incretins and Glucose-Intolerance

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

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

The consumption of non-nutritive, low, or no-calorie sweeteners (LCS) is increasing globally. Previously thought to be physiologically inert, there is a growing body of evidence that LCS not only provide a sweet taste but may also elicit metabolic effects in the gastrointestinal tract. This review provides a brief overview of the chemical and receptor-binding properties and effects on chemosensation of different LCS but focuses on the extent to which LCS stimulates glucose transport, incretin and insulin secretion, and effects on glucose tolerance. Aspartame and sucralose both bind to a similar region of the sweet receptor. For sucralose, the data are contradictory regarding effects on glucose tolerance in humans and may depend on the food or beverage matrix and the duration of administration, as suggested by longer term rodent studies. For aspartame, there are fewer data. On the other hand, acesulfame-potassium (Ace-K) and saccharin have similar binding characteristics to each other but, while Ace-K may increase incretin secretion and glucose responses in humans, there are no data on saccharin except in rats, which show impaired glucose tolerance after chronic administration. Additional research, particularly of the effects of chronic consumption, is needed to provide concrete evidence for beneficial or detrimental effects of LCS on blood glucose regulation in humans.

Topics: Animals; Aspartame; Blood Glucose; Carbohydrate Metabolism; Gastrointestinal Tract; Glucose Intolerance; Humans; Incretins; Insulin; Insulin Secretion; Meta-Analysis as Topic; Models, Animal; Non-Nutritive Sweeteners; Randomized Controlled Trials as Topic; Saccharin; Sucrose; Thiazines

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

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

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

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

A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear.. The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR.. We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients.

Topics: Blood Glucose; Fatty Acids; Glucose Intolerance; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Metabolic Syndrome; Metformin; Myocardium; Prognosis; Risk Factors; Treatment Outcome

Impaired glucose tolerance (IGT) in cystic fibrosis (CF) manifests as postprandial hyperglycaemia. Pancreatic enzyme supplementation reduces the latter; restoring incretin secretion and slowing gastric emptying. We aimed to determine the acute effect of exenatide on postprandial glycaemia in young people with CF and IGT. Six participants with CF and IGT were studied on 2 days, in a double-blind randomized crossover trial. After overnight fasting, they received exenatide 2.5 mcg or placebo (0.9% saline) subcutaneously 15 minutes before a pancake meal labelled with

Topics: Adolescent; Adult; Blood Glucose; Child; Cross-Over Studies; Cystic Fibrosis; Double-Blind Method; Exenatide; Female; Gastric Emptying; Glucose Intolerance; Humans; Hyperglycemia; Incretins; Male; Postprandial Period; Young Adult

We evaluated whether patients with histologically verified nonalcoholic fatty liver disease (NAFLD) have an impaired incretin effect and hyperglucagonaemia.. Four groups matched for age, sex and body mass index were studied: (i) 10 patients with normal glucose tolerance and NAFLD; (ii) 10 patients with type 2 diabetes and NAFLD; (iii) eight patients with type 2 diabetes and no liver disease; and (iv) 10 controls. All participants underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycaemic intravenous glucose infusion (IIGI). We determined the incretin effect by relating the beta cell secretory responses during the OGTT and IIGI. Data are presented as medians (interquartile range), and the groups were compared by using the Kruskal-Wallis test.. Controls exhibited a higher incretin effect [55% (43-73%)] compared with the remaining three groups (P < 0.001): 39% (44-71%) in the nondiabetic NAFLD patients, 20% (-5-50%) in NAFLD patients with type 2 diabetes, and 2% (-8-6%) in patients with type 2 diabetes and no liver disease. We found fasting hyperglucagonaemia in NAFLD patients with [7.5 pmol L(-1) (6.8-15 pmol L(-1))] and without diabetes [7.5 pmol L(-1) (5.0-8.0 pmol L(-1))]. Fasting glucagon levels were lower but similar in patients with type 2 diabetes and no liver disease [4.5 pmol L(-1) (3.0-6.0 pmol L(-1))] and controls [3.4 pmol L(-1) (1.8-6.0 pmol L(-1) )]. All groups had similar glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide responses.. Patients with NAFLD have a reduced incretin effect and fasting hyperglucagonaemia, with the latter occurring independently of glucose (in)tolerance.

Topics: Adult; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Incretins; Insulin; Male; Middle Aged; Non-alcoholic Fatty Liver Disease

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

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

Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)₄ receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion.

Topics: Adult; Benzamides; Blood Glucose; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Gastrointestinal Tract; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Morpholines; Postprandial Period; Serotonin 5-HT4 Receptor Agonists; Up-Regulation

The aim of this study was to evaluate the separate impact of insulin resistance and impaired glucose tolerance (IGT) on the incretin effect.. Twenty-one healthy glucose-tolerant first-degree relatives of patients with type 2 diabetes underwent a 75 g OGTT, an isoglycaemic i.v. glucose test and a mixed meal to evaluate the incretin effect before and after treatment with dexamethasone to increase insulin resistance. Beta cell glucose sensitivity, beta cell index and fasting proinsulin were measured as indices of beta cell function.. After dexamethasone, ten individuals had increased insulin resistance but normal glucose tolerance (NGT), while 11 individuals with an equal increase in insulin resistance developed IGT. In the NGT and IGT groups, the incretin effects were 71 ± 3.2% and 67 ± 4.6% (p = 0.4) before treatment, but decreased significantly in both groups to 58 ± 5.2% and 32 ± 8.8% (p < 0.05 between groups) after treatment. Dexamethasone increased total glucagon-like peptide-1 and glucose-dependent insulinotropic peptide responses to the OGTT. The impaired incretin effect in NGT was observed in the absence of reductions in beta cell glucose sensitivity and beta cell index during i.v. glucose, corrected for insulin resistance, but in parallel with increased proinsulin/C-peptide ratio.. Insulin resistance and IGT, representing two stages in the path towards diabetes, are associated with differential reductions in the incretin effect seen before the development of IGT and overt type 2 diabetes. The reduction is unrelated to secretion of incretin hormones, but is related to insulin resistance and subtle beta cell defects, and is further aggravated on development of IGT.. ClinicalTrials.gov NCT00784745.. This study was supported by a grant from the Novo Nordisk Foundation.

Topics: Adult; Blood Glucose; Dexamethasone; Female; Glucocorticoids; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin Resistance; Male; Young Adult

The insulinotropic effect of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) is impaired in patients with type 2 diabetes. It remains unclear whether this impairment is a primary pathophysiological trait or a consequence of developing diabetes. Therefore, we aimed to investigate the insulinotropic effect of GIP and GLP-1 compared with placebo before and after 12 d of glucose homeostatic dysregulation in healthy subjects.. The insulinotropic effect was measured using hyperglycemic clamps and infusion of physiological doses of GIP, GLP-1, or saline in 10 healthy Caucasian males before and after intervention using a high-calorie diet, sedentary lifestyle, and administration of prednisolone (37.5 mg once daily) for 12 d.. The intervention resulted in increased insulin resistance according to the homeostatic model assessment (1.2 ± 0.2 vs. 2.6 ± 0.5, P = 0.01), and glucose tolerance deteriorated as assessed by the area under curve for plasma glucose during a 75-g oral glucose tolerance test (730 ± 30 vs. 846 ± 57 mm for 2 h, P = 0.021). The subjects compensated for the change in insulin resistance by significantly increasing their postintervention insulin responses during saline infusion by 2.9 ± 0.5-fold (P = 0.001) but were unable to do so in response to incretin hormones (which caused insignificant increases of only 1.78 ± 0.3 and 1.38 ± 0.3-fold, P value not significant).. These data show that impairment of the insulinotropic effect of both GIP and GLP-1 can be induced in healthy male subjects without risk factors for type 2 diabetes, indicating that the reduced insulinotropic effect of the incretin hormones observed in type 2 diabetes most likely is a consequence of insulin resistance and glucose intolerance rather than a primary event causing the disease.

Topics: Adult; Blood Glucose; C-Peptide; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Infusions, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Kinetics; Male; Severity of Illness Index; Young Adult

Low glucagon-like peptide-1 (GLP-1) concentrations have been observed in impaired fasting glucose (IFG). It is uncertain whether these abnormalities contribute directly to the pathogenesis of IFG and impaired glucose tolerance. Dipeptidyl peptidase-4 (DPP-4) inhibitors raise incretin hormone concentrations enabling an examination of their effects on glucose turnover in IFG.. We studied 22 subjects with IFG using a double-blinded, placebo-controlled, parallel-group design. At the time of enrollment, subjects ate a standardized meal labelled with [1-(13)C]-glucose. Infused [6-(3)H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-(2)H(2)] glucose enabled measurement of endogenous glucose production (EGP) and glucose disappearance (Rd). Subsequently, subjects were randomized to 100 mg of sitagliptin daily or placebo. After an 8-week treatment period, the mixed meal was repeated.. As expected, subjects with IFG who received placebo did not experience any change in glucose concentrations. Despite raising intact GLP-1 concentrations, treatment with sitagliptin did not alter either fasting or postprandial glucose, insulin or C-peptide concentrations. Postprandial EGP (18.1 +/- 0.7 vs 17.6 +/- 0.8 micromol/kg per min, P = 0.53), Rd (55.6 +/- 4.3 vs 58.9 +/- 3.3 micromol/kg per min, P = 0.47) and MRa (6639 +/- 377 vs 6581 +/- 316 micromol/kg per 6 h, P = 0.85) were unchanged. Sitagliptin was associated with decreased total GLP-1 implying decreased incretin secretion.. DPP-4 inhibition did not alter fasting or postprandial glucose turnover in people with IFG. Low incretin concentrations are unlikely to be involved in the pathogenesis of IFG.

Topics: Blood Glucose; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Fasting; Female; Glucose Intolerance; Humans; Incretins; Male; Middle Aged; Placebos; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Triazoles

SUMOylation reduces oxidative stress and preserves islet mass at the expense of robust insulin secretion. To investigate a role for the deSUMOylating enzyme sentrin-specific protease 1 (SENP1) following metabolic stress, we put pancreas/gut-specific SENP1 knockout (pSENP1-KO) mice on a high-fat diet (HFD). Male pSENP1-KO mice were more glucose intolerant following HFD than littermate controls but only in response to oral glucose. A similar phenotype was observed in females. Plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses were identical in pSENP1-KO and wild-type littermates, including the HFD-induced upregulation of GIP responses. Islet mass was not different, but insulin secretion and β-cell exocytotic responses to the GLP-1 receptor agonist exendin-4 (Ex4) and GIP were impaired in islets lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, so we generated β-cell-specific SENP1 KO mice. These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired β-cell exocytosis and insulin secretion to Ex4 and GIP without changes in cAMP or Ca

Topics: Animals; Cysteine Endopeptidases; Diet, High-Fat; Gene Expression Regulation; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeodomain Proteins; Incretins; Insulin-Secreting Cells; Insulin, Regular, Human; Mice; Mice, Knockout; Trans-Activators

Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/β-catenin signalling pathway implicated in type 2 diabetes risk through genome-wide association studies. Although its expression is critical for adipocyte development, the potential roles of changes in adipose tissue TCF7L2 levels in diabetes risk are poorly defined. Here, we investigated whether forced changes in Tcf7l2 expression in adipocytes affect whole body glucose or lipid metabolism and crosstalk between disease-relevant tissues.. Tcf7l2 was selectively ablated in mature adipocytes in C57BL/6J mice using Cre recombinase under Adipoq promoter control to recombine Tcf7l2 alleles floxed at exon 1 (referred to as aTCF7L2 mice). aTCF7L2 mice were fed normal chow or a high-fat diet for 12 weeks. Glucose and insulin sensitivity, as well as beta cell function, were assessed in vivo and in vitro. Levels of circulating NEFA, selected hormones and adipokines were measured using standard assays.. Reduced TCF7L2 expression in adipocytes altered glucose tolerance and insulin secretion in male but not in female mice. Thus, on a normal chow diet, male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance at 16 weeks (p = 0.03) and increased fat mass (1.4 ± 0.1-fold, p = 0.007) but no changes in insulin secretion. In contrast, male homozygote knockout (aTCF7L2hom) mice displayed normal body weight but impaired oral glucose tolerance at 16 weeks (p = 0.0001). These changes were mechanistically associated with impaired in vitro glucose-stimulated insulin secretion (decreased 0.5 ± 0.1-fold vs control mice, p = 0.02) and decreased levels of the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (0.6 ± 0.1-fold and 0.4 ± 0.1-fold vs control mice, p = 0.04 and p < 0.0001, respectively). Circulating levels of plasma NEFA and fatty acid binding protein 4 were increased by 1.3 ± 0.1-fold and 1.8 ± 0.3-fold vs control mice (p = 0.03 and p = 0.05, respectively). Following exposure to a high-fat diet for 12 weeks, male aTCF7L2hom mice exhibited reduced in vivo glucose-stimulated insulin secretion (0.5 ± 0.1-fold vs control mice, p = 0.02).. Loss of Tcf7l2 gene expression selectively in adipocytes leads to a sexually dimorphic phenotype, with impairments not only in adipocytes, but also in pancreatic islet and enteroendocrine cells in male mice only. Our findings suggest novel roles for adipokines and incretins in the effects of diabetes-associated variants in TCF7L2, and further illuminate the roles of TCF7L2 in glucose homeostasis and diabetes risk. Graphical abstract.

Topics: Adipocytes; Animals; Body Composition; Fatty Acid-Binding Proteins; Fatty Acids, Nonesterified; Female; Gene Expression; Glucose; Glucose Intolerance; Incretins; Insulin Secretion; Insulin-Secreting Cells; Integrases; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Transcription Factor 7-Like 2 Protein

Post-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear.. To understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF).. Hypoglycemia, defined as glucose <70 mg/dL, occurred in 9/34 subjects at 150 (range:120-210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[-] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[-] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[-]. Compared to hypoglycemia[-] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC. Hypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC

Topics: Adolescent; Area Under Curve; Blood Glucose; C-Peptide; Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Female; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemia; Incretins; Insulin; Insulin Secretion; Male; Young Adult

Probiotics are defined as microorganisms that can exert health benefits for the host. Among the recognized probiotics, Bifidobacterium are the most frequently used probiotics in humans. The aim of this study was to evaluate the antidiabetic activity of Bifidobacterium strains isolated from breastfed infant faeces, both in vitro, using the Caco-2 monolayer transwell model, and in vivo, using a mice model of impaired glucose tolerance induced by a high-fat diet (HFD).. The cell-free supernatant of Bifidobacterium lactis A12 showed better inhibitory activity of α-glucosidase and inhibited the glucose absorption and transport than B. lactis BB12, which is a typical probiotic with antidiabetic capabilities. B. lactis A12 improved the impaired glucose intolerance, restored islet function and morphology with insulin resistance induced by the HFD in C57BL/6J mice. Furthermore, in small intestine tissues, the cell-free supernatant of B. lactis A12 decreased the messenger RNA expressions of sucrase-isomaltase, live B. lactis A12 cells decreased glucose transporters 2. B. lactis A12 significantly stimulated the glucagon like peptide-1 (GLP-1) secretion and upregulated proglucagon messenger RNA levels.. B. lactis A12 protect against the deleterious effects of HFD-induced diabetes by inhibiting the utilization, absorption, and transport of glucose by intestinal epithelial cells and promoting the expression and secretion of GLP-1. © 2020 Society of Chemical Industry.

Topics: Animals; Bifidobacterium; Breast Feeding; Diet, High-Fat; Feces; Glucose; Glucose Intolerance; Humans; Incretins; Male; Mice; Mice, Inbred C57BL; Probiotics

Impaired glucose homeostasis is a common finding in pheochromocytoma (PHEO), especially with adrenergic phenotype. The possible contribution of incretin dysfunction to dysglycemia in PHEO patients has not been studied.. To compare changes in pancreatic endocrine function and gut hormones' production during a liquid meal test before and 1 year after adrenalectomy.. In a prospective study, we included 18 patients with PHEO (13 females) with adrenergic biochemical phenotype. A liquid meal test with predefined isocaloric enteral nutrition was performed to evaluate dynamic changes in pancreatic hormones and incretins.. During the meal test, insulin levels were significantly lower before adrenalectomy only in the early phase of insulin secretion, but changes in area under the curve (AUC) did not reach statistical significance (AUC = 0.07). Plasma glucagon (AUC < 0.01) and pancreatic polypeptide levels (AUC < 0.01) were suppressed in comparison with the postoperative state. Impaired response to the meal was found preoperatively for glucagon-like peptide-1 (GLP-1; AUC P < 0.05), but not glucose-dependent insulinotropic polypepide (GIP; AUC P = 0.21). No significant changes in insulin resistance indices were found, except for the homeostatic model assessment-beta index, an indicator of the function of islet β cells, which negatively correlated with plasma metanephrine (R = -0.66, P < 0.01).. Our study shows suppression of pancreatic α and β cell function and impaired GLP-1 secretion during a dynamic meal test in patients with PHEO, which is improved after its surgical treatment. These data demonstrate a novel and potentially significant interconnection between excessive catecholamine production and the secretion of glucoregulatory hormones.

Topics: Adrenal Gland Neoplasms; Adrenergic Agents; Adult; Aged; Biomarkers; Blood Glucose; Female; Follow-Up Studies; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Incretins; Male; Meals; Middle Aged; Pancreatic Hormones; Phenotype; Pheochromocytoma; Prognosis; Prospective Studies

Dietary polyphenols including anthocyanins target multiple organs.. We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G).. Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2).. In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and β-klotho (>3-fold, P < 0.05).. Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21.

Topics: Animals; Anthocyanins; Diet, High-Fat; Dietary Fats; Fibroblast Growth Factors; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Intolerance; Glucosides; Incretins; Leptin; Liver; Male; Mice; Random Allocation; Weight Gain; Weight Loss

Diabetes is a chronic, progressive disease that calls for longitudinal data and analysis. We introduce a longitudinal mathematical model that is capable of representing the metabolic state of an individual at any point in time during their progression from normal glucose tolerance to type 2 diabetes (T2D) over a period of years. As an application of the model, we account for the diversity of pathways typically followed, focusing on two extreme alternatives, one that goes through impaired fasting glucose (IFG) first and one that goes through impaired glucose tolerance (IGT) first. These two pathways are widely recognized to stem from distinct metabolic abnormalities in hepatic glucose production and peripheral glucose uptake, respectively. We confirm this but go beyond to show that IFG and IGT lie on a continuum ranging from high hepatic insulin resistance and low peripheral insulin resistance to low hepatic resistance and high peripheral resistance. We show that IFG generally incurs IGT and IGT generally incurs IFG on the way to T2D, highlighting the difference between innate and acquired defects and the need to assess patients early to determine their underlying primary impairment and appropriately target therapy. We also consider other mechanisms, showing that IFG can result from impaired insulin secretion, that non-insulin-dependent glucose uptake can also mediate or interact with these pathways, and that impaired incretin signaling can accelerate T2D progression. We consider whether hyperinsulinemia can cause insulin resistance in addition to being a response to it and suggest that this is a minor effect.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Fasting; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liver; Models, Theoretical; Signal Transduction

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

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

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

Despite excellent results of bariatric surgery in the treatment of type 2 diabetes and weight loss in human subjects, some patients do not obtain desired results. One of the reasons for this is that not all patients follow caloric intake recommendations.. The aim of this study was to investigate the effect of duodenojejunal omega switch (DJOS) surgery on body weight, glucose tolerance, and incretins in rats.. DJOS and SHAM surgery were performed on rats maintained for 8 weeks on high-fat diet (HF) and control diet (CD), respectively. After surgery, four groups were kept on the same diet as before the surgery, and four groups had a changed diet (CD vs. HF and HF vs. CD) for the next 8 weeks. Glucose tolerance, insulin tolerance, glucose-stimulated insulin, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) secretion, food intake, and body weight were measured.. A change of diet after surgery resulted in reduced glucose tolerance. Plasma insulin levels were lowered between DJOS and SHAM surgeries for the HF/HF and CD/HF groups. DJOS surgery did not reduce body weight in the studied groups, irrespective of diet. In the HF/HF group, ΔGLP-1 was lower for DJOS surgery in comparison with other groups. Differences of weight changes were observed for groups HF/HF and HF/CD. After DJOS surgery, ΔGIP was lower in the CD/HF group compared with HF/HF.. Our results show that applications of different types of diets, before and after surgery, is a sensitive method for studies of mechanism of glucose intolerance after DJOS surgery.

Topics: Anastomosis, Surgical; Animals; Bariatric Surgery; Biopsy; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; Disease Models, Animal; Duodenum; Glucose Intolerance; Glucose Tolerance Test; Incretins; Jejunum; Liver; Male; Obesity, Morbid; Rats; Rats, Sprague-Dawley

Insulin secretion (IS) declines with age, which increases the risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in older adults. IS is regulated by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Here we tested the hypotheses that incretin release is lower in older adults and that this decline is associated with β-cell dysfunction.. A total of 40 young (25 ± 3 years) and 53 older (74 ± 7 years) lean nondiabetic subjects underwent a 2-hour oral glucose tolerance test (OGTT). Based on the OGTT, subjects were divided into three groups: young subjects with normal glucose tolerance (Y-NGT; n = 40), older subjects with normal glucose tolerance (O-NGT; n = 32), and older subjects with IGT (O-IGT; n = 21).. Plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15 to 30 minutes. We quantitated insulin sensitivity (Matsuda index) and insulin secretory rate (ISR) by deconvolution of C-peptide with the calculation of β-cell glucose sensitivity.. Matsuda index, early phase ISR (0 to 30 minutes), and parameters of β-cell function were lower in O-IGT than in Y-NGT subjects but not in O-NGT subjects. GLP-1 concentrations were elevated in both older groups [GLP-1 area under the curve (AUC)0-120 was 2.8 ± 0.1 in Y-NGT, 3.8 ± 0.5 in O-NGT, and 3.7 ± 0.4 nmol/L∙120 minutes in O-IGT subjects; P < 0.05], whereas GIP secretion was higher in O-NGT than in Y-NGT subjects (GIP AUC0-120 was 4.7 ± 0.3 in Y-NGT, 6.0 ± 0.4 in O-NGT, and 4.8 ± 0.3 nmol/L∙120 minutes in O-IGT subjects; P < 0.05).. Aging is associated with an exaggerated GLP-1 secretory response. However, it was not sufficient to increase insulin first-phase release in O-IGT and overcome insulin resistance.

Topics: Adult; Aged; Aging; Blood Glucose; C-Peptide; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male

Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in the WFS1 (Wolframin1) gene. The syndrome first manifests as diabetes mellitus, followed by optic nerve atrophy, deafness, and neurodegeneration. The underlying mechanism is believed to be a dysregulation of endoplasmic reticulum (ER) stress response, which ultimately leads to cellular death. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to normalize ER stress response in several in vitro and in vivo models. Early chronic intervention with the GLP-1 receptor agonist liraglutide starting before the onset of metabolic symptoms prevented the development of glucose intolerance, improved insulin and glucagon secretion control, reduced ER stress and inflammation in Langerhans islets in Wfs1 mutant rats. Thus, treatment with GLP-1 receptor agonists might be a promising strategy as a preventive treatment for human WS patients.

Topics: Animals; Blood Glucose; Calmodulin-Binding Proteins; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Knockout Techniques; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Injections, Subcutaneous; Insulin; Islets of Langerhans; Liraglutide; Male; Membrane Proteins; Rats; Rats, Transgenic; Treatment Outcome; Wolfram Syndrome

Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated β-cell function and insulin hypersecretion, in response to intravenous (iv) glucose, compared with Whites. To investigate if the same holds true during an oral glucose challenge and because of the important role of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in augmenting insulin secretion, we examined β-cell function and incretin hormones in 85 Black and 78 White obese adolescents, with normal glucose tolerance (NGT), during a 2-h oral glucose tolerance test (OGTT) with mathematical modeling of plasma glucose and C-peptide concentrations to assess β-cell glucose sensitivity (βCGS), rate sensitivity, potentiation factor, and insulin sensitivity. Incretin, pancreatic polypeptide, and glucagon concentrations were measured during the OGTT. Black obese youth had a heightened early insulin secretion together with significantly greater βCGS, rate sensitivity, and potentiation factor compared with Whites, with no differences in incretin and glucagon concentrations. Basal and stimulated insulin clearance was lower (p = 0.001) in Black vs. White youth. In conclusion, during an OGTT Black obese youth with NGT demonstrate a pronounced early insulin secretion jointly with heightened β-cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in β-cell function and the pathophysiological components of T2D are unlikely to be attributed to incretin hormones and remain to be investigated further to explain the metabolic basis for the enhanced risk of T2D in back youth.

Topics: Adolescent; Black or African American; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Pediatric Obesity; Risk Factors; White People

Secretion of glucagon-like peptide-1 has been suggested to be impaired in T2DM and in conditions associated with hyperglycemia. 3-Deoxyglucosone, a dietary composition, has been suggested as an independent factor for the development of prediabetes. A-pathophysiological very high condition of 3DG concentrations administered i. v. induced acute glucose intolerance in rats. In this study, to examine the acute effects of single intragastric administration of 3DG at dose of potentially single-meal intake on plasma glucose, insulin, glucagon, total GLP-1 and total GIP levels in response to a glucose load, OGTT was performed immediately in normal Kunming mice or Sprague-Dawleys rats after 3DG administration. GLP-1 secretion, intracellular cAMP levels and 2-NBDG uptake were examined in STC-1 cells exposured to 3DG. In rats, 20 mg/kg 3DG i.g. (3DG-20 i.g.) impaired glucose tolerance (

Topics: Animals; Cyclic AMP; Deoxyglucose; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Incretins; Insulin; Male; Mice; Prediabetic State; Rats

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

Incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP), and dipeptidyl peptidase-4 (DPP-4) activity are important factors in glucose metabolism and have not been investigated in patients with obstructive sleep apnea (OSA).. The objective of this study was to investigate the association between OSA and incretin and DPP-4 activity.. This study included 96 consecutive patients without diabetes who were suspected of having OSA. We investigated the fasting and post-prandial incremental area under the curve (IAUC) of GLP-1, GIP serum levels, and serum DPP-4 activity levels, as well as their association with OSA. Changes in clinical variables were evaluated in the 43 patients who continued continuous positive airway pressure therapy for 3 months.. Apnea-hypopnea index was an independent determining factor for fasting GLP-1 (β = 0.31; P = 0.0019) and IAUC GIP (β = -0.21; P = 0.037) after adjusting for known confounding factors. In those with very severe OSA (apnea-hypopnea index ≥50), the IAUCs for GLP-1 and GIP were significantly decreased, while fasting GLP-1 and fasting GIP were significantly increased. DPP-4 activity had no relation to OSA parameters or severity, while body mass index was significantly higher in those with severe OSA. Although significant changes in incretin secretion were not seen for 3 months after onset of continuous positive airway pressure therapy, the fasting GLP-1 level in the treated patients with severe OSA decreased to the same level as in untreated patients with normal to moderately severe OSA.. OSA is associated with elevated serum levels of the incretin hormones GLP-1 (fasting) and GIP (post-prandial) in patients without diabetes. A significant association between body mass index and DPP-4, which is said to exist in healthy persons, was not found in the patients with OSA. Fasting GLP-1 in patients without diabetes with OSA may influence fasting glucose levels.

Topics: Adult; Aged; Dipeptidyl Peptidase 4; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Incretins; Japan; Male; Middle Aged; Regression Analysis; Sleep Apnea, Obstructive

To examine the relationship between beta-cell function and the incretin effect.. We performed a 180-min hyperglycaemic clamp study with oral glucose administration at 60 min in Korean subjects with normal glucose tolerance (NGT, n = 9), impaired fasting glucose (IFG, n = 6) and type 2 diabetes mellitus (T2DM, n = 6).. First- and second-phase insulin secretions were measured during the first 60 min. The insulin response to intravenous glucose during the 60- to 120-min interval (Insiv) was calculated using a prediction method. The insulin response to oral glucose (Ins(oral)) was calculated by subtracting the Insiv from the overall insulin response during the 60- to 120-min interval (Ins(overall)). The incretin effect under the hyperglycaemic clamp condition (IE(clamp)) was calculated by the equation: 100 × [(Ins(overall) - Insiv)/Ins(overall)].. The IE(clamp) was comparable among the three groups (46.3 ± 6.4%, 35.7 ± 8.8% and 51.4 ± 7.4% for the NGT, IFG and T2DM group, respectively, P = 0.327) and was not correlated with the first- and second-phase insulin secretions. However, the Ins(oral) (mU/l 60 min) was significantly different between the NGT, IFG and T2DM groups (5199 ± 1185, 2164 ± 956 and 1034 ± 355, respectively; P = 0.010) and was well correlated with the first- and second-phase insulin secretions.. The incretin effect measured by the hyperglycaemic clamp with oral glucose loading was neither correlated with beta-cell function nor different between NGT, IFG and T2DM groups in Koreans.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Glucose Intolerance; Humans; Hyperglycemia; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Republic of Korea; Young Adult

Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the number of intestinal L cells, which produce GLP-1, is an alternative strategy to augment insulin responses and improve glucose tolerance. Blocking the NOTCH signaling pathway with the γ-secretase inhibitor dibenzazepine increased the number of L cells in intestinal organoid-based mouse and human culture systems and augmented glucose-stimulated GLP-1 secretion. In a high-fat diet-fed mouse model of impaired glucose tolerance and type 2 diabetes, dibenzazepine administration increased L cell numbers in the intestine, improved the early insulin response to glucose, and restored glucose tolerance. Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation of the development of incretin-producing cells in the intestine has potential as a therapeutic strategy to improve glycemic control.

Topics: Animals; Cells, Cultured; Diet, High-Fat; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Ileum; Incretins; Insulin; Insulin Secretion; Male; Mice, Inbred C57BL; Receptors, Notch

Pulses, including dried peas, are nutrient- and fibre-rich foods that improve glucose control in diabetic subjects compared with other fibre sources. We hypothesized feeding cooked pea seed coats to insulin-resistant rats would improve glucose tolerance by modifying gut responses to glucose and reducing stress on pancreatic islets. Glucose intolerance induced in male Sprague-Dawley rats with high-fat diet (HFD; 10% cellulose as fibre) was followed by 3 weeks of HFD with fibre (10%) provided by cellulose, raw-pea seed coat (RP), or cooked-pea seed coat (CP). A fourth group consumed low-fat diet with 10% cellulose. Oral and intraperitoneal glucose tolerance tests (oGTT, ipGTT) were done. CP rats had 30% and 50% lower glucose and insulin responses in oGTT, respectively, compared with the HFD group (P < 0.05) but ipGTT was not different. Plasma islet and incretin hormone concentrations were measured. α- and β-cell areas in the pancreas and density of K- and L-cells in jejunum and ileum were quantified. Jejunal expression of hexose transporters was measured. CP feeding increased fasting glucagon-like peptide 1 and glucose-stimulated gastric inhibitory polypeptide responses (P < 0.05), but K- and L-cells densities were comparable to HFD, as was abundance of SGLT1 and GLUT2 mRNA. No significant difference in β-cell area between diet groups was observed. α-cell area was significantly smaller in CP compared with RP rats (P < 0.05). Overall, our results demonstrate that CP feeding can reverse adverse effects of HFD on glucose homeostasis and is associated with enhanced incretin secretion and reduced α-cell abundance.

Topics: Animals; Blood Glucose; Cooking; Diet, High-Fat; Dietary Fiber; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 2; Glucose Transporter Type 5; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Pancreatic Hormones; Pisum sativum; Rats; Rats, Sprague-Dawley; Seeds; Sodium-Glucose Transporter 1

We tested the exendin-4 and des-fluoro-sitagliptin effects on fructose-induced increase in liver glucokinase activity in rats with impaired glucose tolerance and the exendin-4 effect on glucokinase activity in HepG2 cells incubated with fructose in the presence/absence of exendin-9-39. After 3 weeks of in vivo fructose administration we measured: (1) serum glucose, insulin and triglyceride levels; (2) liver and HepG2 cells glucokinase activity and (3) liver glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein levels. Fructose fed rats had: hypertriglyceridemia, hyperinsulinemia and high liver glucokinase activity (mainly located in the cytosolic fraction) together with higher glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein concentrations compared to control rats. Co-administration of either exendin-4 or des-fluoro-sitagliptin prevented serum and liver changes except glucokinase protein expression. Exendin-4 also prevented fructose-induced increase in glucokinase activity in cultured HepG2 cells, effect blunted by co-incubation with exendin-9-36. In conclusion exendin-4/des-fluro-sitagliptin prevented fructose-induced effect on glucokinase activity, mainly affecting enzyme activity modulators. Exendin 9-39 blunted in vitro protective exendin-4 effect on glucokinase activity, thus suggesting a direct effect of the later on hepatocytes through GLP-1 receptor. Alterations of glucokinase activity modulators could play a role in the pathogenesis of liver dysfunction, becoming a potential new treatment target for GLP-1 receptor agonists.

Topics: Animals; Exenatide; Fructose; Gene Expression; Glucokinase; Glucose Intolerance; Hep G2 Cells; Humans; Incretins; Liver; Male; Peptides; Rats; Rats, Wistar; Sitagliptin Phosphate; Venoms

Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7(Δβ cell)) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7(Δβ cell) mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7(Δβ cell) mice. The α cell mass was not affected by β cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in β cells could regulate incretin-induced glucagon expression and release in α cells, and that cAMP may play a role in this process.

Topics: Animals; Autophagy; Diabetes Mellitus, Experimental; Glucagon; Glucagon-Secreting Cells; Glucose Intolerance; Incretins; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice

The frog skin host-defense peptide tigerinin-1R (RVCSAIPLPICH.NH2) is insulinotropic both in vitro and in vivo. This study investigates the effects on insulin release and cytotoxicity of changes in cationicity and hydrophobicity produced by selected substitutions of amino acids by l-arginine, l-lysine and l-tryptophan. The [A5W], [L8W] and [I10W] analogs produced a significant (P<0.01) increase in the rate of insulin release from BRIN-BD11 rat clonal β cells at concentration of 0.01 nM compared with 0.1 nM for tigerinin-1R. The increase in the rate of insulin release produced by a 3 μM concentration of the [S4R], [H12K], and [I10W] analogs from both BRIN-BD11 cells and mouse islets was significantly greater (P<0.05) than that produced by tigerinin-1R. No peptide stimulated the release of lactate dehydrogenase at concentrations up to 3 μM indicating that plasma membrane integrity had been preserved. [A5W] tigerinin-1R was the only analog tested that showed cytotoxic activity against human erythrocytes (LC50=265 ± 16 μM) and inhibited growth of Escherichia coli (MIC=500 μM) and Staphylococcus aureus (MIC=250 μM). The circular dichroism spectra of tigerinin-1R and [A5W] tigerinin-1R indicate that the peptides adopt a mixture of β-sheet, random coil and reverse β-turn conformations in 50% trifluoroethanol/water and methanol/water. Administration of [S4R] tigerinin-1R (75 nmol/kg body weight) to high-fat fed mice with insulin resistance significantly (P<0.05) enhanced insulin release and improved glucose tolerance over a 60 min period following an intraperitoneal glucose load. The study supports the claim that tigerinin-1R shows potential for development into novel therapeutic agents for treatment of type 2 diabetes mellitus.

Topics: Amphibian Proteins; Animals; Anti-Bacterial Agents; Calcium Signaling; Cell Line; Escherichia coli; Glucose Intolerance; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Membrane Potentials; Mice, Inbred C57BL; Microbial Sensitivity Tests; Rats; Staphylococcus aureus; Structure-Activity Relationship

Oral glucose elicits a higher insulin secretory response than intravenous glucose at matched glucose concentrations. This potentiation, known as the incretin effect, is typically expressed as the difference between the total insulin response to oral vs intravenous glucose. This approach does not describe the dynamics of insulin secretion potentiation. We developed a model for the simultaneous analysis of oral and isoglycaemic intravenous glucose responses to dissect the impact of hyperglycaemia and incretin effect on insulin secretion and beta cell function.. Fifty individuals (23 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT] and ten with type 2 diabetes) received an OGTT and an isoglycaemic test with measurement of plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Our model featured an incretin potentiation factor (PINCR) for the dose–response function relating insulin secretion to glucose concentration, and an effect on early secretion (rate sensitivity).. In NGT, PINCR rapidly increased and remained sustained during the whole OGTT (mean PINCR>1, p<0.009). The increase was transient in IGT and virtually absent in diabetes. Mean PINCR was significantly but loosely correlated with GLP-1 AUC (r=0.49, p<0.006), while the relationship was not significant for GIP. An incretin effect on rate sensitivity was present in all groups (p<0.002).. The onset of the incretin effect is rapid and sustained in NGT, transient in IGT and virtually absent in diabetes. The profiles of the incretin effect are poorly related to those of the incretin hormones.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Models, Theoretical

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

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

The pathophysiological role of gut incretin hormone argumentation on acute insulin release in the genesis of type 2 diabetes (TDM2) is uncertain. We examined retrospectively at 0 year and 10 years the endogenous incretin hormone action (IHA) on acute insulin release and glucose tolerance in normoglycemic relatives (REL) of TDM2 and control (CON) subjects.. At 0 year and 10 years, glucose tolerance, paired oral glucose tolerance test (OGTT)- and i.v. glucose tolerance test (IVGTT)-induced acute (0-30 min) insulin release (insulinogenic index IGIOGTT and IGIIVGTT), and IHA were calculated in 19 REL and 18 CON subjects by cross-correlation linear regression slope analyses of the OGTT (0-30 min) matched insulin/glucose profiles vs the early (0-5 min) and delayed (10-30 min) IVGTT profiles.. At 0 year, REL and CON IGIOGTT and IGIIVGTT were similar, but the REL 2- to 5-min IVGTT-induced insulin responses were reduced (P < .03). By 10 years, glucose tolerance deteriorated in nine dysglycemic REL (RELDGT), with raised fasting glucose and 2-hour OGTT glucose. Retrospective analyses of RELDGT at 0 year demonstrated raised proinsulin/insulin molar ratios and fasting glucose and a reduced IVGTT insulin/glucose slope, but the RELDGT IHA was similar to normoglycemic REL (RELNGT) and CON. By 10 years, RELDGT OGTT insulin/glucose slopes were reduced (P = .03-.01), but more so for the early (P < .01-.003) and delayed (P < .005-.002) IVGTT slopes, compared to the normoglycaemic REL and CON subjects.. IHA on acute insulin release is maintained in normoglycemic REL and CON subjects over 10 years. The apparent deterioration in IHA in RELDGT is consistent with a progressive failure of acute β-cell function over 10 years.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Family; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Longitudinal Studies; Male; Retrospective Studies

Meal-fed (MF) rats with access to food for only 4 consecutive hours during the light cycle learn to eat large meals to maintain energy balance. MF animals develop behavioral and endocrine changes that permit glucose tolerance despite increased meal size. We hypothesized that enhanced activity of the enteroinsular axis mediates glucose homeostasis during MF. Cohorts of rats were allocated to MF or ad libitum (AL) regimens for 2-4 wk. Insulin secretion and glucose tolerance were determined after oral carbohydrate and intraperitoneal (ip) and intravenous (iv) glucose. MF rats ate less than AL in the first week but maintained a comparable weight trajectory thereafter. MF rats had decreased glucose excursions after a liquid mixed meal (AUC: MF 75 ± 7, AL 461 ± 28 mmol·l⁻¹·min, P < 0.001), with left-shifted insulin secretion (AUC(0-15): MF 31.0 ± 4.9, AL 9.6 ± 4.4 pM·min, P < 0.02), which peaked before a significant rise in blood glucose. Both groups had comparable fasting glucagon levels, but postprandial responses were lower with MF. However, neither intestinal expression of proGIP and proglucagon mRNA nor plasma incretin levels differed between MF and AL groups. There were no differences in the insulin response to ip or iv glucose between MF and AL rats. These findings demonstrate that MF improves oral glucose tolerance and is associated with significant changes in postprandial islet hormone secretion. Because MF enhanced β-cell function during oral but not parenteral carbohydrate administration, and was not accounted for by changes in circulating incretins, these results support a neural mechanism of adaptive insulin secretion.

Topics: Allostasis; Animals; Behavior, Animal; Feeding Behavior; Gastric Inhibitory Polypeptide; Glucagon; Glucose Intolerance; Hyperglycemia; Ileum; Incretins; Insulin; Insulin Secretion; Intestinal Mucosa; Islets of Langerhans; Jejunum; Male; Meals; Neurosecretory Systems; Organ Specificity; Postprandial Period; Proglucagon; Rats, Long-Evans

Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic β cells, which can be restored by glucagon-like peptide 1 (GLP-1), an incretin hormone commonly used for the treatment of type 2 diabetes. However, molecular mechanisms by which GLP-1 affects glucose responsiveness in islet β cells remain poorly understood. Here we investigated a role of SAD-A, an AMP-activated protein kinase (AMPK)-related kinase, in regulating GSIS in mice with conditional SAD-A deletion. We show that selective deletion of SAD-A in pancreas impaired incretin's effect on GSIS, leading to glucose intolerance. Conversely, overexpression of SAD-A significantly enhanced GSIS and further potentiated GLP-1's effect on GSIS from isolated mouse islets. In support of SAD-A as a mediator of incretin response, SAD-A is expressed exclusively in pancreas and brain, the primary targeting tissues of GLP-1 action. Additionally, SAD-A kinase is activated in response to stimulation by GLP-1 through cyclic AMP (cAMP)/Ca(2+)-dependent signaling pathways in islet β cells. Furthermore, we identified Thr443 as a key autoinhibitory phosphorylation site which mediates SAD-A's effect on incretin response in islet β cells. Consequently, ablation of Thr443 significantly enhanced GLP-1's effect on GSIS from isolated mouse islets. Together, these findings identified SAD-A kinase as a pancreas-specific mediator of incretin response in islet β cells.

Topics: Animals; Calcium; Cell Line; Cyclic AMP; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Incretins; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Pancreas; Phosphorylation; Protein Serine-Threonine Kinases; Threonine

In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO). ANOVA on kxgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10(-5)±9.36×10(-5) min(-1)pM(-1)), IFG (5.30×10(-5)±5.18×10(-5)) and combined IGT, IFG+IGT and T2DM (2.09×10(-5)±1.95×10(-5), 2.38×10(-5)±2.28×10(-5) and 2.38×10(-5)±2.09×10(-5) respectively). No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically diverse subject groups. The SIMO model may therefore be of value for the quantification of glucose homeostasis from clinical OGTT data.

Topics: Adult; Algorithms; Female; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Internet; Liver; Male; Middle Aged; Models, Theoretical; Reproducibility of Results; Sensitivity and Specificity; Software; Young Adult

Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.

Topics: Animals; Cyclic AMP; Gastric Inhibitory Polypeptide; Gene Deletion; Gene Knock-In Techniques; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Immunohistochemistry; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Peptide Fragments; Proglucagon; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

This study investigated the impact of incretin on early-phase insulin secretion and glucose excursion. The normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) groups included 16, 8, and 19 subjects, respectively. Subjects underwent continuous glucose monitoring for 3 days, followed by an oral glucose tolerance test. Plasma glucose, insulin, glucagon, total glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-l (GLP-1) levels were measured at 30-min increments for 2 h after glucose intake. Differences with P < 0.05 were considered statistically significant. The area under the curve (AUC) of total GIP (120-min GIP-AUC) of the T2DM group was significantly lower than those of the NGT and IGT groups. The 120-min GLP-1-AUC of the NGT group was significantly larger than those of the T2DM and IGT groups. The early-phase insulin secretion index (ΔI30/ΔG30) of the T2DM group was significantly lower than those of the NGT and IGT groups. Mean amplitudes of glycemic excursions (MAGEs) went in the order of NGT < IGT < T2DM (P < 0.01, IGT vs. NGT; P < 0.001, T2DM vs. IGT). The 120-min GIP-AUC was negatively correlated with MAGE (r = -0.464), but uncorrelated with ΔI30/ΔG30. The 120-min GLP-1-AUC was positively correlated with ΔI30/ΔG30 (r = 0.580), but negatively correlated with MAGE (r = -0.606). Incretin may ameliorate glucose excursions, and GLP-1 may exert them by promoting early-phase insulin secretion. No correlation was observed between GIP secretion and early-phase insulin secretion.

Topics: Adult; Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged

Topics: Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male

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

Impaired secretion of glucagon-like peptide 1 (GLP-1) has been suggested to contribute to the deficient incretin effect in patients with type 2 diabetes mellitus (T2DM). Recent studies, however, have not always supported this notion. Since Japanese patients with T2DM usually have severe impairment in the earlyphase of insulin secretion, the measurement of incretin secretions in Japanese T2DM patients would be useful for assessing the association between incretin levels and insulin secretion. We conducted an oral glucose tolerance test (75 g) (OGTT) and meal tolerance test (480 kcal) (MTT) for subjects with normal glucose tolerance (NGT, n=12), subjects with impaired glucose tolerance (IGT, n=7), and T2DM patients (n=21). The tests were carried out over 120-min study periods on separate occasions. Intact GLP-1, GIP, and dipeptidyl peptidase (DPP)-IV were measured by ELISA. T2DM exhibited an impaired early phase of insulin secretion and a reduction in glucagon suppression. There were no significant differences in GLP-1 or GIP levels at each sampling time among NGT, IGT, and T2DM after the ingestions; hence the incremental areas under the curve (IAUC) for the three groups were quite similar. The levels of DPP-IV, a limiting enzyme for the degradation of incretins, were comparable among the three groups. The GLP-1-IAUC was not correlated with IAUCs of insulin, C-peptide, or glucagon determined by the OGTT or the MTT. We concluded that intact GLP-1 levels are comparable between non-diabetics and T2DM, suggesting that impaired insulin secretion in Japanese T2DM is not attributable to defect in GLP-1 secretion.

Topics: Adult; Aged; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Middle Aged

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucose Intolerance; Humans; Incretins

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucose Intolerance; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Islets of Langerhans; Nitriles; Pyrrolidines; Vildagliptin

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

It has been observed, as a collateral outcome of bariatric surgery, that morbidly obese patients with frank type 2 diabetes mellitus or impaired glucose tolerance undergone Roux-en-Y Gastric Bypass (RYGB) or bilio-pancreatic diversion (BPD) became and remained euglycemic since surgery. But, most interestingly, the conversion to euglycemia happened within few days from the operation, long before a significant weight loss could intervene. The purpose of this viewpoint is to try to elucidate the mechanisms involved in the resolution/remission of diabetes after bariatric surgery, in particular highlighting the role played by the modifications in incretin secretion.. The effect of purely restrictive procedures in improving glucose control is directly proportional to the degree of weight loss. In contrast, either RYGB or BPD, the first a mainly restrictive and the second a quite purely malabsorptive bariatric technique, operate through a different mechanism, as a probable consequence of the small intestine bypass. The bypass of different intestinal portions covers a central role in the mechanisms of action of these two surgical procedures. In fact, while RYGB does not affect insulin resistance but increases insulin secretion via the stimulation of nutrient-mediated incretin secretion, BPD induces a full normalization of insulin resistance and, consequently, a significant reduction of insulin secretion. The insulin resistance reversion is only partially explained by the incretin level changes after BPD.. A role of incretins in type 2 diabetes improvement or resolution is ascertained although it is possible that other, not yet identified, hormone(s) can cooperate with them.

Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Glucose Intolerance; Humans; Incretins; Insulin Resistance; Obesity, Morbid; Proglucagon; Remission Induction; Weight Loss

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

Defects in glucagon-like peptide 1 (GLP-1) secretion have been reported in some patients with type 2 diabetes after meal ingestion. We addressed the following questions: 1) Is the quantitative impairment in GLP-1 levels different after mixed meal or isolated glucose ingestion? 2) Which endogenous factors are associated with the concentrations of GLP-1? In particular, do elevated fasting glucose or glucagon levels diminish GLP-1 responses?. Seventeen patients with mild type 2 diabetes, 17 subjects with impaired glucose tolerance, and 14 matched control subjects participated in an oral glucose tolerance test (75 g) and a mixed meal challenge (820 kcal), both carried out over 240 min on separate occasions. Plasma levels of glucose, insulin, C-peptide, glucagon, triglycerides, free fatty acids (FFAs), gastric inhibitory polypeptide (GIP), and GLP-1 were determined.. GIP and GLP-1 levels increased significantly in both experiments (P < 0.0001). In patients with type 2 diabetes, the initial GIP response was exaggerated compared with control subjects after mixed meal (P < 0.001) but not after oral glucose ingestion (P = 0.98). GLP-1 levels were similar in all three groups in both experiments. GIP responses were 186 +/- 17% higher after mixed meal ingestion than after the oral glucose load (P < 0.0001), whereas GLP-1 levels were similar in both experiments. There was a strong negative association between fasting glucagon and integrated FFA levels and subsequent GLP-1 concentrations. In contrast, fasting FFA and integrated glucagon levels after glucose or meal ingestion and female sex were positively related to GLP-1 concentrations. Incretin levels were unrelated to measures of glucose control or insulin secretion.. Deteriorations in glucose homeostasis can develop in the absence of any impairment in GIP or GLP-1 levels. This suggests that the defects in GLP-1 concentrations previously described in patients with long-standing type 2 diabetes are likely secondary to other hormonal and metabolic alterations, such as hyperglucagonemia. GIP and GLP-1 concentrations appear to be regulated by different factors and are independent of each other.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Male; Middle Aged; Triglycerides

Topics: Animals; Chronic Disease; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucose Intolerance; Hepatitis C, Chronic; Humans; Incretins; Liver Diseases

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