Weight loss and incretin responsiveness improve glucose control independently after gastric bypass surgery

Background: The aim of the present study was to determine the mechanisms underlying Type 2 diabetes remission after gastric bypass (GBP) surgery by characterizing the short‐ and long‐term changes in hormonal determinants of blood glucose. Methods: Eleven morbidly obese women with diabetes were studied before and 1, 6, and 12 months after GBP; eight non‐diabetic morbidly obese women were used as controls. The incretin effect was measured as the difference in insulin levels in response to oral glucose and to an isoglycemic intravenous challenge. Outcome measures were glucose, insulin, C‐peptide, proinsulin, amylin, glucagon, glucose‐dependent insulinotropic polypeptide (GIP), glucagon‐like peptide‐1 (GLP‐1) levels and the incretin effect on insulin secretion. Results: The decrease in fasting glucose (r = 0.724) and insulin (r = 0.576) was associated with weight loss up to 12 months after GBP. In contrast, the blunted incretin effect (calculated at 22%) that improved at 1 month remained unchanged with further weight loss at 6 (52%) and 12 (52%) months. The blunted incretin (GLP‐1 and GIP) levels, early phase insulin secretion, and other parameters of β‐cell function (amylin, proinsulin/insulin) followed the same pattern, with rapid improvement at 1 month that remained unchanged at 1 year. Conclusions: The data suggest that weight loss and incretins may contribute independently to improved glucose levels in the first year after GBP surgery.     

Dissociated incretin hormone response to protein versus fat ingestion in obese subjects

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

Incretins and other peptides in the treatment of diabetes.

Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone, released postprandially,which stimulates insulin secretion and insulin gene expression as well as pancreatic B-cell growth. Together with glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect which is the augmentation of insulin secretion following oral administration of glucose. Patients with Type 2 diabetes have greatly impaired or absent incretin-mediated insulin secretion which is mainly as a result of decreased secretion of GLP-1. However,the insulinotropic action of GLP-1 is preserved in patients with Type 2 diabetes,and this has encouraged attempts to treat Type 2 diabetic patients with GLP-1.GLP-1 also possesses a number of potential advantages over existing agents for the treatment of Type 2 diabetes. In addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion,delays gastric emptying and inhibits food intake. Continuous intravenous and subcutaneous administration significantly improves glycaemic control and causes reductions in both HbA1c and body weight. However, GLP-1 is metabolized extremely rapidly in the circulation by the enzyme dipeptidyl peptidase IV(DPP-IV). This is the probable explanation for the short-lived effect of single doses of native GLP-1, making it an unlikely glucose-lowering agent. The DPP-IV resistant analogue, exenatide, has Food and Drug Administration (FDA) approval for the treatment of Type 2 diabetes and selective DPP-IV inhibitors are underdevelopment. Both approaches have demonstrated remarkable efficacy in animal models and human clinical studies. Both are well tolerated and appear to have advantages over current therapies for Type 2 diabetes, particularly in terms of the effects on pancreatic B-cell restoration and potential weight loss.     

Twelve weeks treatment with the DPP‐4 inhibitor,sitagliptin, prevents degradation of peptide YY and improves glucose and non‐glucose induced insulin secretion in patients with type 2 diabetes mellitus

Aim: To examine the effects of 12 weeks of treatment with the DPP‐4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non‐glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes. Method: A double‐blinded, placebo‐controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add‐on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90‐min 20 mM hyperglycaemic clamp with 5 g of l ‐arginine infusion. Main outcome measure was postprandial total glucagon‐like peptide 1 (GLP‐1) concentration. Additional measures were insulin and C‐peptide, glycaemic control, intact and total peptide YY (PYY) and glucose‐dependent insulinotropic polypeptide (GIP), and intact glucagon‐like peptide 2 (GLP‐2) and GLP‐1. Results: All patients [sitagliptin n = 12, age: 59.5 (39–64) years, HbA1c: 8.0 (7.3–10.0)%, BMI: 33.2 (29.3–39.4); placebo n = 12, age: 60 (31–72) years, HbA1c: 7.7 (7.1–9.8)%, BMI: 30.7 (25.7–40.5)] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP‐1, GIP or intact GLP‐2, but reduced total PYY and PYY_{3‐ 36}, and increased PYY_{1‐ 36} and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group. Conclusion: The postprandial responses of total GLP‐1 and GIP and intact GLP‐2 were unaltered. PYY degradation was prevented. Glucose and non‐glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment.     

Evolution of pharmacological obesity treatments: focus on adverse side‐effect profiles

Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity‐associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g. flenfluramine‐induced valvopathy, stroke [phenylpropanolamine (PPA)], excess non‐fatal cardiovascular events (sibutramine), and neuro‐psychiatric issues (rimonabant; approved in Europe, but not in the USA). This negative experience has helped mould the current drug development and approval process for new anti‐obesity drugs. Differences between the US Food and Drug Administration (FDA) and the European Medicines Agency, however, in perceptions of risk–benefit considerations for individual drugs have resulted in discrepancies in approval and/or withdrawal of weight‐reducing medications. Thus, two drugs recently approved by the FDA, i.e. lorcaserin and phentermine + topiramate extended release, are not available in Europe. In contrast, naltrexone sustained release (SR)/bupropion SR received FDA approval, and liraglutide 3.0 mg was recently approved in both the USA and Europe. Regulatory strategies adopted by the FDA to manage the potential for uncommon but potentially serious post‐marketing toxicity include: (i) risk evaluation and mitigation strategy programmes; (ii) stipulating post‐marketing safety trials; (iii) considering responder rates and limiting cumulative exposure by discontinuation if weight loss is not attained within a reasonable timeframe; and (iv) requiring large cardiovascular outcome trials before or after approval. We chronicle the adverse effects of anti‐obesity pharmacotherapy and consider how the history of high‐profile toxicity issues has shaped the current regulatory landscape for new and future weight‐reducing drugs.     

Phenotyping of type 2 diabetes mellitus at onset on the basis of fasting incretin tone: Results of a two‐step cluster analysis

Aims/Introduction

According to some authors, in type 2 diabetes there is a reduced postprandial action of glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP). However, little is known about the role of fasting incretins in glucose homeostasis. Our aim was to evaluate, through a two‐step cluster analysis, the possibility of phenotyping patients with type 2 diabetes at onset on the basis of fasting GLP‐1, GIP and ghrelin.

Materials and Methods

A total of 96 patients with type 2 diabetes within 6 months of onset (mean age 62.40 ± 6.36 years) were cross‐sectionally studied. Clinical, anthropometric and metabolic parameters were evaluated. At fasting the following were carried out: assay of GLP‐1, GIP, ghrelin, insulin, C‐peptide, glucagon and a panel of adipocytokines (visfatin, resistin, leptin, soluble leptin receptor and adiponectin).

Results

The analysis resulted in two clusters: cluster 1 (63 patients) had significantly lower levels of GLP‐1 (4.93 ± 0.98 vs 7.81 ± 1.98 pmol/L; P < 0.001), GIP (12.73 ± 9.44 vs 23.88 ± 28.56 pmol/L; P < 0.001) and ghrelin (26.54 ± 2.94 vs 39.47 ± 9.84 pmol/L; P < 0.001) compared with cluster 2 (33 patients). Between the two clusters, no differences in age, duration of disease, sex, clinical‐anthropometric parameters, insulin sensitivity and adipocytokines were highlighted. However, cluster 1 was associated with significantly higher levels of glycated hemoglobin (7.4 ± 0.61 vs 6.68 ± 0.57%, P = 0.007), glucagon (232.02 ± 37.27 vs 183.33 ± 97.29 ng/L; P = 0.001), fasting glucose (7.85 ± 1.60 vs 6.93 ± 1.01 mmol/L; P = 0.003) and significantly lower levels of C‐peptide (0.12 ± 0.11 vs 0.20 ± 0.20 nmol/L; P = 0.017).

Conclusions

The present study suggests that fasting incretins play an important role in the pathophysiology of type 2 diabetes, which requires to further investigation.     

Current evidence for a role of GLP-1 in Roux-en-Y gastric bypass-induced remission of type 2 diabetes

Weight-reducing surgical procedures such as Roux-en-Y gastric bypass (RYGB) have proven efficient as means of decreasing excess body weight. Furthermore, some studies report that up to 80% of patients with type 2 diabetes mellitus (T2DM) undergoing RYGB experience complete remission of their T2DM. Interestingly, the majority of remissions occur almost immediately following the operation and long before significant weight loss has taken place. Following RYGB, dramatic increases in postprandial plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1) have been recorded, and the known antidiabetic effects of GLP-1 are thought to be key mediators in RYGB-induced remission of T2DM. However, the published studies on the impact of RYGB on GLP-1 secretion are few, small and often not controlled properly. Furthermore, mechanistic studies delineating the role of endogenous GLP-1 secretion in RYGB-induced remission of T2DM are lacking. This article critically evaluates the current evidence for a role of GLP-1 in RYGB-induced remission of T2DM.     

Four weeks of near‐normalization of blood glucose has no effect on postprandial GLP‐1 and GIP secretion,but augments pancreatic B‐cell responsiveness to a meal in patients with Type 2 diabetes

Objective The aim of the present study was to investigate whether 4 weeks of near‐normalization of blood glucose (BG) improves incretin hormone secretion and pancreatic B‐cell function during a mixed meal. Research design and methods Nine patients with Type 2 diabetes in poor glycaemic control [glycated haemoglobin (HbA_1c) 8.0 ± 0.4%] were investigated before and after 4 weeks of near‐normalization of BG (mean BG 6.4 ± 0.3 mmol/l) using insulin treatment. HbA_1c after insulin treatment was 6.6 ± 0.3%. For comparison, nine healthy control subjects were also studied. Postprandial glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) incremental responses were assessed during a mixed meal test. Fasting and postprandial pancreatic B‐cell function was determined from calculations of insulin secretion rates in relation to plasma glucose. Results There was no difference in IAUC_totalGLP‐1 or in IAUC_totalGIP between the two experimental days. B‐cell sensitivity to glucose (insulinogenic index) did not differ before and after insulin treatment in the fasting state (0.21 ± 0.17 vs. 0.25 ± 0.10 pmol kg^?1 min^?1/mmol l^?1), but improved significantly during the first 30 min after start of the meal (0.28 ± 0.07 vs. 0.46 ± 0.06 pmol kg^?1 min^?1/mmol l^?1) and during the following 4 h (0.34 ± 0.09 vs. 0.56 ± 0.07 pmol kg^?1 min^?1/ mmol l^?1). The B‐cell responsiveness to changes in plasma glucose, expressed as the slope of the linear relationship between the insulin secretion rate and the concomitant plasma glucose increased from 0.59 ± 0.16 to 0.94 ± 0.13 pmol kg^?1 min^?1/ mmol l^?1 (P < 0.07). Conclusions Four weeks of near‐normalization of BG had no effect on postprandial secretion of incretin hormones. Nevertheless, several parameters of meal‐induced insulin secretion improved after insulin treatment.     

The incretin system ABCs in obesity and diabetes – novel therapeutic strategies for weight loss and beyond

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

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of various nutrients to stimulate insulin secretion from pancreatic β‐cells glucose‐dependently. GIP and GLP‐1 undergo degradation by dipeptidyl peptidase‐4 (DPP‐4), and rapidly lose their biological activities. The actions of GIP and GLP‐1 are mediated by their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which are expressed in pancreatic β‐cells, as well as in various tissues and organs. A series of investigations using mice lacking GIPR and/or GLP‐1R, as well as mice lacking DPP‐4, showed involvement of GIP and GLP‐1 in divergent biological activities, some of which could have implications for preventing diabetes‐related microvascular complications (e.g., retinopathy, nephropathy and neuropathy) and macrovascular complications (e.g., coronary artery disease, peripheral artery disease and cerebrovascular disease), as well as diabetes‐related comorbidity (e.g., obesity, non‐alcoholic fatty liver disease, bone fracture and cognitive dysfunction). Furthermore, recent studies using incretin‐based drugs, such as GLP‐1 receptor agonists, which stably activate GLP‐1R signaling, and DPP‐4 inhibitors, which enhance both GLP‐1R and GIPR signaling, showed that GLP‐1 and GIP exert effects possibly linked to prevention or treatment of diabetes‐related complications and comorbidities independently of hyperglycemia. We review recent findings on the extrapancreatic effects of GIP and GLP‐1 on the heart, brain, kidney, eye and nerves, as well as in the liver, fat and several organs from the perspective of diabetes‐related complications and comorbidities.     

Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.     

Combining GLP‐1 receptor agonists with insulin: therapeutic rationales and clinical findings

Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) increase insulin release and suppress glucagon secretion in a glucose‐dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP‐1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and, compared with insulin, the antihyperglycaemic efficacy of GLP‐1RAs is limited. The combination of a GLP‐1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic potential of GLP‐1RA–insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale for using GLP‐1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined.     

Effects of incretins on blood pressure: a promising therapy for type 2 diabetes mellitus with hypertension

The prevalence of type 2 diabetes mellitus (T2DM) has increased markedly worldwide. A recent epidemiological study reported that approximately 63% of T2DM patients also have high blood pressure (>130/80 mmHg), which doubles their risk of cardiac events. Of the medications used to treat T2DM, the incretins are a group of peptides that not only regulate blood glucose effectively and moderately, but also protect patients against cardiovascular events and improve several cardiovascular parameters. Here were review data from preclinical and short- and long-term clinical studies investigating the antihypertensive effects of incretins. We also elucidate four possible mechanisms underlying the antihypertensive effects of incretins. We conclude that incretins can lower blood pressure of T2DM patients, independent of weight loss, and will surely improve the prognosis of these patients.