incretins and Body-Weight

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

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

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

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

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

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

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

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

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

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

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

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

Many persons with type 1 diabetes do not achieve glycemic targets, why new treatments, complementary to insulin, are of interest. Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist could be a potential pharmacological supplement to insulin. This review discusses the mechanism of actions, efficacy and safety of liraglutide as add-on to insulin in persons with type 1 diabetes.. Physiological and clinical data on liraglutide in type 1 diabetes were reviewed. We searched the Cochrane library, MEDLINE and EMBASE, with the final search performed February 16, 2016.. Liraglutide as adjunct to insulin treatment reduced body weight and daily dose of insulin compared with insulin alone. The effect on HbA1c was inconsistent with mostly uncontrolled, small-scale studies reporting improvements in glycemic control. In placebo-controlled studies there was no clinically relevant effect on HbA1c. Adverse events were mostly transient gastrointestinal side effects, primarily nausea. Based on the available data, liraglutide cannot be recommended as add-on therapy to insulin in persons with type 1 diabetes with the aim to improve glycemic control. Ongoing trials in newly diagnosed patients with type 1 diabetes and in insulin pump-treated patients will help define the future role of liraglutide therapy in type 1 diabetes.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide

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

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

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

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

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

Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Metformin; Treatment Outcome; Weight Loss

Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists, are the latest addition to the range of available medications for the management of patients with type 2 diabetes. The GLP-1 analog liraglutide has been approved for use in Europe and the US for over a year and has undergone evaluation in several pharmacokinetic/pharmacodynamics studies and in an extensive phase 3 clinical program. The aim of this review is to assess the pharmacokinetics, efficacy and safety of the phase 3 data.. Data are presented from the pharmacokinetics/pharmacodynamics studies of liraglutide and from nine published phase 3 studies, including the six Liraglutide Effect and Action in Diabetes (LEAD) studies.. Liraglutide is effective at improving indices of glycemic control, and has a good tolerability and safety profile. Beneficial effects on weight (mean reduction of 1-3.4 kg) and blood pressure (systolic blood pressure decreased by 2.1-6.7 mmHg) are also observed.. Liraglutide is an effective and well tolerated option for the treatment of type 2 diabetes.

Topics: Blood Glucose; Blood Pressure; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin-Secreting Cells; Liraglutide; Male; Randomized Controlled Trials as Topic; Receptors, Glucagon; Treatment Outcome

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

Glucagon-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors are two classes of treatments for type 2 diabetes, which enhance the well-known 'incretin effect' of increased insulin secretion in response to food intake. This concise review introduces both types of incretin-based therapies and focuses on the extra-pancreatic effect of GLP-1 on body weight. As well as improving glycaemic control in subjects with type 2 diabetes, these treatments have the additional benefits of improving weight management in these patients, with GLP-1 receptor agonists causing weight loss and DPP-4 inhibitors being weight neutral.

Topics: Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome

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

Incretin hormones are intestinally derived peptides that are known to augment glucose-stimulated insulin secretion and suppress glucagon levels. Incretin mimetics are attractive adjunctive therapy for type 2 diabetes due to its efficacy on reducing hyperglycemia with a minimal risk of hypoglycemia. In contrast to most available hypoglycemia agents that cause weight gain, incretin mimetics are associated with moderate weight loss. In this review, we focused our discussion on the actions of glucagon-like peptide 1 (GLP-1) in the brain regulation of energy expenditure and food intake. Furthermore, we reviewed the data from preclinical and clinical studies in humans and discussed the actions of GLP-1, GLP-1 analogs, dipeptidyl pepidase 4 (DPP-4) inhibitors on body weight regulation as well as mechanism by which these effects may occur. The gastrointestinal side effects common to GLP-1 based therapeutics such as nausea hamper its wide spread use. Here, we discussed theoretical possibilities for maximizing weight loss and minimizing nausea with of incretin-based therapy.

Topics: Animals; Body Weight; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Weight Loss

The management of type 2 diabetes mellitus and, in particular, blood glucose levels can be complex and challenging for physicians and patients. Many patients are frustrated with the agents currently available because they have associated limitations of weight gain, hypoglycemia, and tolerability issues. Advantages of glucagon-like peptide-1 (GLP-1) agonists include their efficacy in lowering blood glucose levels, their lack of association with weight gain, and their indirect association with weight loss. Patients likely to benefit from GLP-1 agonist therapy are those in the early stages of the disease and those in need of sufficient benefit from an agent with good efficacy. Setting appropriate expectations for patients is important, as well as explaining the significance of glucose control and reminding patients that this is the main goal of therapy. Patients (and physicians) who have concerns about hypoglycemia can be reassured that GLP-1 agonists work only in the presence of hyperglycemia. Longer-acting GLP-1 agonists are dosed less frequently, appear to be associated with less nausea, and may be associated with better rates of adherence than shorter-acting agents. When initiating therapy with GLP-1 agonists, doses should be gradually escalated to minimize gastrointestinal adverse effects. The dose of a sulfonylurea may need to be lowered if a GLP-1 agonist is added. A review of possible adverse effects, contraindications, dosing and administration techniques, and expected benefits of therapy is provided in the present article to optimize success rates with this new class of agents.

Topics: Algorithms; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Metformin; Middle Aged; Peptides; Sulfonylurea Compounds; Treatment Outcome; Venoms

Incretin therapy includes treatment with incretin analogues (exenatid and liraglutid) and so called incretin enhancers (gliptins and DPP-4 inhibitors respectively--sitagliptin, vildagliptin, saxagliptin, linagliptin). In patients with type 2 diabetes, this novel antidiabetic treatment usually leads to successful reduction in fasting as well as postprandial glycaemia and glycosylated haemoglobin. At the same time, it importantly improves all components of metabolic syndrome (dyslipidemia, hypertension, systemic inflammation). Incretin analogues also reduce body weight while DPP-4 inhibitors are weight-neutral. Both groups of drugs are expected to have positive cardiovascular effects, although it is not clear whether these are likely to be direct or indirect, i.e. facilitated by improved compensation of metabolic syndrome components.

Topics: Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Metabolic Syndrome

Type 2 diabetes mellitus is a chronic debilitating disease characterized by insulin resistance and progressive pancreatic dysfunction. Concomitant with declining pancreatic function and decreasing insulin production, there is a progressive increase in blood glucose levels. Hyperglycemia plays a major role in the development of the microvascular and macrovascular complications of diabetes. Traditional agents used for the treatment of type 2 diabetes are able to improve glycemia, but their use is often limited by treatment-associated side effects, including hypoglycemia, weight gain, and edema. Moreover, these agents do not have any sustained effect on beta-cell mass or function. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both exenatide (the first dipeptidyl peptidase-4-resistant glucagonlike peptide-1 receptor agonist approved by the US Food and Drug Administration [FDA]), and liraglutide (a long-acting incretin mimetic), improve beta-cell function and glycemia with minimal hypoglycemia. Both agents have trophic effects on beta-cell mass in animal studies. The use of these agents is also associated with reduced body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic function, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

Topics: Animals; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Endothelium, Vascular; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Liraglutide; Liver; Peptides; Receptors, Glucagon; Venoms

Type 2 diabetes mellitus traditionally has been characterized by insulin resistance and beta-cell dysfunction, leading to hyperglycemia and eventual micro- and macrovascular complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of drugs available for the management of type 2 diabetes. In order to provide a comprehensive evaluation and comparison of the pharmacology, pharmacokinetics, efficacy, and safety of the DPP-4 inhibitors-sitagliptin, vildagliptin, saxagliptin, and alogliptin-in the treatment of type 2 diabetes, we conducted a MEDLINE search (1966-July 2009) for pertinent English-language articles. Abstracts of the annual meetings of the American Diabetes Association and European Association for the Study of Diabetes from 2005-2009 were also searched. As a drug class, the DPP-4 inhibitors have become widely accepted in clinical practice because of their low risk of hypoglycemia, favorable adverse-effect profile, and once-daily dosing. They are weight neutral (do not cause weight gain or loss) and appear to decrease beta-cell apoptosis and increase beta-cell survival. Because clinical studies directly comparing agents from this class have not, to our knowledge, been conducted, making comparisons in terms of efficacy and safety will become difficult for clinicians as more agents become available. Based on information from preclinical, clinical, and postmarketing data, there does not appear to be a compelling advantage of one DPP-4 inhibitor over another in terms of efficacy, safety, or ease of clinical use. Although theoretical advantages exist for agents with a higher specificity for DPP-4 inhibition versus inhibition of other isoenzymes associated with toxicity, comparative studies and/or increased clinical experience with this class of drug will determine the clinical advantages, if any, of one agent over another.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Enzyme Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells

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 stomach is commonly the source of chronic digestive symptoms in patients with diabetes mellitus; erratic stomach emptying may result in poor glycemic control. On the other hand, medications that mimic or enhance the function of the endogenous incretins retard gastric emptying to enhance glycemic control. In patients with obesity and type 2 diabetes, bariatric procedures alter food intake and weight; however, effects on glycemic control precede and are out of proportion with the degree of weight loss. The mechanisms responsible for the improved glycemic control after bariatric surgery are the subject of ongoing research, and include increased circulating incretins stimulated by the delivery of nutrients to the intestine, contributing to weight loss and independently to glycemic control. The stomach is not always a villain, but is an ally in patients with type 2 diabetes.

Topics: Bariatric Surgery; Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Stomach

The single-tablet combination of vildagliptin and metformin addresses key defects of type 2 diabetes for improved glycemic control. By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, vildagliptin raises the levels of the active incretin hormones, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. This leads to increased synthesis and release of insulin from the pancreatic beta cells and decreased release of glucagon from the pancreatic alpha cells. The combination tablet also contains metformin, which addresses insulin resistance. The complementary mechanisms of action of the two agents in combination have been shown to provide additive and sustained reductions in hemoglobin A(1c) compared with metformin monotherapy. In active-controlled trials, the vildagliptin-metformin combination has been shown to produce equivalent reductions in hemoglobin A(1c) to pioglitazone-metformin and glimepiride-metformin combinations, without significant risk of hypoglycemia and without causing weight gain. In clinical trials, the overall incidence of any adverse event was similar in patients randomized to vildagliptin plus metformin and placebo plus metformin. Available data support the use of vildagliptin in combination with metformin as a promising second-line treatment for the management of type 2 diabetes and this is reflected in the latest UK National Institute for Health and Clinical Excellence draft guideline for consultation on new agents for blood glucose control in type 2 diabetes.

Topics: Adamantane; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipids; Metformin; Nitriles; Practice Guidelines as Topic; Pyrrolidines; Safety; Treatment Outcome; Vildagliptin

Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying.. In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c

Topics: Blood Glucose; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Fasting; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Bariatric surgery offers a safe and effective treatment of type II diabetes for morbidly obese persons with complete and permanent remission as well as a clear reduction in mortality. Current data suggest that surgical treatment could be extended to merely overweight and even slender diabetes patients. Bariatric surgery also offers invaluable new approaches for research into type II diabetes. Evidence that the foregut plays a decisive role in the pathogenesis of the disease opens promising opportunities for improved treatment of this serious disease.

Topics: Animals; Body Weight; Cost-Benefit Analysis; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Duodenum; Gastric Bypass; Germany; Humans; Incretins; Insurance Coverage; Jejunum; National Health Programs

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

Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue that has received marketing approval from the European Commission, is a treatment for type 2 diabetes mellitus (DM) that is administered as a once-daily subcutaneous injection.. The aim of this review was to summarize the efficacy and safety data published about liraglutide, focusing on data from Phase III clinical trials.. Relevant English-language publications were identified through a search of MEDLINE and EMBASE (from 1948 to October 2009). The search terms included the following: GLP-1, incretin effect, liraglutide, NN2211, exenatide, sitagliptin, and vildagliptin. Original research papers about liraglutide that were published in peer-reviewed journals were considered.. The literature search identified 39 relevant publications. The efficacy and tolerability of oncedaily liraglutide at doses of 0.6, 1.2, and 1.8 mg for type 2 DM, in combination with, and compared with, other type 2 DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program. In the LEAD studies, consistent reductions in glycosylated hemoglobin (HbA(1c)) of up to 1.6% were seen with liraglutide, and up to 66% of patients achieved the HbA(1c) goal of <7%. Fasting and postprandial plasma glucose levels were also consistently reduced across the LEAD trials by up to 43 mg/dL (2.4 mmol/L) and 49 mg/dL (2.7 mmol/L), respectively. Hypoglycemia was reported at a rate of 0.03 to 1.9 events per patient annually. Liraglutide significantly improved beta-cell function, as measured by homeostasis model assessment for beta-cell function analysis (20%-44%) and by ratios of pro-insulin to insulin (-0.11 to 0.01). Consistent reductions in systolic blood pressure up to 6.7 mm Hg were also observed for liraglutide treatment. Liraglutide treatment, as monotherapy and in combination with oral antidiabetic drugs (OADs), was associated with weight loss of up to 3.24 kg. Overall, liraglutide was well tolerated. Nausea was the most common adverse event observed with liraglutide treatment, reported by 5% to 29% of patients; however, nausea was generally mild and transient.. Once-daily liraglutide was effective and well tolerated when used as monotherapy or in combination with OADs in patients with type 2 DM, and is therefore a promising new treatment option for the management of type 2 DM.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Liraglutide; Risk Factors

The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inhibitors reduce elevated A1C, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. Collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with T2DM.

Topics: Adamantane; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fasting; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Nitriles; Peptides; Postprandial Period; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Glucagon-like peptide-1 (GLP-1), a gastrointestinal hormone mainly produced in the post-prandial state, reduces blood glucose through the stimulation of insulin secretion and the inhibition of glucagon release. Long-acting GLP-1 receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors which increase GLP-1 levels, are used as hypoglycemic treatments in type 2 diabetes. This paper aims at reviewing the potential benefit of those treatments in the prevention of cardiovascular risk in type 2 diabetic patients.. Experimental studies have shown that GLP-1 has several potentially beneficial actions on cardiovascular risk. Some of those, such as protection from myocardial ischemic damage and improvement of cardiac function, have also been demonstrated in humans. However, the equivalence of GLP-1 agonists and DPP-4 inhibitors with GLP-1, with respect to cardiovascular risk profile, cannot be assumed or taken for granted. Drugs of those two classes have been shown to effectively reduce glycated hemoglobin and to have a specific effect on post-prandial glucose; furthermore, they seem to reduce blood pressure and to have some favorable effects on lipid profiles. Additionally, GLP-1 agonists induce weight loss in diabetic patients.. The profile of action of GLP-1 receptor agonists and DPP-4 inhibitors suggests the possibility of an actual reduction in cardiovascular risk, which needs to be confirmed by large long-term clinical trials.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Rate; Humans; Incretins; Insulin Resistance; Myocardial Contraction; Myocardial Ischemia; Risk Factors

This paper briefly reviews the concept of incretins and describes the biological effects of the two incretins identified so far: the glucose-dependent insulinotropic polypeptide (GIP); and the glucagon-like peptide-1 (GLP-1). GIP is released by the Kcells of the duodenum, while GLP-1 is released by the Lcells of the distal ileum, in response to nutrient absorption. GIP and GLP-1 stimulate insulin biosynthesis and insulin secretion in a glucose-dependent manner. In addition, they increase beta-cell mass. GIP has a specific effect on adipose tissue to facilitate the efficient disposal of absorbed fat and, thus, may be involved in the development of obesity. GLP-1 has specific effects on pancreatic alpha cells, the hypothalamus, and gastrointestinal and cardiovascular systems. By inhibiting glucagon secretion and delaying gastric-emptying, GLP-1 plays an important role in glucose homoeostasis and, by inhibiting food intake, prevents the increase in body weight. As the metabolic effects of GIP are blunted in type 2 diabetes, this peptide cannot be used as an efficient therapy for diabetes. In contrast, GLP-1 effects are preserved at high concentrations in type 2 diabetes, making this peptide of great interest for the treatment of diabetes, a topic that will be discussed in the second part of this review.

Topics: Adipose Tissue; Body Weight; Diabetes Mellitus, Type 2; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Overweight; Receptors, Glucagon

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

Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet.. To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin.. Review of Phase III clinical trials based on Medline search published up to April 2008.. The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 - 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost.. Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.

Topics: Adamantane; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Nausea; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Vomiting

To review data from clinical trials of incretin mimetics in patients with type 2 diabetes.. Incretin mimetics are a new class of antidiabetic medication that mimic the actions of the hormone glucagon-like peptide-1. They exhibit several properties, including glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and induction of satiety, which result in improvements in glycemic control with weight loss in patients with type 2 diabetes. Recent 2-year data with exenatide, the only commercially available incretin mimetic, have demonstrated long-term sustained reductions in hemoglobin A1c with progressive weight loss. Glycemic and weight benefits were also recently reported in a 15-week study assessing once-weekly administration of long-acting release exenatide, a formulation currently in phase 3 of clinical development. Once-daily administration of liraglutide, also in phase 3 of development, has recently been shown to improve glycemic and weigh control as monotherapy, and in combination with metformin. The most common side effects of incretin mimetics are gastrointestinal in nature, particularly nausea.. The ability of incretin mimetics to improve glycemic control and reduce body weight is a unique property that fills an important void in the treatment of patients with type 2 diabetes.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Molecular Mimicry; Peptides; Venoms

Glucagon-like peptide-1 (GLP-1)-based therapy is a novel treatment for type 2 diabetes. It is executed either by GLP-1 mimetics or by dipeptidyl peptidase-IV inhibitors. In type 2 diabetes, the two strategies reduce hemoglobin A(1c) by 0.6% to 1.1% from baseline levels of 7.7% to 8.5%. They are efficient both in monotherapy and in combination with metformin or thiazolidinediones. Both treatments are well tolerated with low risk of hypoglycemia.

Topics: Adamantane; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Islets of Langerhans; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP-1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and HDL cholesterol from baseline to week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (-0.70%; paired t test, P < .001). Significant changes were also observed in FPG (-34.7 mg/dL), body weight (-4.46%), SBP (-7.90 mm Hg), and HDL cholesterol (7.60%; all P < .001). The incidence of AEs, adverse drug reactions and hypoglycaemia was 71.8%, 32.4% and 9.9%, respectively. All hypoglycaemic events were mild. These findings suggest that the long-term combination of canagliflozin with a GLP-1RA is effective and well tolerated in Japanese patients with T2DM.

Topics: Aged; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Cholesterol, HDL; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Incretins; Japan; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM).. LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.. LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.. Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.

Topics: Adult; Animals; Appetite; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diarrhea; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Male; Mice; Mice, Inbred C57BL; Middle Aged; Receptors, Gastrointestinal Hormone; Vomiting

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

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

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

Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes.. One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months.. Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide.. Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Female; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Peptides; Proinsulin; Resistin; Retinol-Binding Proteins, Plasma; Venoms; Young Adult

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

Long-term sleep deprivation (SD) is a bad lifestyle habit, especially among specific occupational practitioners, characterized by circadian rhythm misalignment and abnormal sleep/wake cycles. SD is closely associated with an increased risk of metabolic disturbance, particularly obesity and insulin resistance. The incretin hormone, glucagon-like peptide-1 (GLP-1), is a critical insulin release determinant secreted by the intestinal L-cell upon food intake. Besides, the gut microbiota participates in metabolic homeostasis and regulates GLP-1 release in a circadian rhythm manner. As a commonly recognized intestinal probiotic,

Topics: Animals; Bifidobacterium; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Circadian Rhythm; Dietary Supplements; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Incretins; Insulin; Insulin Resistance; Macaca mulatta; Male; Sleep Deprivation; Treatment Outcome; Triglycerides

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates beta cell function and improves glycemia through its incretin actions. GIP also regulates endothelial function and suppresses adipose tissue inflammation through control of macrophage activity. Activation of the GIP receptor (GIPR) attenuates experimental atherosclerosis and inflammation in mice, however whether loss of GIPR signaling impacts the development of atherosclerosis is uncertain.. Atherosclerosis and related metabolic phenotypes were studied in Apoe. Body weight was lower, circulating myeloid cells were reduced, and glucose tolerance was not different, however, aortic atherosclerosis was increased in Apoe. Loss of the Gipr in mice results in increased aortic atherosclerosis and enhanced inflammation in aorta and liver, despite reduced weight gain and preserved glucose homeostasis. These findings extend concepts of GIPR in the suppression of inflammation-related pathophysiology beyond its classical incretin role in the control of metabolism.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Body Weight; Gastric Inhibitory Polypeptide; Incretins; Inflammation; Mice; Proprotein Convertase 9; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; RNA, Messenger

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: Animals; Blood Glucose; Body Weight; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Fish Proteins; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Incretins; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Lampreys; Mice; Receptors, Glucagon

According to the data, there are 387 million people with diabetes in the world, and the number of people with diabetes is expected to reach 600 million by 2035 (Nature Reviews Endocrinology, 14, 2018, Zheng et al.). At present, there are nearly 110 million diabetic patients in China, the incidence of which is increasing (Diabetologia, 61, 2018, Ma). Islet β cell apoptosis and proliferation is an important basis for the occurrence and development of diabetes. It has been reported that enhancing the activity of incretin-cAMP signaling pathway can also promote islet β cell proliferation, reduce β cell apoptosis and promote insulin secretion (Diabetologia, 59, 2016, Iida et al.). Tibetan medicine Triphala (THL) is a traditional national medicine, it plays a good role in anti-fatigue, antioxidation, prevention and treatment of polycythemia at high altitude. Research have shown that it can reduce blood glucose in patients with diabetes and inhibit the activity of glucosidase in the intestines (The Journal of Alternative and Complementary Medicine, 23, 2017, Peterson et al.). After the diabetic Wistar rat model induced by Streptozocin (STZ) was successfully duplicated, the positive drug sitagliptin tablet and THL were given and the changes of body weight and blood glucose were measured. After 6 weeks, the expression of related factors in serum and pancreas was observed. Compared with the model group, in the treatment group, blood glucose decreased, body weight increased, incretin-cAMP signaling pathway related factors glucose-dependent insulin-promoting polypeptide (GIP), glucagon-like peptide-1 (GLP-1), GLP-1R, cAMP, P-protein kinase A (PKA), AKT were up-regulated, insulin secretion was increased, liporing protein interaction protein (TXNIP) expression was down-regulated. In addition, in the treatment group, the degree of islet atrophy was alleviated and the number of islet β cells increased. This study shows that THL may enhance the activity of incretin-cAMP signal pathway and affect the proliferation and apoptosis of islet β cells, so as to achieve the effect of anti-diabetes.

Topics: Animals; Apoptosis; Body Weight; Cell Cycle Proteins; Cell Proliferation; Cyclic AMP-Dependent Protein Kinases; Glucagon-Like Peptide 1; Incretins; Insulin; Insulin-Secreting Cells; Male; Pancreas; Plant Extracts; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Sitagliptin Phosphate

The role of exendin-4 in brown adipose tissue (BAT) activation was not very clear. This study is to verify the role of BAT involved in renal benefits of exendin-4 in diabetes mellitus (DM).. In vivo, C57BL/6 mice were randomly divided into nondiabetic (control) and diabetic groups (DM). The diabetic mice were randomized into a control group (DM-Con), BAT-excision group (DM+Exc), exendin-4-treated group (DM+E4), and BAT-excision plus exendin-4-treated group (DM+Exc+E4). The weight, blood glucose and lipids, 24 h urine albumin and 8-OH-dG, and renal fibrosis were analyzed. In vitro, we investigated the role of exendin-4 in the differentiation process of 3T3-L1 and brown preadipocytes and its effect on the rat mesangial cells induced by oleate.. The expressions of UCP-1, PGC-1. Exendin-4 could decrease the renal lipid deposit and improve diabetic nephropathy via activating the renal AMPK pathway independent of BAT activation.

Topics: 3T3-L1 Cells; 8-Hydroxy-2'-Deoxyguanosine; Adenylate Kinase; Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Albuminuria; Animals; Blood Glucose; Blotting, Western; Body Weight; CD36 Antigens; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Exenatide; Fibrosis; Gene Expression; Incretins; Kidney; Lipase; Mesangial Cells; Mice; Mice, Inbred C57BL; Myofibroblasts; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Rats; Real-Time Polymerase Chain Reaction; Triglycerides; Uncoupling Protein 1

To describe glucose metabolism in the late, weight stable phase after Roux-en-Y Gastric Bypass (RYGB) in patients with and without preoperative type 2 diabetes we invited 55 RYGB-operated persons from two existing cohorts to participate in a late follow-up study. 44 (24 with normal glucose tolerance (NGT)/20 with type 2 diabetes (T2D) before surgery) accepted the invitation (median follow-up 2.7 [Range 2.2-5.0 years]). Subjects were examined during an oral glucose stimulus and results compared to preoperative and 1-year (1 y) post RYGB results. Glucose tolerance, insulin resistance, beta-cell function and incretin hormone secretion were evaluated. 1 y weight loss was maintained late after surgery. Glycemic control, insulin resistance, beta-cell function and GLP-1 remained improved late after surgery in both groups. In NGT subjects, nadir glucose decreased 1 y after RYGB, but did not change further. In T2D patients, relative change in weight from 1 y to late after RYGB correlated with relative change in fasting glucose and HbA1c, whereas relative changes in glucose-stimulated insulin release correlated inversely with relative changes in postprandial glucose excursions. In NGT subjects, relative changes in postprandial nadir glucose correlated with changes in beta-cell glucose sensitivity. Thus, effects of RYGB on weight and glucose metabolism are maintained late after surgery in patients with and without preoperative T2D. Weight loss and improved beta-cell function both contribute to maintenance of long-term glycemic control in patients with type 2 diabetes, and increased glucose stimulated insulin secretion may contribute to postprandial hypoglycemia in NGT subjects.

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucose; Humans; Incretins; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Weight Loss

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

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Herein, the potential of hydrolysates of chicken feet proteins as natural dipeptidyl-peptidase IV (DPP-IV) inhibitors was investigated; moreover, three hydrolysates were selected due to their high DPP-IV inhibitory capacity (>80% inhibition), showing the IC50 values of around 300 μg estimated protein per mL; one of them (named p4H) was selected for the posterior analysis. In addition, its effect on glucose tolerance was investigated in two rat models (diet and age-induced) of glucose-intolerance and healthy animals; the amount of 300 mg estimated peptide per kg body weight improved the plasma glucose profile in both glucose-intolerance models. Moreover, it stimulated active GLP-1 release in the enteroendocrine STC-1 cells and rat ileum tissue. In conclusion, our results indicate that chicken feet proteins are a good source of bioactive peptides as DPP-IV inhibitors. Moreover, our results highlight the potential of the selected hydrolysate p4H in the management of type 2 diabetes due to its dual function of inhibition of the DPP-IV activity and induction of the GLP-1 release.

Topics: Animals; Blood Glucose; Body Weight; Cell Line; Chickens; Diabetes Mellitus, Type 2; Diet; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Drug Delivery Systems; Female; Foot; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Incretins; Inhibitory Concentration 50; Male; Protein Hydrolysates; Rats; Rats, Wistar

In randomized controlled trials (RCTs), sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to confer glycaemic and extra-glycaemic benefits. The DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase-4 inhibitors, gliclazide, or glucagon-like peptide-1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose-lowering medications (GLMs), 6751 of whom had a follow-up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real-world study shows an initial channelling of dapagliflozin to difficult-to-treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs.

Topics: Aged; Benzhydryl Compounds; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Gliclazide; Glucagon-Like Peptide-1 Receptor; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Italy; Male; Middle Aged; Retrospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

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

Preservation of pancreatic beta cell function has been increasingly appealing in the treatment of type 2 diabetes. Evidence is still limited on how bariatric surgery affects pancreatic beta cell apoptosis.. University medical center.. The study aimed to investigate the effect of a major component of Roux-en-Y gastric bypass, duodenal-jejunal bypass, on protecting pancreatic beta cells from progressive loss.. Forty-five normal Sprague-Dawley rats were randomly assigned into 3 groups: duodenal-jejunal bypass (DJB) group (n = 16) and sham (S) group (n = 17), based upon the procedure received, and a control (C) group (n = 12) without any procedure performed, to eliminate potential traumatic effects from surgery. Ten days after surgery, streptozotocin (STZ, 45 mg/kg weight) was injected intraperitoneally into each animal, including the control animals, to selectively induce pancreatic beta cell apoptosis. Weight, food intake, plasma glucose level, and the results of an oral glucose tolerance test were measured before surgery, pre-STZ injection, and up to 4 weeks after STZ injection. Plasma insulin and glucagon-like peptide-1 levels were also assayed during oral glucose tolerance test. At the end, pancreatic tissues were sliced and stained for beta cell analysis.. There were no significant differences in weight among all groups at any time points measured, despite rats in the S and C groups consuming more food than those in the DJB group as measured on day 10 (P<.05) and day 20 (P<.01) after STZ injection. Animals undergoing DJB did not experience symptoms typical of uncompensated diabetes, including hyperphagia and progressive weight loss. After STZ injection, fasting plasma glucose levels in the DJB group were significantly lower than those in the C and S groups (P<.001). When challenged by glucose load, DJB rats also had a better glycemic excursion (P<.01) and incretin response compared with C and S rats (P<.05). In addition, pancreatic beta cell size and mass was better preserved in DJB rats (P< .001).. DJB is able to protect pancreatic beta cells from apoptosis, which leads to better glycemic control and delayed onset of diabetes. These results imply the necessity of including a DJB component when designing bariatric procedure to achieve a better long-term outcome.

Topics: Analysis of Variance; Anastomosis, Surgical; Animals; Apoptosis; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenum; Eating; Fasting; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Incretins; Injections, Intraperitoneal; Insulin; Islets of Langerhans; Jejunum; Male; Random Allocation; Rats, Sprague-Dawley; Streptozocin

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

Topics: Animals; Autophagy; Body Weight; Cells, Cultured; Diet; Drug Evaluation, Preclinical; Energy Intake; Exenatide; Fructose; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Male; Membrane Proteins; Microscopy, Electron; Peptides; Rats, Wistar; RNA, Messenger; Sitagliptin Phosphate; Venoms

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

This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function.. Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified using in-phase, out-of-phase MRI. Also measured were the first-phase insulin response to a stepped intravenous glucose infusion, hepatic insulin sensitivity, and glycemic and incretin responses to a semisolid test meal.. Weight loss after surgery was similar (NGT: 12.8 ± 0.8% and T2DM: 13.6 ± 0.7%) as was the change in fat mass (56.7 ± 3.3 to 45.4 ± 2.3 vs. 56.6 ± 2.4 to 43.0 ± 2.4 kg). Pancreatic triacylglycerol did not change in NGT (5.1 ± 0.2 to 5.5 ± 0.4%) but decreased in the group with T2DM (6.6 ± 0.5 to 5.4 ± 0.4%; P = 0.007). First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT (0.24 [0.13-0.46] to 0.23 [0.19-0.37] nmol ⋅ min(-1) ⋅ m(-2)) but normalized in T2DM (0.08 [-0.01 to -0.10] to 0.22 [0.07-0.30]) nmol ⋅ min(-1) ⋅ m(-2) at week 8 (P = 0.005). No differential effect of incretin secretion was observed after gastric bypass, with more rapid glucose absorption bringing about equivalently enhanced glucagon-like peptide 1 secretion in the two groups.. The fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Middle Aged; Pancreas; Randomized Controlled Trials as Topic; Triglycerides; Weight Loss

Incretin-based therapies are widely used to treat type 2 diabetes. Although hypoglycemic actions of incretins are mostly due to their insulinotropic/glucagonostatic effects, they may also influence extrapancreatic metabolism. We administered exendin-4 (Ex-4), a long-acting glucagon-like peptide receptor agonist, at low dose (0.1 nmol/kg/day) for a short period (10 days), in obese nondiabetic fa/fa Zucker rats (ZFRs). Ex-4-treated ZFRs were compared to vehicle (saline)-treated ZFRs and vehicle- and Ex-4-treated lean rats (LRs). Blood glucose levels were measured at days 0, 9, and 10. Ingested food and animal weight were recorded daily. On the day of sacrifice (d10), blood was sampled along with liver, epididymal, subcutaneous, brown adipose, and skeletal muscle tissues from animals fasted for 24 h. Plasma insulin and blood glucose levels, food intake, and body and epididymal fat weight were unchanged, but gross morphological changes were observed in insulin-sensitive tissues. The average size of hepatocytes was significantly lower in Ex-4-treated ZFRs, associated with decreased number and size of lipid droplets and 4-hydroxy-2-nonenal (HNE) staining, a marker of oxidative stress (OS). Myocytes, which were smaller in ZFRs than in LRs, were significantly enlarged and depleted of lipid droplets in Ex-4-treated ZFRs. Weak HNE staining was increased by Ex-4. A similar observation was made in brown adipose tissue, whereas the elevated HNE staining observed in epididymal adipocytes of ZFRs, suggestive of strong OS, was decreased by Ex-4. These results suggest that incretins by acting on OS in insulin-sensitive tissues may contribute to weight-independent improvement in insulin sensitivity.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Exenatide; Hepatocytes; Incretins; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Organ Size; Organ Specificity; Oxidative Stress; Peptides; Rats; Rats, Zucker; Venoms

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

FGF21 is a hormonal factor with important functions in the control of metabolism. FGF21 is found in rodent and human milk. Radiolabeled FGF21 administered to lactating dams accumulates in milk and is transferred to neonatal gut. The small intestine of neonatal (but not adult) mice highly expresses β-Klotho in the luminal area. FGF21-KO pups fed by FGF21-KO dams showed decreased expression and circulating levels of incretins (GIP and GLP-1), reduced gene expression of intestinal lactase and maltase-glucoamylase, and low levels of galactose in plasma, all associated with a mild decrease in body weight. When FGF21-KO pups were nursed by wild-type dams (expressing FGF21 in milk), intestinal peptides and digestive enzymes were up-regulated, lactase enzymatic activity was induced, and galactose levels and body weight were normalized. Neonatal intestine explants were sensitive to FGF21, as evidenced by enhanced ERK1/2 phosphorylation. Oral infusion of FGF21 into neonatal pups induced expression of intestinal hormone factors and digestive enzymes, lactase activity and lactose absorption. These findings reveal a novel role of FGF21 as a hormonal factor contributing to neonatal intestinal function via its presence in maternal milk. Appropriate signaling of FGF21 to neonate is necessary to ensure optimal digestive and endocrine function in developing intestine.

Topics: Administration, Oral; Animals; Animals, Newborn; Body Weight; Female; Fibroblast Growth Factors; Galactose; Gene Expression Regulation, Developmental; Glucuronidase; Hormones; Humans; Incretins; Intestinal Absorption; Intestinal Mucosa; Intestines; Klotho Proteins; Lactase; Lactation; Mice, Knockout; Milk; Milk, Human; Models, Biological; Rats

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

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

Folk medicine stories accredited the aptitude of camel milk (CMK) as a hypoglycemic agent and recent studies have confirmed this in the diabetic patients and experimental animals. However, the mechanism(s) by which CMK influences glucose homeostasis is yet unclear. The current study investigated the changes in the glucose homeostatic parameters, the incretin hormones, and the inflammatory cytokines in the CMK-treated diabetic animals. A model of type 2 diabetes mellitus was induced in rats by intraperitoneal injection of streptozotocin 40 mg/kg/day for 4 repeated doses. Camel milk treatment was administered for 8 weeks. The changes in glucagon like peptide-1 (GLP-1), glucose dependent insulinotropic peptide (GIP), glucose tolerance, fasting and glucose-stimulated insulin secretion, insulin resistance (IR), TNF-α, TGF-β1, lipid profile, atherogenic index (AI), and body weight were investigated. The untreated diabetic animals showed hyperglycemia, increased HOMA-IR, hyperlipidemia, elevated AI, high serum incretins [GLP-1 and GIP], TNF-α, and TGF-β1 levels and weight loss as compared with the control group. Camel milk treatment to the diabetic animals resulted in significant lowered fasting glucose level, hypolipidemia, decreased HOMA-IR, recovery of insulin secretion, weight gain, and no mortality during the study. Additionally, CMK inhibits the diabetes-induced elevation in incretin hormones, TNF-α and TGF-β1 levels. The increase in glucose-stimulated insulin secretion, decreased HOMA-IR, modulation of the secretion and/or the action of incretins, and the anti-inflammatory effect are anticipated mechanisms to the antidiabetic effect of CMK and suggest it as a valuable adjuvant antidiabetic therapy.

Topics: Animals; Atherosclerosis; Blood Glucose; Body Weight; Camelus; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fasting; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Incretins; Inflammation Mediators; Insulin; Insulin Resistance; Lipids; Male; Milk; Rats, Wistar; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are widely used in combinations with metformin in the treatment of type 2 diabetes; however, data on long-term safety compared with conventional combination therapies are limited.. Danish individuals without prior myocardial infarction or stroke that initiated combinations of metformin with sulphonylurea (SU), DPP-4 inhibitors, GLP-1 agonists or insulin between 9 May 2007 and 31 December 2011 were followed up for the risk of all-cause mortality, cardiovascular (CV) mortality or a combined end point of myocardial infarction, stroke and CV mortality. Rate ratios (RR) were calculated using time-dependent multivariable Poisson regression analysis.. A total of 40 028 patients (59% men, mean age 60 ± 13 years) used metformin with SU (n = 25 092), DPP-4 inhibitor (n = 11 138), GLP-1 agonist (n = 4345) or insulin (n = 6858). Crude incidence rates per 1000 patient years for the combined end point were 18 (SU), 10 (DPP-4 inhibitor), 8 (GLP-1 agonist) and 21 (insulin). In adjusted analyses with metformin + SU as reference, metformin + DPP-4 inhibitor was associated with an RR of 0.65 (0.54-0.80) for mortality, an RR of 0.57 (0.40-0.80) for CV mortality and an RR of 0.70 (0.57-0.85) for the combined end point. For metformin + GLP-1 agonist, the RR for mortality was 0.77 (0.51-1.17), for CV mortality 0.89 (0.47-1.68), and for the combined end point 0.82 (0.55-1.21).. Incretin-based drugs combined with metformin were safe compared with conventional combinations of glucose-lowering therapy. Use of incretin-based therapy may be target for strategies to lower CV risk in type 2 diabetes, although it should be recognized that the multivariable analysis may not have fully accounted for important baseline differences.

Topics: Blood Glucose; Body Weight; Denmark; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Incretins; Male; Metformin; Middle Aged; Myocardial Infarction; Retrospective Studies; Stroke; Sulfonylurea Compounds; Treatment Outcome

Diabetes is a huge burden in China, where about 100 million people have been diagnosed with the disease. Treatments are needed that are optimal for treating Chinese patients with diabetes. Chinese patients with type 2 diabetes are characterised by having relatively low bodyweight and significant β-cell deterioration. β-cell failure results in deficiency of insulin secretion, particularly at the early phase of insulin secretion in Chinese patients. As a result, postprandial hyperglycaemia is more pronounced in Chinese patients with early type 2 diabetes than most other ethnic groups. These characteristics point to the key strategies when considering early therapy for Chinese patients with type 2 diabetes, including control of postprandial hyperglycaemia and β-cell preservation. Besides metformin, insulin secretagogues and α-glucosidase inhibitors that target postprandial hyperglycaemia are recommended for drug-naive patients. Short-term intensive insulin therapy is suggested for patients with severe hyperglycaemia at diagnosis to help restore β-cell function. Use of incretin-based drugs is also recommended when treatment fails with metformin, insulin secretagogues, and α-glucosidase inhibitors. Although data on antidiabetic drugs in Chinese patients are growing, there are still gaps in the evidence base. Research is needed to strengthen the evidence-based treatment guidelines for Chinese patients with type 2 diabetes.

Topics: Asian People; Body Weight; China; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Time Factors

It is believed that oxidative stress plays a role in the pathogenesis of diabetes mellitus. Several strategies have been developed with the objective of minimizing diabetic complications. Among these, inhibitors of dipeptidyl peptidase-IV (DPP-IV), which act by blocking degradation of incretin hormones, glucagon-like peptide hormone (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have been the focus of many studies. It is known that, among the effects of incretins, we highlight its insulinotropic and cytoprotective effects on pancreatic β-cells. The objective of this study was to evaluate the possible protective effects of treatment with vildagliptin, a DPP-IV inhibitor, in β-cells in an experimental model of type 1 diabetes induced by streptozotocin (STZ).. Rats were treated for 4 weeks with vildagliptin at concentrations of 5 and 10 mg/kg. In order to observe the pancreatic damage and the possible protective effects of vildagliptin treatment, we measured stress markers TBARS and protein carbonyl, antioxidant enzymes SOD and catalase, and analyzed pancreatic histology.. The treatment was effective in modulating stress in pancreatic tissue, both by reducing levels of stress markers as well as by increasing activity of SOD and catalase. After analyzing the pancreatic histology, we found that vildagliptin was also able to preserve islets and pancreatic β-cells, especially at the concentration of 5 mg/kg.. Thus, our results suggest that vildagliptin ameliorates oxidative stress and pancreatic beta cell destruction in type 1 diabetic rats. However, to evaluate the real potential of this medication in type 1 diabetes, further studies are needed.

Topics: Adamantane; Animals; Antioxidants; Biomarkers; Blood Glucose; Body Weight; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Incretins; Insulin; Insulin-Secreting Cells; Nitriles; Oxidation-Reduction; Oxidative Stress; Pyrrolidines; Rats; Streptozocin; Superoxide Dismutase; Vildagliptin

Atherosclerosis and cardiovascular events are highly prevalent and represent the major cause of mortality in patients with type 2 diabetes. Therefore, there is significant interest in the non-glycemic properties of anti-diabetic agents, particularly on those that are effective on cardiovascular risk factors. Thiazolidinediones and incretin-based therapies (IBTs) represent some of the most recent treatment options approved for the management of type 2 diabetes; these agents have shown important glycemic effects, as well as a number of non-glycemic effects. The latter include those on body weight, inflammation, hypertension and dyslipidemia, thus impacting the different components of the metabolic syndrome. Pioglitazone has been shown to significantly reduce cardiovascular adverse outcomes, while preliminary data on IBTs are very encouraging as well. Although highlighting the non-glycemic effects of pioglitazone and incretin-based therapies is of potential significance, clinical practice and patient care must be based largely on evidence-based medicine. Therefore, definitive opinions will await additional data from ongoing studies evaluating the effects of both GLP-1 agonists and DPP-4 inhibitors on cardiovascular morbidity and mortality.

Topics: Body Weight; Cardiovascular Diseases; Dyslipidemias; Humans; Hypoglycemic Agents; Incretins; Pioglitazone; Thiazolidinediones

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase circulating levels of incretin hormones, which can enhance insulin secretion and β cell function. The aim of this study was to evaluate the effectiveness of MK-626 (a novel DPP-4 inhibitor) to reduce the hyperglycemia and hyperinsulinemia of nonobese type 2 diabetic MKR mice. Twelve to 14-week-old hyperglycemic MKR mice were gavaged daily with MK-626 (3 mg/kg body weight) or vehicle (0.5% methyl cellulose (MC)) for 2 weeks. MK-626-treated mice displayed no change in body weight or adverse reactions, suggesting good tolerance of the drug. Fed blood glucose was significantly reduced over the 2-week experiment; however, it was also reduced in the MC group, suggesting an effect of gavage alone. Fed plasma insulin and glucagon levels and glucose tolerance of MK-626-treated mice were similar to those of MC mice. Therefore, treatment with MK-626 did not correct the prolonged hyperglycemia and impaired glucose tolerance of MKR mice.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucose; Glucose Intolerance; Homeostasis; Hyperglycemia; Hyperinsulinism; Incretins; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Obese; Phenylalanine; Triazoles

Dramatic improvement of type 2 diabetes is commonly observed after bariatric surgery. However, the mechanisms behind the alterations in glucose homeostasis are still elusive. We examined the effect of duodenal-jejunal bypass (DJB), which maintains the gastric volume intact while bypassing the entire duodenum and the proximal jejunum, on glycemic control, β-cell mass, islet morphology, and changes in enteroendocrine cell populations in nonobese diabetic Goto-Kakizaki (GK) rats and nondiabetic control Wistar rats. We performed DJB or sham surgery in GK and Wistar rats. Blood glucose levels and glucose tolerance were monitored, and the plasma insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) levels were measured. β-Cell area, islet fibrosis, intestinal morphology, and the density of enteroendocrine cells expressing GLP-1 and/or GIP were quantified. Improved postprandial glycemia was observed from 3 mo after DJB in diabetic GK rats, persisting until 12 mo after surgery. Compared with the sham-GK rats, the DJB-GK rats had an increased β-cell area and a decreased islet fibrosis, increased insulin secretion with increased GLP-1 secretion in response to a mixed meal, and an increased population of cells coexpressing GIP and GLP-1 in the jejunum anastomosed to the stomach. In contrast, DJB impaired glucose tolerance in nondiabetic Wistar rats. In conclusion, although DJB worsens glucose homeostasis in normal nondiabetic Wistar rats, it can prevent long-term aggravation of glucose homeostasis in diabetic GK rats in association with changes in intestinal enteroendocrine cell populations, increased GLP-1 production, and reduced β-cell deterioration.

Topics: Animals; Bariatric Surgery; Blood Glucose; Body Composition; Body Weight; Diabetes Mellitus, Type 2; Duodenum; Endocrine System; Enzyme-Linked Immunosorbent Assay; Fibrosis; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hyperglycemia; Immunohistochemistry; Incretins; Insulin-Secreting Cells; Islets of Langerhans; Jejunum; Male; Rats; Rats, Wistar

Bypass of the foregut following Roux-en-Y gastric bypass (RYGB) surgery results in altered nutrient absorption, which is proposed to underlie the improvement in glucose tolerance and insulin sensitivity. We conducted a prospective crossover study in which a mixed meal was delivered orally before RYGB (gastric) and both orally (jejunal) and by gastrostomy tube (gastric) postoperatively (1 and 6 wk) in nine subjects. Glucose, insulin, and incretin responses were measured, and whole-body insulin sensitivity was estimated with the insulin sensitivity index composite. RYGB resulted in an improved glucose, insulin, and glucagon-like peptide-1 (GLP-1) area under the curve (AUC) in the first 6 wk postoperatively (all P ≤ 0.018); there was no effect of delivery route (all P ≥ 0.632) or route × time interaction (all P ≥ 0.084). The glucose-dependent insulinotropic polypeptide (GIP) AUC was unchanged after RYGB (P = 0.819); however, GIP levels peaked earlier after RYGB with jejunal delivery. The ratio of insulin AUC to GLP-1 and GIP AUC decreased after surgery (P =.001 and 0.061, respectively) without an effect of delivery route over time (both P ≥ 0.646). Insulin sensitivity improved post-RYGB (P = 0.001) with no difference between the gastric and jejunal delivery of the mixed meal over time (P = 0.819). These data suggest that exclusion of nutrients from the foregut with RYGB does not improve glucose tolerance or insulin sensitivity. However, changes in the foregut response post-RYGB due to lack of nutrient exposure cannot be excluded. Our findings suggest that foregut bypass may alter the incretin response by enhanced nutrient delivery to the hindgut.

Topics: Adult; Anastomosis, Roux-en-Y; Area Under Curve; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Duodenum; Female; Food; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Jejunum; Laparoscopy; Male; Metabolism; Middle Aged

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

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists-which can be dosed to pharmacologic levels-act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%-1.7%) compared with DPP-4 inhibitors (0.4%-1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Hypersensitivity; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Pancreatitis; Peptides; Receptors, Glucagon; Venoms

We present a collection case report performed in 29 inadequately controlled diabetic and obese outpatients. The aim of this study was to verify metabolic effects of liraglutide in combination with other antidiabetic drugs. Across this study, liraglutide effectively and rapidly improves glycemic control (both fasting glycemia and HbAlc), body weight and systolic blood pressure, thus promoting the achievement of therapeutic targets proposed by the American Diabetes Association and European Association for the study of Diabetes and reducing cardiovascular risk profile of diabetic patients. (www.actabiomedica.it).

Topics: Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Middle Aged

The loss of incretin effect in patients with type 2 diabetes mellitus may be secondary to impaired glucose homeostasis. We investigated whether reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet in healthy young males would impair the incretin effect.. The incretin effect was measured using 75 g oral glucose tolerance test (OGTT) and isoglycemic iv glucose infusion (IIGI) in 10 healthy Caucasian normal glucose-tolerant male subjects without any family history of diabetes [age 24 + or - 3 yr (mean + or - sd); body mass index 23 + or - 2 kg/m(2); glycosylated hemoglobin 5.4 + or - 0.1%] before and at the end of a 12-d period with oral administration of prednisolone (37.5 mg once daily), high-calorie diet, and relative physical inactivity.. The 12-d intervention period resulted in significant increases in body weight [79 + or - 5 vs. 80 + or - 6 kg (mean + or - sd), P = 0.03] and fasting plasma glucose (5.1 + or - 0.1 vs. 5.6 + or - 0.2 mm, P = 0.016), whereas insulin sensitivity (Matsuda index 17.6 + or - 1.7 vs. 9.2 + or - 1.0, P = 0.0001) decreased. Glucose tolerance [as assessed by the 120-min plasma glucose value after OGTT (4.9 + or - 1.1 vs. 7.8 + or - 2.5 mm, P < 0.0001) and area under curve (AUC) (152 + or - 45 vs. 384 + or - 53 mm.4 h, P = 0.002)] during the OGTT deteriorated. Also, the incretin effect [incretin effect (percent) = 100% x (AUC(insulin,OGTT) - AUC(insulin,IIGI))/AUC(insulin,OGTT))] deteriorated (72 + or - 5 vs. 43 + or - 7%, P = 0.002). An increase in glucose-dependent insulinotropic polypeptide response during OGTT, but no significant changes in glucagon-like peptide-1 or glucagon responses, was observed after glucose homeostatic dysregulation.. Impairment of the incretin effect can be elicited by a short period of reduced glucose tolerance and insulin resistance in healthy male subjects not disposed for type 2 diabetes.

Topics: Adult; Area Under Curve; Blood Glucose; Body Weight; C-Peptide; Diet; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Male; Motor Activity; Prednisolone

In older populations there is significant increase in incidence of impaired glucose tolerance and diabetes. Glucose-dependent insulinotropic polypeptide (GIP) improves glycemic control but its use as a therapeutic is hindered by short biological half-life. The present study examined effects of a longer-acting form of GIP, GIP[mPEG], on glucose homeostasis and beta-cell function in mice with age-related glucose intolerance. GIP[mPEG] decreased glucose and increased insulin concentrations when administered prior to a glucose challenge. Daily administration of GIP[mPEG] for 20 days had no effect on body weight and food intake. However, non-fasting glucose concentrations were decreased and insulin concentrations increased. Glycemic response to intraperitoneal glucose was improved and glucose-mediated insulin secretion enhanced. Insulin sensitivity, circulating triglycerides and resistin levels were unchanged by the treatment regimen, but plasma adiponectin levels increased. These data indicate that prolonged activation of the GIP receptor with GIP[mPEG] counters aspects of impaired beta-cell function and age-related glucose intolerance.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Eating; Gastric Inhibitory Polypeptide; Glucose Intolerance; Incretins; Insulin-Secreting Cells; Male; Mice; Polyethylene Glycols; Receptors, Gastrointestinal Hormone; Resistin; Triglycerides

We examined whether chronic administration of a glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (Ex-4), a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist D-Ala(2)-GIP (DA-GIP), or a dipeptidyl peptidase-4 (DPP-4) inhibitor (DPP-4i) des-fluoro-sitagliptin produced comparable antidiabetic actions in high fat-fed mice.. High fat-fed mice were administered twice-daily injections of Ex-4, DA-GIP, vehicle (saline), or vehicle with the addition of des-fluoro-sitagliptin (DPP-4i) in food to produce sustained inhibition of DPP-4 activity.. Mice treated with vehicle alone or DA-GIP exhibited progressive weight gain, whereas treatment with Ex-4 or DPP-4i prevented weight gain. Although Ex-4 improved oral glucose tolerance and insulin-to-glucose ratios after an intraperitoneal glucose tolerance test (IPGTT), DPP-4i had no significant effect after IPGTT but improved glucose excursion and insulin levels after an oral glucose tolerance test. The extent of improvement in glycemic control was more sustained with continuous DPP-4 inhibition, as evidenced by loss of glucose control evident 9 h after peptide administration and a significant reduction in A1C observed with DPP-4i but not with DA-GIP or Ex-4 therapy. DA-GIP, but not Ex-4 or DPP-4i, was associated with impairment in insulin sensitivity and increased levels of plasma leptin and resistin. Although none of the therapies increased beta-cell mass, only Ex-4-treated mice exhibited increased pancreatic mRNA transcripts for Irs2, Egfr, and Gck. These findings highlight significant differences between pharmacological administration of incretin receptor agonists and potentiation of endogenous GLP-1 and GIP via DPP-4 inhibition.

Topics: Animals; Blood Glucose; Body Weight; Calorimetry, Indirect; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Energy Intake; Exenatide; Hypoglycemic Agents; Incretins; Insulin; Mice; Mice, Inbred C57BL; Motor Activity; Peptides; Receptors, Gastrointestinal Hormone; Venoms

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 impact of strategies for prevention of type 2 diabetes in isolated impaired fasting glycaemia (i-IFG) vs isolated impaired glucose tolerance (i-IGT) may differ depending on the underlying pathophysiology. We examined insulin secretion during OGTTs and IVGTTs, hepatic and peripheral insulin action, and glucagon and incretin hormone secretion in individuals with i-IFG (n = 18), i-IGT (n = 28) and normal glucose tolerance (NGT, n = 20).. Glucose tolerance status was confirmed by a repeated OGTT, during which circulating insulin, glucagon, glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) levels were measured. A euglycaemic-hyperinsulinaemic clamp with [3-3H]glucose preceded by an IVGTT was performed.. Absolute first-phase insulin secretion during IVGTT was decreased in i-IFG (p = 0.026), but not in i-IGT (p = 0.892) compared with NGT. Hepatic insulin sensitivity was normal in i-IFG and i-IGT individuals (p > or = 0.179). Individuals with i-IGT had peripheral insulin resistance (p = 0.003 vs NGT), and consequently the disposition index (DI; insulin secretion x insulin sensitivity) during IVGTT (DI(IVGTT))) was reduced in both i-IFG and i-IGT (p < 0.005 vs NGT). In contrast, the DI during OGTT (DI(OGTT)) was decreased only in i-IGT (p < 0.001), but not in i-IFG (p = 0.143) compared with NGT. Decreased levels of GIP in i-IGT (p = 0.045 vs NGT) vs increased levels of GLP-1 in i-IFG (p = 0.013 vs NGT) during the OGTT may partially explain these discrepancies. Basal and post-load glucagon levels were significantly increased in both i-IFG and i-IGT individuals (p < or = 0.001 vs NGT).. We propose that differentiated preventive initiatives in prediabetic individuals should be tested, targeting the specific underlying metabolic defects.

Topics: Blood Glucose; Body Composition; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Gastric Inhibitory Polypeptide; Glucagon-Secreting Cells; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin-Secreting Cells; Myocardial Ischemia; Prediabetic State

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