. This article emphasizes the need for physicians and other health care providers to partner with patients to achieve therapeutic goals and presents a novel, multifaceted approach toward improving the management of diabetes in a clinical practice setting.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Medication Adherence; Obesity; Physician-Patient Relations; Receptors, Glucagon; Risk Reduction Behavior; Weight Loss

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incretins; Obesity; Postprandial Period; Prevalence

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

Incretin enhancers are a new class of antidiabetic drugs with promising therapeutic potential for type 2 diabetes. Therapeutic intervention in prediabetes is an attractive strategy for preventing or delaying diabetes onset. The aim of the present study was to investigate the therapeutic effects of incretin enhancement on incipient impaired glucose tolerance (iIGT) and manifest IGT (mIGT) using the dipeptidyl peptidase IV (DPP-4) inhibitor P32/98- and fatty Zucker rat (ZR, fa/fa) as a model.. ZRs were classified into groups with iIGT and mIGT (n = 10 per group). P32/98 (21.61 mg/kg body weight) was administered orally to ZR with iIGT and mIGT once daily for 6 and 3 weeks respectively. Assessments included body weight, morning blood glucose and insulin, oral glucose tolerance test (oGTT; 2 g glucose/kg), plasma parameters and blood glucose day-night profile (DNP). In addition, glucose responsiveness of isolated islets and islet morphology were analysed.. P32/98 decreased non-fasting morning blood glucose more effectively in ZR with iIGT than in ZR with mIGT. Compared with study entry, P32/98 improved DNP of blood glucose in ZR with mIGT and nearly normalized DNP in ZR with iIGT. An acute bolus of inhibitor reduced glucose load during oGTT in rats chronically treated with placebo or P32/98. In contrast to placebo-treated rats, rats receiving long-term treatment with P32/98 required less insulin during oGTT. This effect was larger in rats with iIGT vs. rats with mIGT. In isolated pancreatic islets of ZR with mIGT, treatment with P32/98 decreased pancreatic insulin content and increased glucose responsiveness, while the beta-cell volume density was unaffected. P32/98 significantly reduced triglycerides and non-esterified fatty acids. Intestinal growth was comparable between inhibitor- and placebo-treated fatty rats.. Enhancement of incretin with the DPP-4 inhibitor P32/98 has therapeutic effects in hyperinsulinaemia, hyperglycaemia and IGT in ZR with iIGT and mIGT. Apparently, administration of P32/98 in ZR with iIGT results in more efficient beta-cell function, which is associated with less need for insulin to cope with deterioration of glucose tolerance. Importantly, P32/98 has a strong effect on dyslipidaemia in mIGT. P32/98 has no side effect on intestinal growth. Daily intake of P32/98 is a promising strategy for treatment of glucose intolerance and has the potential to prevent type 2 diabetes.

Topics: Animals; Blood Glucose; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Fatty Acids, Nonesterified; Glucose; Glucose Intolerance; Incretins; Insulin; Insulin Secretion; Islets of Langerhans; Isoleucine; Male; Models, Animal; Obesity; Rats; Rats, Zucker; Thiazoles; Time Factors; Tissue Culture Techniques; Triglycerides

The K cell is a specific sub-type of enteroendocrine cell located in the proximal small intestine that produces glucose-dependent insulinotropic polypeptide (GIP), xenin, and potentially other unknown hormones. Because GIP promotes weight gain and insulin resistance, reducing hormone release from K cells could lead to weight loss and increased insulin sensitivity. However, the consequences of coordinately reducing circulating levels of all K cell-derived hormones are unknown. To reduce the number of functioning K cells, regulatory elements from the rat GIP promoter/gene were used to express an attenuated diphtheria toxin A chain in transgenic mice. K cell number, GIP transcripts, and plasma GIP levels were profoundly reduced in the GIP/DT transgenic mice. Other enteroendocrine cell types were not ablated. Food intake, body weight, and blood glucose levels in response to insulin or intraperitoneal glucose were similar in control and GIP/DT mice fed standard chow. In contrast to single or double incretin receptor knock-out mice, the incretin response was absent in GIP/DT animals suggesting K cells produce GIP plus an additional incretin hormone. Following high fat feeding for 21-35 weeks, the incretin response was partially restored in GIP/DT mice. Transgenic versus wild-type mice demonstrated significantly reduced body weight (25%), plasma leptin levels (77%), and daily food intake (16%) plus enhanced energy expenditure (10%) and insulin sensitivity. Regardless of diet, long term glucose homeostasis was not grossly perturbed in the transgenic animals. In conclusion, studies using GIP/DT mice demonstrate an important role for K cells in the regulation of body weight and insulin sensitivity.

Topics: Animal Feed; Animals; Dietary Fats; Gastric Inhibitory Polypeptide; Glucose Tolerance Test; Incretins; Insulin Resistance; Mice; Mice, Transgenic; Models, Biological; Obesity; Promoter Regions, Genetic; Rats; Time Factors; Transgenes

Gastric bypass surgery (GBP) results in rapid weight loss, improvement of type 2 diabetes (T2DM), and increase in incretins levels. Diet-induced weight loss also improves T2DM and may increase incretin levels.. Our objective was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss.. Obese women with T2DM studied before and 1 month after GBP (n = 9), or after a diet-induced equivalent weight loss (n = 10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration and control, and amount of weight loss.. This outpatient study was conducted at the General Clinical Research Center.. Glucose, insulin, proinsulin, glucagon, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP)-1 levels were measured after 50-g oral glucose. The incretin effect was measured as the difference in insulin levels in response to oral and to an isoglycemic iv glucose load.. At baseline, none of the outcome variables (fasting and stimulated values) were different between the GBP and diet groups. Total GLP-1 levels after oral glucose markedly increased six times (peak:17 +/- 6 to 112 +/- 54 pmol/liter; P < 0.001), and the incretin effect increased five times (9.4 +/- 27.5 to 44.8 +/- 12.7%; P < 0.001) after GBP, but not after diet. Postprandial glucose levels (P = 0.001) decreased more after GBP.. These data suggest that early after GBP, the greater GLP-1 and GIP release and improvement of incretin effect are related not to weight loss but rather to the surgical procedure. This could be responsible for better diabetes outcome after GBP.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Reducing; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Male; Middle Aged; Obesity; Weight Loss

The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro(3))GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro(3))GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. (Pro(3))GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in (Pro(3))GIP-treated high-fat-fed mice. (Pro(3))GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro(3))GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.

Topics: Adipokines; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Corticosterone; Dietary Fats; Eating; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Incretins; Insulin; Insulin Resistance; Lipids; Liver; Male; Mice; Motor Activity; Muscle, Skeletal; Obesity; Pancreas; Receptors, Gastrointestinal Hormone

Hyperinsulinemic hypoglycemia is newly recognized as a rare but important complication after Roux-en-Y gastric bypass (GB). The etiology of the syndrome and metabolic characteristics remain incompletely understood. Recent studies suggest that levels of incretin hormones are increased after GB and may promote excessive beta-cell function and/or growth.. We performed a cross-sectional analysis of metabolic variables, in both the fasting state and after a liquid mixed-meal challenge, in four subject groups: 1) with clinically significant hypoglycemia [neuroglycopenia (NG)] after GB surgery, 2) with no symptoms of hypoglycemia at similar duration after GB surgery, 3) without GB similar to preoperative body mass index of the surgical cohorts, and 4) without GB similar to current body mass index of the surgical cohorts.. Insulin and C-peptide after the liquid mixed meal were both higher relative to the glucose level achieved in persons after GB with NG compared with asymptomatic individuals. Glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide levels were higher in both post-GB surgical groups compared with both overweight and morbidly obese persons, and glucagon-like peptide 1 was markedly higher in the group with NG. Insulin resistance, assessed by homeostasis model assessment of insulin resistance, the composite insulin sensitivity index, or adiponectin, was similar in both post-GB groups. Dumping score was also higher in both GB groups but did not discriminate between asymptomatic and symptomatic patients. Notably, the frequency of asymptomatic hypoglycemia after a liquid mixed meal was high in post-GB patients.. A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Eating; Female; Food; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Postoperative Complications