glucagon-like-peptide-1 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

Recent studies discuss the evidence of lesser degrees of hyperglycemia contribution to cardiovascular disease (CVD) than impaired glucose tolerance. Indeed, the biggest risk for CVD seems to shift to glucose intolerance in humans with insulin resistance. Although there is a connection between abnormal insulin signaling and heart dysfunction in diabetics, there is also a relation between cardiac insulin resistance and aging heart failure (HF). Moreover, studies have revealed that HF is associated with generalized insulin resistance. Recent clinical outcomes parallel to the experimental data undertaken with antihyperglycemic drugs have shown their beneficial effects on the cardiovascular system through a direct effect on the myocardium, beyond their ability to lower blood glucose levels and their receptor-associated actions. In this regard, several new-class drugs, such as glucagon-like peptide 1 receptor agonists (GLP-1Ra) and sodium-glucose cotransport 2 inhibitors (SGLT2i), can improve cardiac health beyond their ability to control glycemia. In recent years, great improvements have been made toward the possibility of direct heart-targeting effects including modulation of the expression of specific cardiac genes in vivo for therapeutic purposes. However, many questions remain unanswered, regarding their therapeutic effects on cardiomyocytes in heart failure, although there are various cellular levels studies with these drugs. There are also some important comparative studies on the role of SGLT2i versus GLP-1Ra in patients with and without CVD as well as with or without hyperglycemia. Here, we sought to summarize and interpret the available evidence from clinical studies focusing on the effects of either GLP-1Ra or SGLT-2i or their combinations on cardiac structure and function. Furthermore, we documented data from experimental studies, at systemic, organ, and cellular levels. Overall, one can summarize that both clinical and experimental data support that either SGLT2i or GLP-1R agonists have similar benefits as cardioprotective agents in patients with or without impaired glucose tolerance.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose Intolerance; Heart Failure; Humans; Hypoglycemic Agents; Insulin Resistance; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes.

Topics: Animals; Dietary Proteins; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Phytochemicals

Dysglycaemia (i.e. type 2 diabetes mellitus or impaired glucose tolerance) is not only common in patients with cardiovascular disease but increases the risk for future cardiovascular complications. Hyperglycaemia, the hallmark of diabetes, has since long been considered to be the link between diabetes and cardiovascular disease. Diabetes is, however, a complex, multifactorial disorder to which, for example, insulin resistance, endothelial dysfunction and factors such as increased thrombogenicity, hypertension and dyslipidaemia contribute. Thus, treatment needs to be multifactorial and to take cardiovascular aspects into account. Life-style adjustments are, together with blood pressure, lipid and glucose control, important parts of such management. Recent trial data reveal a beneficial effect on cardiovascular prognosis and mortality of blood glucose lowering agents belonging to the classes: sodium-glucose-transporter 2 inhibitors and glucagon-like peptide 1 agonists. The precise mechanisms by which certain sodium-glucose-transporter 2 inhibitors and glucagon-like peptide receptor agonists lead to these beneficial effects are only partly understood. An important impact of the benefits of sodium-glucose-transporter 2 inhibitors is a reduction in heart failure while glucagon-like peptide receptor agonists may retard the development of atherosclerotic vascular disease or stabilising plaques. Although there has been a considerable improvement in the prognosis for people with atherosclerotic diseases over the last decades there is still a gap between those with dysglycaemia, who are at higher risk, than those without dysglycaemia. This residual risk is reasonably related to two major factors: a demand for improved management and a need for new and improved therapeutic opportunities of type 2 diabetes, both routes to an improved prognosis that are at hands. This review is a comprehensive description of the possibilities to improve the prognosis for patients with dysglycaemia by a multifactorial management according to the most recent European guidelines issued in 2019 by the European Society of Cardiology in collaboration with the European Association for the Study of Diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Europe; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Resistance; Practice Guidelines as Topic; Prognosis; Risk Factors; Risk Reduction Behavior; Sodium-Glucose Transporter 2 Inhibitors

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

Insulin resistance alone does not result in the development of type 2 diabetes; progressive dysfunction of pancreatic islet alpha and beta cells, which results in inadequate control of hyperglycemia, must be present for the disease to develop. Because of these defects, meal-stimulated insulin secretion from beta cells is reduced and fails to meet the demands of the insulin-resistant state; in addition, glucagon production by alpha cells, which normally maintains hepatic glucose production during fasting periods, is not suppressed. This increased glucagon secretion leads to inappropriate levels of hepatic glucose output in the post-prandial state and consequently to hyperglycemia.. This review will examine the pathophysiologic processes of type 2 diabetes and provide an overview of some of the new and emerging treatments targeting pancreatic islet dysfunction. A MEDLINE search was performed for literature published in the English language from 1966-August 2006. Abstracts and presentations from the American Diabetes Association Scientific Sessions (2002-2006) and the European Association for the Study of Diabetes Annual Meetings (1998-2006) were also searched for relevant studies.. Key factors in maintaining the normal balance between insulin and glucagon levels are the incretins--glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Intestinal absorption of glucose stimulates secretion of these hormones, which act to increase insulin and decrease glucagon secretion. Studies demonstrating that incretin activity is impaired in type 2 diabetes have led to investigations into incretin-based therapies such as incretin mimetics (analogues of GLP-1) and inhibitors of the enzyme dipeptidyl peptidase-4 (DPP-4), which inactivates native incretins.. Pancreatic islet dysfunction is a rational target for the treatment of type 2 diabetes. Incretin mimetics and DPP-4 inhibitors have been shown to improve glucose tolerance and may also hold the potential for improving overall pancreatic islet health. It should be noted, however, that the long-term effect of these agents on glycemic control has not yet been established, and their potential impact on beta-cell function in humans remains an area of active investigation.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glycoproteins; Humans; Hypoglycemic Agents; Islets of Langerhans; Models, Biological

Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Under some conditions of hyperglycemic challenge, insulin levels are lower in older people, suggesting beta-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, beta-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired beta-cell compensation to age-related insulin resistance may predispose older people to develop postchallenge hyperglycemia and type 2 diabetes. An improved understanding of the metabolic alterations associated with aging is essential for the development of preventive and therapeutic interventions in this population at high risk for glucose intolerance.

Topics: Adult; Aged; Aged, 80 and over; Aging; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Middle Aged; Nutrition Surveys; Peptide Fragments

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Secretion; Islets of Langerhans; Monosaccharide Transport Proteins; Peptide Fragments; Protein Precursors

Impaired glucose tolerance (IGT) is a pathophysiological condition characterized by insulin resistance with known metabolic consequences such as postprandial hyperglycemia and hypertriglyceridemia. We hypothesized that fortifying a meal with mushrooms rich in β-glucans may diminish glucose and triglyceride responses by improving postprandial gastrointestinal hormone release.. In a randomized controlled crossover study, 22 subjects with IGT ingested a meal either enriched with 20 g powder (8.1 g β-glucans) of oven-dried Pleurotus ostreatus (enriched meal, EN) or without enrichment (control meal, CON). Blood was collected before and repeatedly within 4 h after the meal to determine AUC of glucose (primary outcome), insulin, triglycerides, non-esterified free fatty acids (NEFAs), glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and ghrelin. Appetite sensations (hunger, satiety, fullness, and desire to eat) were assessed before and after meal consumption by visual analog scales.. Postprandial glucose, insulin, triglycerides, GIP and ghrelin concentrations as well as the corresponding AUCs did not differ between EN and CON. NEFAs-AUC was 14% lower (P = 0.026) and GLP-1-AUC 17% higher (P = 0.001) after EN compared to CON. Appetite ratings did not differ between treatments, except for hunger (AUC 22% lower after EN vs. CON; P = 0.031).. The observed immediate postprandial metabolic changes indicate that an easily manageable fortification of a single meal with powder from dried oyster mushrooms as β-glucan source may improve postprandial metabolism. If the effect is preserved long term, this measure can diminish the risk for further development of overweight/obesity and type 2 diabetes in subjects with IGT.. German Clinical Trial Register on 09/08/2018; trial-ID: DRKS00015244.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hunger; Insulin; Pleurotus; Postprandial Period; Powders; Sensation

Topics: Adult; Area Under Curve; Blood Glucose; Blood Glucose Self-Monitoring; Cross-Over Studies; Diet; Fasting; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Secretion; Male; Meals; Time Factors

Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed-nutrient meal. Fifteen healthy men and women completed the study. Each consumed a standard meal on four separate occasions with a superimposed infusion of

Topics: Adolescent; Adult; Blood Glucose; Female; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Humans; Insulin; Male; Postprandial Period; Young Adult

Specific combinations of dietary fiber (DF) have been observed to result in improved glucose tolerance at a subsequent standardized breakfast. Arabinoxylan oligosaccharides (AXOS) are considered as DF with prebiotic potential, but so far no studies have investigated their metabolic effects in humans. This randomized cross-over study evaluated the overnight impact of breads containing AXOS-rich wheat bran extract and resistant starch (RS, Hi-Maize), separately or combined, on glucose tolerance, related metabolic parameters and markers of gut fermentation in healthy subjects.. Evening reference and test products were: (1) reference white wheat flour bread (WWB), WWB supplemented with (2) AXOS and RS (WWB + AXOS + RS), (3) an increased content of either AXOS (WWB + hiAXOS) or (4) RS (WWB + hiRS). At the subsequent standardized breakfast, blood was sampled for 3 h to monitor glucose, insulin, nonesterified fatty acids, glucagon-like peptide (GLP)-1 and GLP-2. Breath hydrogen (H2) and short chain fatty acids (SCFA) were measured as markers of gut fermentation, and subjective appetite was rated using visual analog scales.. Dose-dependent decreases in glucose responses were observed with increased AXOS over the duration of 3 h. Insulin sensitivity index was improved in the morning after the WWB + hiAXOS evening meal. An increase in breath H2 concentration and circulating SCFA was observed in the morning after both evening meals containing AXOS.. The present study indicates that AXOS have the potential of improving glucose tolerance in an overnight perspective and suggested mechanisms are improved insulin sensitivity and increased gut fermentation.

Topics: Adult; Appetite; Biomarkers; Blood Glucose; Body Mass Index; Bread; Breakfast; Breath Tests; Cross-Over Studies; Dietary Fiber; Fatty Acids, Nonesterified; Fatty Acids, Volatile; Female; Fermentation; Flour; Food, Fortified; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Male; Oligosaccharides; Postprandial Period; Prebiotics; Starch; Xylans; 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

Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [(2)H5]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating β-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP, lowered TGD, and stimulated lipolysis, LOx, and ketogenesis. The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former. With chronic (4 weeks) versus acute (first dose) drug administration, glucose flux responses were attenuated, whereas lipid responses were enhanced; in patients with T2D, fasting β-hydroxybutyrate levels rose from 246 ± 288 to 561 ± 596 µmol/L (P < 0.01). We conclude that by shunting substantial amounts of carbohydrate into urine, SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates. The associated hormonal milieu (lower insulin-to-glucagon ratio) favors glucose release and ketogenesis.

Topics: 3-Hydroxybutyric Acid; Algorithms; Benzhydryl Compounds; C-Reactive Protein; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glucosides; Glycosuria; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Lipid Metabolism; Lipolysis; Membrane Transport Modulators; Renal Elimination; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Time Factors

Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans.. ClinicalTrials.gov NCT01434901.

Topics: Administration, Oral; Adult; Bethanechol; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Hormones; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Muscarinic Agonists; Neurotensin; Non-Randomized Controlled Trials as Topic; Pancreatic Polypeptide; Postprandial Period

Intake of sugar-sweetened beverages (SSB) may contribute to cardiovascular risk. The aim of this study was to investigate whether functional sugars with low compared to high glycemic index (GI) have beneficial effects on arterial stiffness during a period of low-physical activity. In a controlled cross-over dietary intervention (55% CHO, 30% fat, 15% protein), 13 healthy men (age: 23.7 ± 2.2 years, body mass index: 23.6 ± 1.9 kg/m²) completed 2 × 1 week of low physical activity following 1 week of normal physical activity (2363 ± 900 vs. 11,375 ± 3124 steps/day). During inactive phases participants consumed either low-GI (isomaltulose) or high-GI SSB (maltodextrin-sucrose), providing 20% of energy requirements. Postprandial vasodilatation (augmentation index, AIx), insulin sensitivity (IS) and Glucagon-like-peptide 1 (GLP-1) responses were measured during a meal test before and after SSB-intervention. Compared to maltodextrin-sucrose-SSB, postprandial vasodilatation was prolonged (AIx after 120 min: 9.9% ± 4.3% vs. 11.4% ± 3.7%,

Topics: Adult; Beverages; Cardiovascular Diseases; Cross-Over Studies; Dietary Carbohydrates; Dietary Sucrose; Exercise; Germany; Glucagon-Like Peptide 1; Glucose Intolerance; Glycemic Index; Humans; Insulin Resistance; Isomaltose; Male; Polysaccharides; Postprandial Period; Risk Factors; Sedentary Behavior; Single-Blind Method; Vascular Stiffness; Vasodilation

Topics: Administration, Intravenous; Aged; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Male; Middle Aged; Overweight

Secreted frizzled-related protein-5 (Sfrp5) is a novel adipocyte-secreted hormone that has been shown to link obesity with diabetes. Studies in mice have revealed that Sfrp5 represents a potential target for the control of obesity-linked abnormalities in glucose homeostasis.. Our objective was to gain insight into the physiological role of circulating Sfrp5 in humans.. We conducted a series of cross-sectional and interventional studies of the general population and outpatients of the Internal Medicine Department at the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Subjects included 104 healthy subjects, 101 with impaired glucose tolerance, and 112 with newly diagnosed type 2 diabetes mellitus and, in a separate study, 30 healthy women, and 32 women with polycystic ovarian syndrome (PCOS). Oral glucose tolerance test and euglycemic-hyperinsulinemic clamp were performed to assess glucose tolerance and insulin sensitivity.. Circulating Sfrp5 was significantly lower in both impaired glucose intolerance and newly diagnosed type 2 diabetes mellitus than in individuals with normal glucose tolerance (P < 0.01). Overweight/obese subjects had significantly lower Sfrp5 levels than lean individuals (P < 0.01), but females had higher Sfrp5 levels than males (P < 0.05). In a separate study, Sfrp5 levels were lower in PCOS women than healthy women (P < 0.05). Moreover, circulating Sfrp5 correlated with markers of adiposity, including body mass index, waist-to-hip ratio, percent body fat, homeostasis model assessment of insulin resistance, lipid profile, and adiponectin. Hyperglycemia decreased circulating Sfrp5 levels, whereas liraglutide increased Sfrp5 levels. In the euglycemic-hyperinsulinemic state, circulating Sfrp5 was significantly decreased in healthy women but not in PCOS women.. We conclude that circulating Sfrp5 is likely to play a major role in insulin resistance in humans.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Eye Proteins; Female; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Male; Membrane Proteins; Metabolic Diseases; 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

Newly detected impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM) are common in patients with acute coronary syndrome (ACS; i.e. unstable angina/myocardial infarction) and related to disturbed beta-cell function. The aim of this study is to test the hypothesis that treatment with a dipeptidyl peptidase-4 inhibitor initiated soon after a coronary event improves beta-cell function.. Acute coronary syndrome ACS patients with IGT or T2DM (n = 71), screened by oral glucose tolerance test (OGTT) 4-23 days (median 6 days) after hospital admission, were randomly assigned to sitagliptin 100 mg (n = 34) or placebo (n = 37) and treated for a duration of 12 weeks. All patients received lifestyle advice but no glucose-lowering agents other than the study drug. The study end-point was beta-cell function assessed using the insulinogenic index (IGI = ΔInsulin30 /ΔGlucose30 ), derived from an OGTT, and acute insulin response to glucose (AIRg) assessed by a frequently sampled intravenous glucose tolerance test.. The IGI and AIRg did not differ at baseline between the sitagliptin and placebo groups (69.9 vs. 66.4 pmol mmol(-1) and 1394 vs. 1106 pmol L(-1) min(-1) respectively). After 12 weeks, the IGI was 85.0 in the sitagliptin and 58.1 pmol/mmol in the placebo group (P = 0.013) and AIRg was 1909 and 1043 pmol L(-1) min(-1) (P < 0.0001) in the sitagliptin and placebo groups respectively. Fasting glucose at baseline was 6.1 mmol L(-1) in sitagliptin-treated patients and 6.0 mmol L(-1) in those who received placebo compared with 5.8 and 5.9 mmol L(-1) respectively, after 12 weeks of treatment. Post load glucose metabolism improved in significantly more sitagliptin-treated patients compared with the placebo group (P = 0.003). Sitagliptin was well tolerated.. Sitagliptin improved beta-cell function and glucose perturbations in patients with ACS and newly diagnosed glucose disturbances.

Topics: Acute Coronary Syndrome; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Follow-Up Studies; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Prospective Studies; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

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

Glucocorticoids (GCs) are regarded as diabetogenic because they impair insulin sensitivity and islet-cell function. This study assessed whether treatment with the glucagon-like peptide receptor agonist (GLP-1 RA) exenatide (EXE) could prevent GC-induced glucose intolerance.. A randomized, placebo-controlled, double-blind, crossover study in eight healthy men (age: 23.5 [20.0-28.3] years; BMI: 26.4 [24.3-28.0] kg/m(2)) was conducted. Participants received three therapeutic regimens for 2 consecutive days: 1) 80 mg of oral prednisolone (PRED) every day (q.d.) and intravenous (IV) EXE infusion (PRED+EXE); 2) 80 mg of oral PRED q.d. and IV saline infusion (PRED+SAL); and 3) oral placebo-PRED q.d. and intravenous saline infusion (PLB+SAL). On day 1, glucose tolerance was assessed during a meal challenge test. On day 2, participants underwent a clamp procedure to measure insulin secretion and insulin sensitivity.. PRED+SAL treatment increased postprandial glucose levels (vs. PLB+SAL, P = 0.012), which was prevented by concomitant EXE (vs. PLB+SAL, P = NS). EXE reduced PRED-induced hyperglucagonemia during the meal challenge (P = 0.018) and decreased gastric emptying (vs. PRED+SAL, P = 0.028; vs. PLB+SAL, P = 0.046). PRED+SAL decreased first-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL, P = 0.017 and P = 0.05, respectively), whereas PRED+EXE improved first- and second-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL; P = 0.017, 0.012, and 0.093, respectively).. The GLP-1 RA EXE prevented PRED-induced glucose intolerance and islet-cell dysfunction in healthy humans. Incretin-based therapies should be explored as a potential strategy to prevent steroid diabetes.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Exenatide; Glucagon-Like Peptide 1; Glucocorticoids; Glucose Clamp Technique; Glucose Intolerance; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Male; Peptides; Prednisone; Venoms; Young Adult

Improved glucose tolerance to sequential glucose loading (Staub-Traugott effect) is an important determinant of day-to-day glycemic exposure. Its mechanisms have not been clearly established. We recruited 17 healthy volunteers to receive two sequential oral glucose tolerance tests (OGTTs), at time 0 min and 180 min (Study I). The protocol was repeated on a separate day (Study II) except that plasma glucose was clamped at 8.3 mmol/l between 60 and 180 min. beta-Cell function was analyzed by mathematical modeling of C-peptide concentrations. In a subgroup, glucose kinetics were measured by a triple-tracer technique (infusion of [6,6-(2)H(2)]glucose and labeling of the 2 glucose loads with [1-(2)H]glucose and [U-(13)C]glucose). In both Studies I and II, the plasma glucose response to the second OGTT equaled 84 +/- 2% (P = 0.003) of the response to the first OGTT. Absolute insulin secretion was lower (37.8 +/- 4.3 vs. 42.8 +/- 5.1 nmol/m(2), P = 0.02), but glucose potentiation (i.e., higher secretion at the same glycemia) was stronger (1.08 +/- 0.02- vs. 0.92 +/- 0.02-fold, P = 0.006), the increment being higher in Study II (+36 +/- 5%) than Study I (+19 +/- 6%, P < 0.05). In pooled data, a higher glucose area during the first OGTT was associated with a higher potentiation during the second OGTT (rho=0.60, P = 0.002). Neither insulin clearance nor glucose clearance differed between loads, and appearance of glucose over 3 h totalled 60 +/- 6 g for the first load and 52 +/- 5 g for the second load (P = not significant). Fasting endogenous glucose production [13.3 +/- 0.6 micromol x min(-1) x kg fat-free mass (FFM)(-1)] averaged 6.0 +/- 3.8 micromol x min(-1) x kg FFM(-1) between 0 and 180 min and 1.7 +/- 2.6 between 180 and 360 min (P < 0.03). Glucose potentiation and stronger suppression of endogenous glucose release are the main mechanisms underlying the Staub-Traugott effect.

Topics: Adult; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Signal Transduction

This study was conducted to determine the effects of vildagliptin on incretin hormone levels, islet function, and postprandial glucose control in subjects with impaired glucose tolerance (IGT).. A 12-week, double-blind, randomized, parallel-group study comparing vildagliptin (50 mg q.d.) and placebo was conducted in 179 subjects with IGT (2-h glucose 9.1 mmol/l, A1C 5.9%). Plasma levels of intact glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide, and glucagon were measured during standard meal tests performed at baseline and at week 12. Insulin secretory rate (ISR) was estimated by C-peptide deconvolution. The between-group differences (vildagliptin - placebo) in the adjusted mean changes from baseline to end point in the total and incremental (Delta) area under the curve (AUC)(0-2 h) for these analytes were assessed by ANCOVA; glucose AUC(0-2 h) was the primary outcome variable.. Relative to placebo, vildagliptin increased GLP-1 (DeltaAUC, +6.0 +/- 1.2 pmol x l(-1) x h(-1), P < 0.001) and GIP (DeltaAUC, +46.8 +/- 5.4 pmol . l(-1) x h(-1), P < 0.001) and decreased glucagon (DeltaAUC, -3.0 +/- 1.0 pmol x l(-1) x h(-1), P = 0.003). Although postprandial insulin levels were unaffected (DeltaAUC, +20.8 +/- 35.7 pmol x l(-1) x h(-1), P = 0.561), prandial glucose excursions were reduced (DeltaAUC, -1.0 +/- 0.3 mmol x l(-1) x h(-1), P < 0.001), representing an approximately 30% decrease relative to placebo. Beta-cell function as assessed by the ISR AUC(0-2 h)/glucose AUC(0-2 h) was significantly increased (+6.4 +/- 2.0 pmol x min(-1) x m(-2) x mmol x l(-1), P = 0.002). Adverse event profiles were similar in the two treatment groups, and no hypoglycemia was reported.. The known effects of vildagliptin on incretin levels and islet function in type 2 diabetes were reproduced in subjects with IGT, with a 32% reduction in postprandial glucose excursions and no evidence of hypoglycemia or weight gain.

Topics: Adamantane; Blood Glucose; C-Peptide; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Inulin; Kinetics; Male; Nitriles; Placebos; Postprandial Period; Pyrrolidines; Vildagliptin

Low-glycemic index (GI) foods and foods rich in whole grain are associated with reduced risk of type 2 diabetes and cardiovascular disease. We studied the effect of cereal-based bread evening meals (50 g available starch), varying in GI and content of indigestible carbohydrates, on glucose tolerance and related variables after a subsequent standardized breakfast in healthy subjects (n = 15). At breakfast, blood was sampled for 3 h for analysis of blood glucose, serum insulin, serum FFA, serum triacylglycerides, plasma glucagon, plasma gastric-inhibitory peptide, plasma glucagon-like peptide-1 (GLP-1), serum interleukin (IL)-6, serum IL-8, and plasma adiponectin. Satiety was subjectively rated after breakfast and the gastric emptying rate (GER) was determined using paracetamol as a marker. Breath hydrogen was measured as an indicator of colonic fermentation. Evening meals with barley kernel based bread (ordinary, high-amylose- or beta-glucan-rich genotypes) or an evening meal with white wheat flour bread (WWB) enriched with a mixture of barley fiber and resistant starch improved glucose tolerance at the subsequent breakfast compared with unsupplemented WWB (P < 0.05). At breakfast, the glucose response was inversely correlated with colonic fermentation (r = -0.25; P < 0.05) and GLP-1 (r = -0.26; P < 0.05) and positively correlated with FFA (r = 0.37; P < 0.001). IL-6 was lower (P < 0.01) and adiponectin was higher (P < 0.05) at breakfast following an evening meal with barley-kernel bread compared with WWB. Breath hydrogen correlated positively with satiety (r = 0.27; P < 0.01) and inversely with GER (r = -0.23; P < 0.05). In conclusion, the composition of indigestible carbohydrates of the evening meal may affect glycemic excursions and related metabolic risk variables at breakfast through a mechanism involving colonic fermentation. The results provide evidence for a link between gut microbial metabolism and key factors associated with insulin resistance.

Topics: Adiponectin; Adult; Biomarkers; Blood Glucose; Carbohydrates; Digestion; Fatty Acids, Nonesterified; Female; Food Analysis; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Inflammation; Insulin; Interleukin-6; Interleukin-8; Male; Satiety Response; Triglycerides

The insulinotropic gut hormone glucagon-like peptide (GLP)-1 increases secretory burst mass and the amplitude of pulsatile insulin secretion in healthy volunteers without affecting burst frequency. Effects of GLP-1 on secretory mechanisms in type 2 diabetic patients and subjects with impaired glucose tolerance (IGT) known to have impaired pulsatile release of insulin have not yet been studied. Eight type 2 diabetic patients (64+/-9 years, BMI 28.9+/-7.2 kg/m2, HbA1c 7.7+/-1.3%) and eight subjects with IGT (63+/-10 years, BMI 31.7+/-6.4 kg/m2, HbA1c 5.7+/-0.4) were studied on separate occasions in the fasting state during the continued administration of exogenous GLP-1 (1.2 pmol x kg(-1) x min(-1), started at 10:00 P.M. the evening before) or placebo. For comparison, eight healthy volunteers (62+/-7 years, BMI 27.7+/-4.8 kg/m2, HbA1c 5.4+/-0.5) were studied only with placebo. Blood was sampled continuously over 60 min (roller-pump) in 1-min fractions for the measurement of plasma glucose and insulin. Pulsatile insulin secretion was characterized by deconvolution, autocorrelation, and spectral analysis and by estimating the degree of randomness (approximate entropy). In type 2 diabetic patients, exogenous GLP-1 at approximately 90 pmol/l improved plasma glucose concentrations (6.4+/-2.1 mmol/l vs. placebo 9.8+/-4.1 mmol/l, P = 0.0005) and significantly increased mean insulin burst mass (by 68%, P = 0.007) and amplitude (by 59%, P = 0.006; deconvolution analysis). In IGT subjects, burst mass was increased by 45% (P = 0.019) and amplitude by 38% (P = 0.02). By deconvolution analysis, insulin secretory burst frequency was not affected by GLP-1 in either type 2 diabetic patients (P = 0.15) or IGT subjects (P = 0.76). However, by both autocorrelation and spectral analysis, GLP-1 prolonged the period (lag time) between subsequent maxima of insulin concentrations significantly from approximately 9 to approximately 13 min in both type 2 diabetic patients and IGT subjects. Under placebo conditions, parameters of pulsatile insulin secretion were similar in normal subjects, type 2 diabetic patients, and IGT subjects based on all methodological approaches (P > 0.05). In conclusion, intravenous GLP-1 reduces plasma glucose in type 2 diabetic patients and improves the oscillatory secretion pattern by amplifying insulin secretory burst mass, whereas the oscillatory period determined by autocorrelation and spectral analysis is significantly prolonged. This was not the case

Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Entropy; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Hormones; Humans; Injections, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged; Osmolar Concentration; Peptide Fragments; Protein Precursors; Pulsatile Flow; Reference Values

The contribution of endogenous glucagon-like peptide (GLP)-1 to β-cell function after Roux-en-Y gastric bypass surgery (RYGB) is well established in normoglycaemic individuals, but not in those with postoperative hyperglycaemia. We, therefore, studied the effect of GLP-1 on β-cell function in individuals with varying degrees of type 2 diabetes mellitus (T2D) control after RYGB.. EX9 blunted the increase in β-cell glucose sensitivity at 3 months (-44.1%, p < .001) and 12 months (-43.3%, p < .001), but not at 24 months (-12.4%, p = .243). EX9 enhanced postprandial glucagon concentrations by 62.0% at 3 months (p = .008), 46.5% at 12 months (p = .055), and 30.4% at 24 months (p = .017). EX9 counterintuitively decreased glucose concentrations at 3 months in the entire cohort (p < .001) but had no effect on glycaemia at 12 and 24 months in persistent T2D and impaired glucose tolerance; it minimally worsened glycaemia in REM at 12 months.. GLP-1 blockade reversed the improvement in β-cell function observed after RYGB, but this effect varied temporally and by REM status. GLP-1 blockade transiently and minimally worsened glycaemia only in REM, and lowered postprandial glucose values at 3 months, regardless of REM status.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Humans; Insulin; Retrospective Studies

We constructed a recombinant oral GLP-1 analogue in Lactococcus lactis (L. lactis) and evaluated its physiological functions.. In silico docking suggested the alanine at position 8 substituted with serine (A8SGLP-1) reduced binding of DPP4, which translated to reduced cleavage by DPP4 with minimal changes in stability. This was further confirmed by an in vitro enzymatic assay which showed that A8SGLP-1 significantly increased half-life upon DPP4 treatment. In addition, recombinant L. lactis (LL-A8SGLP-1) demonstrated reduced fat mass with no changes in body weight, significant improvement of random glycemic control and reduced systemic inflammation compared with WT GLP-1 in db/db mice.. LL-A8SGLP-1 adopted in live biotherapeutic products reduce blood glucose in db/db mice without affecting its function.

Topics: Alanine; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Mice; Mice, Inbred C57BL; Serine

Recently, the duodenum has garnered interest for its role in treating metabolic diseases, including type 2 diabetes (T2DM). Multiple sessions of external photobiomodulation (PBM) in previous animal studies suggested it resulted in improved hyperglycemia, glucose intolerance, and insulin resistance with a multifactorial mechanism of action, despite the target organ of PBM not being clearly proven. This study aimed to determine whether a single session of a duodenal light-emitting diode (LED) PBM may impact the T2DM treatment in an animal model.. Goto-Kakizaki rats as T2DM models were subjected to PBM through duodenal lumen irradiation, sham procedure, or control in 1-week pilot (630 nm, 850 nm, or 630/850 nm) and 4-week follow-up (630 nm or 630/850 nm) studies. Oral glucose tolerance tests; serum glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, and insulin levels; liver chemistry and histology; and gut microbiome in the PBM, sham control, and control groups were evaluated.. In the 1-week study, duodenal dual-wavelength (D, 630/850 nm) LED PBM showed improved glucose intolerance, alkaline phosphatase and cholesterol levels, and weight gain than other groups. The D-LED PBM group in the 4-week study also showed improved hyperglycemia and liver enzyme levels, with relatively preserved pancreatic islets and increased serum insulin and GLP-1 levels. Five genera (. A single session of D-LED PBM improved hyperglycemia and hepatic parameters through the change of serum insulin, insulin resistance, insulin expression in the pancreatic β-cells, and gut microbiome in T2DM animal models.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Duodenum; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Resistance; Liver; Rats

Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on β-cells plays an indispensable role. Recently, α-cell-derived glucagon but not intestine-derived GLP-1 has been proposed as the critical hormone that potentiates GSIS via GLP-1R. However, the function of glucagon receptors (GCGR) on β-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single β-cells, α-β cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via β-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse β-cells with RAB-ICUE (a genetically encoded cAMP fluorescence indicator) to monitor cAMP level after glucose stimulation and GCGR activation. Using specific inhibitors of different adenylyl cyclase (AC) family members, we revealed that high glucose concentration or GCGR activation independently evoked cAMP elevation via AC5 in β-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated β-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that β-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload.

Topics: Animals; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Glucagon; Signal Transduction

Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy.. We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp.. Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9-a GLP-1 receptor antagonist-worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates.. Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Diet, High-Fat; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Clamp Technique; Glucose Intolerance; Ibuprofen; Insulin; Insulin Resistance; Intestinal Diseases; Liver; Mice; Mice, Inbred C57BL

Elevation of glucagon levels and increase in α-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls glucagon secretion and α-cell mass. In the current studies we investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in α-cells (αTSC2

Topics: Animals; Blood Glucose; Body Weight; Disease Models, Animal; Disease Susceptibility; Eating; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose Intolerance; Insulin; Insulin Secretion; Mechanistic Target of Rapamycin Complex 1; Mice; Receptors, Glucagon; Signal Transduction; Tuberous Sclerosis Complex 2 Protein

Nutrient-mediated release of cholecystokinin and glucagon-like peptide-1 (GLP-1) regulates gastric emptying (GE) via duodenogastric feedback mechanisms; GLP-1 also regulates postprandial insulin secretion. Some patients with functional upper gastrointestinal symptoms have impaired glucose tolerance during enteral dextrose infusion. Our hypothesis was that variants in CCK, GLP-1, and TCF7L2 (transcription factor 7-like 2 locus), which is associated with greatest genetic risk for development of type 2 diabetes mellitus, are associated with GE and independently with glucose tolerance. Our aims were to evaluate the associations between these GE, glucose tolerance, and these single nucleotide polymorphisms (SNPs).. Genetic variants, scintigraphic GE of solids, plasma glucose, insulin, and GLP-1 during enteral dextrose infusion (75gm over 2 hours) were measured. GE and enteral dextrose infusion were, respectively, evaluated in 44 (27 controls and 17 patients with functional dyspepsia or nausea) and 42 (28 controls, 14 patients) participants; of these, 51 participants consented to assessment of SNPs. Four functional SNPs were studied: rs6923761 and rs1042044 at GLP-1 receptor, rs7903146 (TCF7L2), and rs1800857 (CCK receptor).. Gastric emptying was normal in 38, rapid in 4, and delayed in two participants; 38 had normal, and four had impaired glucose tolerance. The T allele at rs7903146 (TCF7L2) was non-significantly associated (P = .14) with faster GE. The associations between SNPs and demographic variables, GE t. There is a trend toward an association between faster GE and the diabetes-associated allele at rs7903146 in TCF7L2. However, these SNPs were not associated with plasma glucose or GLP1 concentrations during enteral dextrose infusion.

Topics: Adult; Female; Gastric Emptying; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Cholecystokinin; Transcription Factor 7-Like 2 Protein

Osteocalcin is a bone-derived hormone that in its uncarboxylated form (GluOC) plays an important role in glucose and energy metabolism by stimulating insulin secretion and pancreatic β-cell proliferation through its putative receptor GPRC6A. We previously showed that the effect of GluOC on insulin secretion is mediated predominantly by glucagon-like peptide-1 (GLP-1) released from intestinal endocrine cells in response to GluOC stimulation. Moreover, oral administration of GluOC was found to reduce the fasting blood glucose level, to improve glucose tolerance, and to increase the fasting serum insulin concentration and β-cell area in the pancreas in wild-type mice. We have now examined the effects of oral GluOC administration for at least 4 weeks in GLP-1 receptor-knockout mice. Such administration of GluOC in the mutant mice triggered glucose intolerance, enhanced gluconeogenesis and promoted both lipid accumulation in the liver as well as adipocyte hypertrophy and inflammation in adipose tissue. Furthermore, inactivation of GLP-1 receptor signaling in association with GluOC administration induced activation of the transcription factor FoxO1 and expression of its transcriptional coactivator PGC1α in the liver, likely accounting for the observed upregulation of gluconeogenic gene expression. Our results thus indicate that the beneficial metabolic effects of GluOC are dependent on GLP-1 receptor signaling.

Topics: Animals; Blood Glucose; Female; Forkhead Box Protein O1; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin-Secreting Cells; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteocalcin; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptors, Glucagon

Glucose-dependent insulinotropic polypeptide (GIP) is released primarily from the proximal small intestine and glucagon-like peptide-1 (GLP-1) from the more distal small intestine and colon. Their relative importance to the incretin effect in health has been contentious in the past, although it now appears that GIP has the dominant role. It is uncertain whether there is a relationship between GIP and GLP-1 secretion. We aimed to evaluate the relationship between plasma GIP and GLP-1 responses to a 75-g oral glucose load in individuals with normal (NGT) and impaired glucose tolerance (IGT).. One hundred healthy subjects had measurements of blood glucose, serum insulin, plasma GIP and GLP-1 concentrations for 240 min after a 300 mL drink containing 75 g glucose.. Fifty had NGT and 41 IGT; 9 had type 2 diabetes and were excluded from analysis. In both groups, there were increases in plasma GIP and GLP-1 following the glucose drink, with no difference in the magnitude of the responses between t = 0-240 min. There was a weak relationship between the iAUC. There is a weak relationship between oral glucose-induced GIP and GLP-1 secretions in non-diabetic subjects.

Topics: Aged; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Male

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

The relationship between disturbances in glucose homeostasis and heart failure (HF) progression is bidirectional. However, the mechanisms by which HF intrinsically impairs glucose homeostasis remain unknown. The present study tested the hypothesis that the bioavailability of intact glucagon-like peptide-1 (GLP-1) is affected in HF, possibly contributing to disturbed glucose homeostasis. Serum concentrations of total and intact GLP-1 and insulin were measured after an overnight fast and 15 min after the ingestion of a mixed breakfast meal in 49 non-diabetic patients with severe HF and 40 healthy control subjects. Similarly, fasting and postprandial serum concentrations of these hormones were determined in sham-operated rats, and rats with HF treated with an inhibitor of the GLP-1-degrading enzyme dipeptidyl peptidase-4 (DPP4), vildagliptin, or vehicle for 4 weeks. We found that HF patients displayed a much lower increase in postprandial intact and total GLP-1 levels than controls. The increase in postprandial intact GLP-1 in HF patients correlated negatively with serum brain natriuretic peptide levels and DPP4 activity and positively with the glomerular filtration rate. Likewise, the postprandial increases in both intact and total GLP-1 were blunted in HF rats and were restored by DPP4 inhibition. Additionally, vehicle-treated HF rats displayed glucose intolerance and hyperinsulinemia, whereas normal glucose homeostasis was observed in vildagliptin-treated HF rats. We conclude that the postprandial increase in GLP-1 is blunted in non-diabetic HF. Impaired GLP-1 bioavailability after meal intake correlates with poor prognostic factors and may contribute to the establishment of a vicious cycle between glucose disturbance and HF development and progression.

Topics: Aged; Animals; Blood Glucose; C-Peptide; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Heart Failure; Humans; Insulin; Male; Middle Aged; Obesity; Peptide Fragments; Postprandial Period; Rats, Wistar

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

Postprandial hyperglycemia interferes with vascular reactivity and is a strong predictor of cardiovascular disease. Macronutrient preloads reduce postprandial hyperglycemia in subjects with impaired glucose tolerance (IGT) or type 2 diabetes (T2D), but the effect on endothelial function is unknown. Therefore, we examined whether a protein/lipid preload can attenuate postprandial endothelial dysfunction by lowering plasma glucose responses in subjects with IGT/T2D. Endothelial function was assessed by the reactive hyperemia index (RHI) at fasting, 60 min and 120 min during two 75 g oral glucose tolerance tests (OGTTs) preceded by either water or a macronutrient preload (i.e., egg and parmesan cheese) in 22 volunteers with IGT/T2D. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, free fatty acids, and amino acids were measured through each test. RHI negatively correlated with fasting plasma glucose. During the control OGTT, RHI decreased by 9% and its deterioration was associated with the rise in plasma glucose. The macronutrient preload attenuated the decline in RHI and markedly reduced postprandial glycemia. The beneficial effect of the macronutrient preload on RHI was proportional to the improvement in glucose tolerance and was associated with the increase in plasma GLP-1 and arginine levels. In conclusion, a protein/lipid macronutrient preload attenuates glucose-induced endothelial dysfunction in individuals with IGT/T2D by lowering plasma glucose excursions and by increasing GLP-1 and arginine levels, which are known regulators of the nitric oxide vasodilator system.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Fats; Dietary Proteins; Endothelium, Vascular; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Postprandial Period; Young Adult

Hypoglycemia in cystic fibrosis (CF), in the absence of glucose-lowering therapies, has long been identified as an important issue in the management of CF. There is currently still no unifying hypothesis for its etiology.. The aims of this study were to perform a 3-h oral glucose tolerance test (OGTT) in participants with CF and (1) document glucose, insulin, glucagon, glucagon-like-peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) release patterns within varying glucose tolerance groups during the OGTT; (2) determine the prevalence of hypoglycemic during the OGTT; and (3) define any association between hypoglycemia and patterns of insulin, glucagon, GLP-1, and GIP release.. Eligible participants attending an adult CF clinic completed a 3-h OGTT. Hypoglycemia on OGTT was defined as mild (glucose 3.4-3.9 mmol/L), moderate (glucose 3.1-3.3 mmol/L), and severe (glucose ≤ 3 mmol/L). Hormones were measured at fasting, 30, 60, 120, and 180 min.. Twenty-four participants completed the study, of which 7 had normal glucose tolerance, 12 had abnormal glucose tolerance, and 5 had cystic fibrosis related diabetes (CFRD). All participants had a delayed insulin response compared with normative data. All glucose tolerance groups showed appropriate and similar suppression of fasting glucagon. Four participants (17%) had mild hypoglycemic, three (13%) had moderate hypoglycemic, and eight (33%) had severe hypoglycemic. No participant with CFRD demonstrated hypoglycemic. Of the 19 participants without CFRD, 15 (79%) experienced hypoglycemic. Participants with hypoglycemic had greater peak glucose and insulin responses than those that did not have hypoglycemic, and this approached significance (p = .0625 for glucose and p = .0862 for insulin). No significant mean differences between GLP-1 and GIP release were found. There was no relationship between hypoglycemic and modulator therapy.. Postprandial hypoglycemic was unmasked by the extension of an OGTT to 3 h. Delayed and abnormal insulin release, and ineffective counter-regulatory action of glucagon may have a role in its etiology.

Topics: Adolescent; Adult; Blood Glucose; Cystic Fibrosis; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Male; Young Adult

Dipeptidyl peptidase IV (DPP-4) and Glucagon like peptide 1 (GLP-1) has profound effect on insulin and glucagon secretion; ultimately decreasing glucose levels. We find out the association of GLP-1 levels and DPP-4 in normal, impaired and newly diagnose type 2 diabetic glucose tolerance. Prospective case control study was conducted at Department of Physiology, Baqai Medical University by the collaboration of Baqai Institute of Diabetology and Endocrinology; Karachi-Pakistan. Study groups were categorized into three groups Control, Impaired glucose tolerant (IGT) and newly diagnose type 2 diabetes mellitus (NDD). Biochemical parameters were estimated by international standard protocols. Logistic regression analysis and Chi square test with statistical significance at p value <0.05 were applied. DPP-4 concentrations were significantly lower in NDD participants compared to control and IGT participants (p=0.01), whereas GLP-1 levels were significantly higher in Control than Impaired glucose tolerant and NDD (p = 0.013). GLP1 levels and SBP were also found to be positively correlated with serum DPP4 levels in NDD group (p<0.05). GLP1 and DPP4 levels in NDD group (p<0.05) and in controls (p<0.001) respectively showed strong significant positive correlation. Effective correlation between GLP1 and DPP4 was found as both contribute to control hyperglycemia in NDD and impaired glucose tolerant people.

Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Logistic Models; Prospective Studies

It is not known whether glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels correlate within individuals, nor whether levels change with age. Previous studies have all been cross-sectional in design.. To evaluate longitudinal changes in fasting and glucose-stimulated incretin hormone concentrations in healthy older subjects.. Forty-one healthy older subjects had measurements of plasma GLP-1 and GIP while fasting and after a 75-g oral glucose load on two occasions separated by 5.9 ± 0.1 years [mean age at the initial study: 71.2 ± 3.8 (SD) years]. Breath samples were collected to calculate the gastric 50% emptying time (T50).. For GLP-1, both fasting concentrations (P < 0.001) and area under the curve 0 to 120 minutes (P = 0.001) were decreased at followup. Fasting GIP was also lower (P = 0.03) at follow up, but there was no change in the area under the curve 0 to 120 minutes (P = 0.26). The gastric emptying T50 was slower at followup (P = 0.008). Neither the change in T50 nor the body mass index at the initial study was a determinant of the change in incretin responses. Between the two study days, fasting GIP (r = 0.72, P < 0.001) correlated well, but not fasting GLP-1 (r = 0.23, P = 0.18). However, both glucose-stimulated GLP-1 (r = 0.50, P = 0.002) and GIP (r = 0.60, P < 0.001) showed correlations between the initial and follow-up studies.. Fasting GIP and glucose-stimulated GLP-1 and GIP concentrations correlate within individuals over a follow-up period of ∼5.9 years. Aging is associated with reductions in fasting GLP-1 and GIP, and glucose-stimulated GLP-1, which may predispose to the development of glucose intolerance and type 2 diabetes.

Topics: Aged; Biomarkers; Blood Glucose; Cross-Sectional Studies; Fasting; Female; Follow-Up Studies; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Healthy Volunteers; Humans; Longitudinal Studies; Male; Prognosis

Previous studies indicated delayed gastric emptying in patients with end-stage renal disease (ESRD) using indirect methods. The objective of the current study was to examine gastrointestinal motility using a direct method as well as the role of the incretin hormones and glucagon.. Patients on chronic hemodialysis and with either normal glucose tolerance, impaired glucose tolerance or type 2 diabetes, and healthy control subjects (N = 8, respectively) were studied. Gastric emptying time was measured by repeated gamma camera imaging for 6 hours after intake of a radioactive labeled standardized mixed solid and liquid meal. Glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) levels were measured.. Patients were age, gender and BMI matched with controls. We found significantly higher gastric retention at 15 minutes, prolonged gastric mean emptying time, and gastric half-emptying time of the solid marker in all three groups of ESRD patients compared to controls. Significant differences in mean total area under the concentration curve (AUC) values across the four groups for GIP (P = 0.001), but not for GLP-1 and glucagon. The ESRD group had significant higher total AUC of GIP and glucagon compared to controls (P < 0.001 and P < 0.04) but not for GLP-1 (P = 0.4). No difference in incremental AUC was found.. We found altered gastrointestinal motility in dialysis patients, with higher gastric retention and prolonged gastric emptying, and higher total AUC of GIP and glucagon independent of the presence of diabetes or prediabetes.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Motility; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced

Topics: Animals; Cells, Cultured; Chemotaxis; Chromatography, Liquid; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; In Situ Hybridization, Fluorescence; Insulin; Male; Mass Spectrometry; Mice; Mice, Knockout; Mice, Obese; Microbiota; Obesity; Oligopeptides

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

The hindgut theory hypothesizes a key role of differential hindgut stimulation following metabolic procedures in ameliorating diabetes mellitus. We used two strategies to remove the hindgut from intestinal continuity in order to analyze its impact on diabetes mellitus.. Loop duodeno-jejunostomy (DJOS) with exclusion of one-third of total intestinal length was performed in 3 groups of 9-week-old Zucker diabetic fatty rats. In group 1, no further alteration of the intestinal tract was made. Group 2 received additional ileal exclusion (IE). Group 3 underwent additional resection of 50% of the ileum with side-to-side ileocecal anastomosis (IR). One, 2, and 4 months after surgery, fasting blood glucose levels, oral glucose tolerance tests (OGTT), and glucose-stimulated hormone analyses were conducted, and bile acid blood levels were compared. Body weight was documented weekly.. In relation to DJOS, glucose control was not impaired in IR or IE. On the contrary, only IR could maintain preOP glucose values until 4 months. There were no significant weight differences between the groups. Confirming effective ileal diversion, bile acid blood levels were significantly higher in the DJOS group compared with both IR and IE (p = 0.0025 and p = 0.0047). Operative interventions had no impact on GLP-1 levels at any time point (ANOVA p > 0.05 for all). Insulin secretion was preserved in all groups.. This data supports the hypothesis that the mechanisms driving amelioration of diabetes mellitus are complex and cannot be reduced to the ileum.

Topics: Animals; Bile Acids and Salts; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Duodenum; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Ileum; Insulin; Intestine, Small; Jejunum; Male; Random Allocation; Rats; Rats, Zucker

Glucagon-like peptide-1 (GLP-1) contributes to insulin secretion after meals. Though Hispanics have increased risk for type 2 diabetes mellitus, it is unknown if impaired GLP-1 secretion contributes to this risk. We therefore studied plasma GLP-1 secretion and action in Hispanic adults.. Hispanic (H; n = 31) and non-Hispanic (nH; n = 15) participants underwent an oral glucose tolerance test (OGTT). All participants were categorized by glucose tolerance into four groups: normal glucose tolerant non-Hispanic (NGT-nH; n = 15), normal glucose tolerant Hispanic (NGT-H; n = 12), impaired glucose tolerant Hispanic (IGT-H; n = 11), or newly diagnosed type 2 diabetes mellitus, Hispanic (T2D-H; n = 8).. Glucose-induced increments in plasma GLP-1 (Δ-GLP-1) were not different in NGT-H and NGT-nH (p = .38), nor amongst Hispanic subgroups with varying degrees of glucose homeostasis (p = .6). In contrast, the insulinogenic index in T2D-H group was lower than the other groups (p = .016). Subjects with abnormal glucose homeostasis (AGH), i.e., T2D-H plus IGT-H, had a diminished glucagon suppression index compared to patients with normal glucose homeostasis (NGT-H plus NGT-nH) (p = .035).. GLP-1 responses to glucose were similar in Hispanic and Non-Hispanic NGT. Despite similar glucose-induced Δ-GLP-1, insulin and glucagon responses were abnormal in T2D-H and AGH, respectively. Thus, impaired GLP-1 secretion is unlikely to play a role in islet dysfunction in T2D. Although GLP-1 therapeutics enhance insulin secretion and glucagon suppression, it is likely due to pharmacological amplification of the GLP-1 pathways rather than treatment of hormonal deficiency.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Hispanic or Latino; Humans; Male; Middle Aged

Three-dimensional (3D) pseudoislets (PIs) can be used for the study of insulin-producing β-cells in free-floating islet-like structures similar to that of primary islets. Previously, we demonstrated the ability of islet-derived endothelial cells (iECs) to induce PIs using murine insulinomas, where PI formation enhanced insulin production and glucose responsiveness. In this report, we examined the ability of iECs to spontaneously induce the formation of free-floating 3D PIs using the EndoC-βH1 human β-cell line murine MS1 iEC. Within 14 days, the coculturing of both cell types produced fully humanized EndoC-βH1 PIs with little to no contaminating murine iECs. The size and shape of these PIs were similar to primary human islets. iEC-induced PIs demonstrated reduced dysregulated insulin release under low glucose levels and higher insulin secretion in response to high glucose and exendin-4 [a glucagon-like peptide-1 (GLP-1) analog] compared with monolayer cells cultured alone. Interestingly, iEC-PIs were also better at glucose sensing in the presence of extendin-4 compared with PIs generated on a low-adhesion surface plate in the absence of iECs and showed an overall improvement in cell viability. iEC-induced PIs exhibited increased expression of key genes involved in glucose transport, glucose sensing, β-cell differentiation, and insulin processing, with a concomitant decrease in glucagon mRNA expression. The enhanced responsiveness to exendin-4 was associated with increased protein expression of GLP-1 receptor and phosphokinase A. This rapid coculture system provides an unlimited number of human PIs with improved insulin secretion and GLP-1 responsiveness for the study of β-cell biology.

Topics: Cells, Cultured; Coculture Techniques; Endothelial Cells; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Signal Transduction

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

Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell-specific

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Gastroplasty; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Organ Specificity; Signal Transduction; Tissue Culture Techniques; Weight Loss

Glucagon-like peptide 1 (GLP1) is produced by L cells in the intestine, and agonists of the GLP1 receptor are effective in the treatment of diabetes. Levels of GLP1 increase with numbers of L cells. Therefore, agents that increase numbers of L cell might be developed for treatment of diabetes. Ras homologue family member A (RhoA) signaling through Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) controls cell differentiation, but it is not clear whether this pathway regulates enteroendocrine differentiation in the intestinal epithelium. We investigated the effects of Y-27632, an inhibitor of ROCK1 and ROCK2, on L-cell differentiation.. We collected intestinal tissues from GLU-Venus, GPR41-RFP, and Neurog3-RFP mice, in which the endocrine lineage is fluorescently labeled, for in vitro culture and histologic analysis. Small intestine organoids derived from these mice were cultured with Y-27632 and we measured percentages of L cells, expression of intestinal cell-specific markers, and secretion of GLP1 in medium. Mice were fed a normal chow or a high-fat diet and given Y-27632 or saline (control) and blood samples were collected for measurement of GLP1, insulin, and glucose.. Incubation of intestinal organoids with Y-27632 increased numbers of L cells and secretion of GLP1. These increases were associated with upregulated expression of genes encoding intestinal hormones, neurogenin 3, neurogenic differentiation factor 1, forkhead box A1 and A2, and additional markers of secretory cells. Mice fed the normal chow diet and given Y-27632 had increased numbers of L cells in intestinal tissues, increased plasma levels of GLP1 and insulin, and lower blood levels of glucose compared with mice fed the normal chow diet and given saline. In mice with insulin resistance induced by the high-fat diet, administration of Y-27632 increased secretion of GLP1 and glucose tolerance compared with administration of saline.. In mouse intestinal organoids, an inhibitor of RhoA signaling increased the differentiation of the secretory lineage and the development of enteroendocrine cells. Inhibitors of RhoA signaling or other strategies to increase numbers of L cells might be developed for treatment of patients with type 2 diabetes or for increasing glucose tolerance.

Topics: Amides; Animals; Biomarkers; Blood Glucose; Cell Differentiation; Cell Lineage; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Ileum; Insulin; Insulin Resistance; Male; Mice, Inbred C57BL; Mice, Transgenic; Organoids; Phenotype; Protein Kinase Inhibitors; Pyridines; rho GTP-Binding Proteins; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Stem Cells; Time Factors; Tissue Culture Techniques

Diabetes and obesity are characterized by glucose intolerance, fat deposition, inflammation, and dyslipidemia. Recent reports postulated that distinct gut microbiota alterations were observed in obese/diabetic subjects and modulating gut microbiota beneficially through specific probiotics could be a potential therapeutic option for type 2 diabetes/obesity. Therefore, we attempted to study the efficacy of probiotics of Indian gut origin (Lactobacillus plantarum MTCC5690 and Lactobacillus fermentum MTCC5689) along with a positive control, Lactobacillus rhamnosus (LGG) on glucose/lipid homeostasis in high-fat-diet-induced diabetic animal model.. C57BL/6J male mice were divided into seven groups (n = 6 per group) comprising feeding on: (1) Normal Pellet Diet (NPD), (2) High-Fat Diet (HFD), (3) HFD with LGG, (4) HFD with MTCC5690, (5) HFD with MTCC5689, (6) HFD with metformin, and 7) HFD with vildagliptin for a period of 6 months. Biochemical markers, glucose tolerance, insulin resistance, and GLP-1 and LPS levels were assessed by standard protocols. Gut integrity was measured by intestinal permeability test. Transcriptional levels of tight junction proteins (TJPs) were probed in small intestinal tissues while inflammatory signals and other pathway specific genes were profiled in liver, visceral adipose tissue, and skeletal muscle.. Mice fed with HFD became insulin resistant, glucose intolerant, hyperglycemic, and dyslipidemic. Diabetic mice were characterized to exhibit decreased levels of GLP-1, increased gut permeability, increased circulatory levels of LPS, decrease in the gene expression patterns of intestinal tight junction markers (occludin and ZO-1), and increased proinflammatory gene markers (TNFα and IL6) in visceral fat along with decreased mRNA expression of FIAF and adiponectin. Diabetic mice also exhibited increased mRNA expression of ER stress markers in skeletal muscle. In addition, liver from HFD-fed diabetic mice showed increased gene expressions of proinflammation, lipogenesis, and gluconeogenesis. Probiotic interventions (most prominently the MTCC5689) resisted insulin resistance and development of diabetes in mice under HFD feeding and beneficially modulated all the biochemical and molecular alterations in a mechanistic way in several tissues. The metabolic benefits offered by the probiotics were also more or less similar to that of standard drugs such as metformin and vildagliptin.. Native probiotic strains MTCC 5690 and MTCC 5689 appear to have potential against insulin resistance and type 2 diabetes with mechanistic, multiple tissue-specific mode of actions.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dyslipidemias; Endoplasmic Reticulum Stress; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose Intolerance; India; Inflammation; Insulin Resistance; Lactobacillus plantarum; Limosilactobacillus fermentum; Lipids; Lipogenesis; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Probiotics; Transcriptome

Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes.

Topics: Adaptation, Physiological; Aging; Animals; Diet, High-Fat; Diphtheria Toxin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice, Inbred C57BL; Mice, Knockout; Obesity; Proprotein Convertases; Rats; Stress, Physiological

Pancreatic-derived factor (PANDER) is a pancreatic islet-specific cytokine that co-secretes with insulin. However, its biological function remains largely unknown. We have recently shown that the intestine might be its novel target tissue. The aim of this study was to clarify whether PANDER impacts the production of glucagon-like peptide-1 (GLP-1).. We treated GLUTag cells from the mouse intestine L cell line with recombinant PANDER protein and hepatic overexpression of PANDER in an obese murine model.. In GLUTag cells, PANDER exposure led to decreased proglucagon gene mRNA expression and GLP-1 secretion without affecting cell viability or caspase-3 activation. Overexpression of PANDER in mice induced glucose intolerance and impaired glucose-stimulated GLP-1 secretion Moreover, PANDER blocked insulin-induced GLP-1 secretion by inhibiting the insulin signalling-Wnt pathway and directly inhibited the cAMP/PKA pathway.. Our findings indicate that intestinal L cells are responsive to PANDER, and elevated PANDER levels impair GLP-1 production in vitro and in vivo.

Topics: Animals; Blood Glucose; Caspase 3; Cell Line; Cytokines; Diet, High-Fat; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Secretion; Intestinal Mucosa; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese

Glucagon-like peptide 1 plays a role in glucose regulation. Sleep disturbances (obstructive sleep apnea, insufficient or poor sleep quality) have been shown to adversely affect glucose metabolism. This study aimed to explore the relationship between sleep and glucagon-like peptide 1 regulation in patients with abnormal glucose tolerance. Seventy-one adults with haemoglobin A1c levels between 5.7% and < 6.5% and no history of diabetes participated. Habitual sleep duration and efficiency were obtained from 7-day actigraphy recordings. Obstructive sleep apnea was assessed using an overnight home monitor. Glucagon-like peptide 1 levels were measured during a 75-g glucose tolerance. The area under the curve of glucagon-like peptide 1 was calculated. The mean age (SD) was 55.1 (8.3) years and median (interquartile range) haemoglobin A1c was 5.97% (5.86, 6.23). There was no relationship between sleep duration or efficiency and fasting or area under the curve glucagon-like peptide 1. Glucagon-like peptide 1 levels did not differ among those sleeping ≤ 5.75, > 5.75-< 6.5 or ≥ 6.5 h per night. Increasing apnea-hypopnea index, an indicator of obstructive sleep apnea severity, correlated with lower area under the curve glucagon-like peptide 1 (B -0.242, P = 0.045), but not with fasting glucagon-like peptide 1 (B -0.213, P = 0.079). After adjusting for sex, haemoglobin A1c and body mass index, increasing apnea-hypopnea index was negatively associated with having area under the curve glucagon-like peptide 1 in the highest quartile (odds ratio 0.581, P = 0.028, 95% CI 0.359, 0.942). This study demonstrated that increasing obstructive sleep apnea severity was associated with lower glucagon-like peptide 1 response to glucose challenge. This could possibly be an additional mechanism by which obstructive sleep apnea affects glucose metabolism. Whether raising glucagon-like peptide 1 levels in patients with abnormal glucose tolerance with more severe obstructive sleep apnea will be beneficial should be explored.

Topics: Actigraphy; Blood Glucose; Body Mass Index; Fasting; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Male; Middle Aged; Sleep; Sleep Apnea, Obstructive; Time Factors

We examined whether glucagon-like peptide-1 (GLP-1) affects β-cell mass and proliferation through neural pathways, from hepatic afferent nerves to pancreatic efferent nerves via the central nervous system, in high-fat diet (HFD)-induced obese rats. The effects of chronic administration of GLP-1 (7-36) and liraglutide, a GLP-1 receptor agonist, on pancreatic morphological alterations, c-fos expression and brain-derived neurotrophic factor (BDNF) content in the hypothalamus, and glucose metabolism were investigated in HFD-induced obese rats that underwent hepatic afferent vagotomy (VgX) and/or pancreatic efferent sympathectomy (SpX). Chronic GLP-1 (7-36) administration to HFD-induced obese rats elevated c-fos expression and BDNF content in the hypothalamus, followed by a reduction in pancreatic β-cell hyperplasia and insulin content, thus resulting in improved glucose tolerance. These responses were abolished by VgX and SpX. Moreover, administration of liraglutide similarly activated the hypothalamic neural pathways, thus resulting in a more profound amelioration of glucose tolerance than native GLP-1 (7-36). These data suggest that GLP-1 normalizes the obesity-induced compensatory increase in β-cell mass and glucose intolerance through a neuronal relay system consisting of hepatic afferent nerves, the hypothalamus, and pancreatic efferent nerves.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cell Proliferation; Cell Size; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Hypothalamus; Injections, Intraperitoneal; Insulin-Secreting Cells; Liraglutide; Neural Pathways; Obesity; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Sympathectomy; Vagotomy

Recent studies show that bile acids are involved in glucose and energy homeostasis through activation of G protein coupled membrane receptor (TGR5) and farnesoid X receptor (FXR). A few researches have explored changes of TGR5 and FXR in animals with impaired glucose regulation. This study aimed to observe changes of plasma total bile acids (TBA), glucagon-like-peptide 1 (GLP-1), fibroblast growth factor 15 (FGF15), intestinal expressions of TGR5 and FXR, and correlations between them in rats with glucose intolerance.. Besides plasma fasting glucose, lipid, TBAs, alanine transaminase (ALT), active GLP-1(GLP-1A) and FGF15, a postprandial meal test was used to compare responses in glucose, insulin and GLP-1A among groups. The expressions of TGR5 and FXR in distal ileum and ascending colon were quantified by real-time PCR and western blot.. TGR5 expression was significantly decreased in distal ileum in DM group compared to other groups, and TGR5 and FXR expressions in ascending colon were also decreased in DM group compared to other groups. Correlation analysis showed correlations between TBA and GLP-1A or FGF15. GLP-1A was correlated with TGR5 mRNA expression in colon, and FGF15 was correlated with FXR mRNA expression in colon.. These results indicates that bile acid-TGR5/FXR axis contributes to glucose homeostasis.

Topics: Animals; Bile Acids and Salts; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Progression; Fibroblast Growth Factors; Glucagon-Like Peptide 1; Glucose Intolerance; Intestinal Mucosa; Liver Diseases; Male; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled

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

Normal glucose metabolism depends on pancreatic secretion of insulin and glucagon. The bihormonal hypothesis states that while lack of insulin leads to glucose underutilisation, glucagon excess is the principal factor in diabetic glucose overproduction. A recent study reported that streptozotocin-treated glucagon receptor knockout mice have normal glucose tolerance. We investigated the impact of acute disruption of glucagon secretin or action in a mouse model of severe diabetes by three different approaches: (1) alpha cell elimination; (2) glucagon immunoneutralisation; and (3) glucagon receptor antagonism, in order to evaluate the effect of these on glucose tolerance.. Severe diabetes was induced in transgenic and wild-type mice by streptozotocin. Glucose metabolism was investigated using OGTT in transgenic mice with the human diphtheria toxin receptor expressed in proglucagon producing cells allowing for diphtheria toxin (DT)-induced alpha cell ablation and in mice treated with either a specific high affinity glucagon antibody or a specific glucagon receptor antagonist.. Near-total alpha cell elimination was induced in transgenic mice upon DT administration and resulted in a massive decrease in pancreatic glucagon content. Oral glucose tolerance in diabetic mice was neither affected by glucagon immunoneutralisation, glucagon receptor antagonism, nor alpha cell removal, but did not deteriorate further compared with mice with intact alpha cell mass.. Disruption of glucagon action/secretion did not improve glucose tolerance in diabetic mice. Near-total alpha cell elimination may have prevented further deterioration. Our findings support insulin lack as the major factor underlying hyperglycaemia in beta cell-deficient diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diphtheria Toxin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Glucagon; Streptozocin

Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized; however, the effect of long-term GCGR activation on β-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2 weeks) infused with the stable glucagon analog ZP-GA-1 and challenged with oral glucose and intravenous glucose±glucagon-like peptide 1 (GLP1). Islets were isolated to evaluate the insulin secretory response to glucose±GLP1 and their pancreas were collected for immunohistochemical analysis. Two weeks of ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP1. Also, we observed increased β-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of β-cell function during development of type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Receptors, Glucagon

To introduce a lower-risk novel surgical procedure to achieve diabetes reversal along with associated hormonal changes.. Diabetic rats were randomly assigned to jejunum-ileum circuit (JIC), sham-JIC, ileal interposition (IT), and sham-IT groups. The JIC group included two subgroups: short (JIC-S) and long (JIC-L), based on the length between anastomosis and Treitz ligament (LAT ). The body weight, food intake, blood glucose, glucose and insulin tolerance, and gut hormones were measured. The liver gene expression of glucose transporter 2 (GLUT2) and protein expression of glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PKC) were also measured. Following a dye infusion, nutrient delivery was measured at termination day.. Compared to sham-JIC group, JIC-S group did not reduce body weight or food intake but significantly improved glucose tolerance and insulin resistance. With fast chyme transit, JIC-S not only promoted the secretion of insulin, glucagon-like peptide 1, and peptide YY and decreased leptin, but also upregulated hepatic GLUT2 and downregulated hepatic G6P and PKC. JIC-L group, however, failed to achieve remission of diabetes.. JIC-S relieves diabetes independent of weight loss, as it promotes the secretion of anti-diabetic hormones and inhibits hepatic glucose production. The prolonging of LAT , however, diminishes the hypoglycemic effect.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose-6-Phosphatase; Ileum; Jejunum; Male; Peptide YY; Rats; Rats, Sprague-Dawley; Weight Loss

To assess glucagon-like peptide 1 (GLP-1) secretion after oral glucose tolerance tests (OGTTs) in subjects with newly diagnosed type 2 diabetes mellitus (T2DM), impaired glucose tolerance (IGT), and normal glucose tolerance (NGT) to clarify changes in GLP-1 secretion during the course of T2DM. . In this cross sectional study, 80 subjects were divided into the NGT, IGT, and T2DM groups after undergoing a 75 g OGTT from March to December 2014 at the School of Medicine, First Affiliated Hospital, Shihezi University, Xinjiang, China. Plasma total GLP-1 was measured at 0, 30, 60, 120, and 180 minutes. Homeostasis model assessment of insulin resistance (HOMA-IR), islet β-cell function (HOMA-β), Gutt index, Matsuda index, incremental GLP-1 (ΔGLP-1), and areas under the curves of GLP-1 (AUCglp-1), glucose (AUCg), and insulin (AUCins) were calculated.. Plasma total GLP-1 at 30-120 minutes and ΔGLP-1 at 30-120 minutes were lower in the T2DM group than in the IGT and NGT groups (p less than 0.05). Peak GLP-1 levels were 35% lower in the T2DM group than in the NGT group. Plasma total GLP-1, ΔGLP-1, and AUCglp-1 correlated negatively with HOMA-IR and AUCg, and positively with HOMA-β, Gutt index, Matsuda index, and AUCins (p less than 0.05). . The GLP-1 secretion after 75 g OGTT was impaired in newly diagnosed T2DM patients, inversely proportional to IR and hyperglycemia, and positively correlated with β-cell function and insulin sensitivity.

Topics: Adult; Area Under Curve; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged

Proglucagon-derived hormones are important for glucose metabolism, but little is known about them in pediatric obesity and type 2 diabetes mellitus (T2DM).. Fasting and postprandial levels of proglucagon-derived peptides glucagon, GLP-1, and glicentin in adolescents with obesity across the glucose tolerance spectrum were investigated.. This was a cross-sectional study with plasma hormone levels quantified at fasting and during an oral glucose tolerance test (OGTT).. This study took place in a pediatric obesity clinic at Uppsala University Hospital, Sweden.. Adolescents with obesity, age 10-18 years, with normal glucose tolerance (NGT, n = 23), impaired glucose tolerance (IGT, n = 19), or T2DM (n = 4) and age-matched lean adolescents (n = 19) were included.. Outcome measures were fasting and OGTT plasma levels of insulin, glucagon, active GLP-1, and glicentin.. Adolescents with obesity and IGT had lower fasting GLP-1 and glicentin levels than those with NGT (0.25 vs 0.53 pM, P < .05; 18.2 vs 23.6 pM, P < .01) and adolescents with obesity and T2DM had higher fasting glucagon levels (18.1 vs 10.1 pM, P < .01) than those with NGT. During OGTT, glicentin/glucagon ratios were lower in adolescents with obesity and NGT than in lean adolescents (P < .01) and even lower in IGT (P < .05) and T2DM (P < .001).. Obese adolescents with IGT have lowered fasting GLP-1 and glicentin levels. In T2DM, fasting glucagon levels are elevated, whereas GLP-1 and glicentin levels are maintained low. During OGTT, adolescents with obesity have more products of pancreatically than intestinally cleaved proglucagon (ie, more glucagon and less GLP-1) in the plasma. This shift becomes more pronounced when glucose tolerance deteriorates.

Topics: Adolescent; Blood Glucose; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glicentin; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Male; Pediatric Obesity; Sweden

Glucagon-like peptide-1 (GLP-1) is a powerful insulin secretagogue that is secreted in response to meal ingestion. The ability to quantify the effect of GLP-1 on insulin secretion could provide insights into the pathogenesis and treatment of diabetes. We used a modification of a model of GLP-1 action on insulin secretion using data from a hyperglycemic clamp with concomitant GLP-1 infusion. We tested this model using data from a mixed meal test (MMT), thereby measuring GLP-1-induced potentiation of insulin secretion in response to a meal.. The GLP-1 model is based on the oral C-peptide minimal model and assumes that over-basal insulin secretion depends linearly on GLP-1 concentration through the parameter Π, representing the β-cell sensitivity to GLP-1. The model was tested on 62 subjects across the spectrum of glucose tolerance (age, 53 ± 1 years; body mass index, 29.7 ± 0.6 kg/m(2)) studied with an MMT and provided a precise estimate of both β-cell responsivity and Π indices. By combining Π with a measure of L-cell responsivity to glucose, one obtains a potentiation index (PI) (i.e., a measure of the L-cell's function in relation to prevailing β-cell sensitivity to GLP-1).. Model-based measurement of GLP-1-induced insulin secretion demonstrates that the PI is significantly reduced in people with impaired glucose tolerance, compared with those with normal glucose tolerance.. We describe a model that can quantitate the GLP-1-based contribution to insulin secretion in response to meal ingestion. This methodology will allow a better understanding of β-cell function at various stages of glucose tolerance.

Topics: Blood Glucose; C-Peptide; Eating; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Healthy Volunteers; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Linear Models; Meals; Middle Aged

We have previously constructed an engineered anti-diabetic fusion protein using glucagon-like peptide-1 and the globular domain of adiponectin. Herein, we evaluated the therapeutic effects of this fusion protein (GAD) on high-fat diet (HFD)-fed ApoE(-/-) mice. The lipid-lowering effect of GAD was determined in C57BL/6 mice using a lipid tolerance test. The effects of GAD on HFD-induced glucose intolerance, atherosclerosis, and hepatic steatosis were evaluated in HFD-fed ApoE(-/-) mice using glucose tolerance test, histological examinations and real-time quantitative PCR. The anti-inflammation activity of GAD was assessed in vitro on macrophages. GAD improved lipid metabolism in C57BL/6 mice. GAD treatment alleviated glucose intolerance, reduced blood lipid level, and attenuated atherosclerotic lesion in HFD-fed ApoE(-/-) mice, which was associated with a repressed macrophage infiltration in the vessel wall. GAD treatment also blocked hepatic macrophage infiltration and prevented hepatic inflammation. GAD suppressed lipopolysaccharide-triggered inflammation responses on macrophages, which can be abolished by H89, an inhibitor of protein kinase A. These findings demonstrate that GAD is able to generate a variety of metabolic benefits in HFD-fed ApoE(-/-) mice and indicate that this engineered fusion protein is a promising lead structure for anti-atherosclerosis drug discovery.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Diet, High-Fat; Fatty Liver; Glucagon-Like Peptide 1; Glucose Intolerance; Lipids; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout

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

Multiple signaling pathways mediate the actions of metabolic hormones to control glucose homeostasis, but the proteins that coordinate such networks are poorly understood. We previously identified the molecular scaffold protein, 14-3-3ζ, as a critical regulator of in vitro β-cell survival and adipogenesis, but its metabolic roles in glucose homeostasis have not been studied in depth. Herein, we report that Ywhaz gene knockout mice (14-3-3ζKO) exhibited elevated fasting insulin levels while maintaining normal β-cell responsiveness to glucose when compared with wild-type littermate controls. In contrast with our observations after an ip glucose bolus, glucose tolerance was significantly improved in 14-3-3ζKO mice after an oral glucose gavage. This improvement in glucose tolerance was associated with significantly elevated fasting glucagon-like peptide-1 (GLP-1) levels. 14-3-3ζ knockdown in GLUTag L cells elevated GLP-1 synthesis and increased GLP-1 release. Systemic inhibition of the GLP-1 receptor attenuated the improvement in oral glucose tolerance that was seen in 14-3-3ζKO mice. When taken together these findings demonstrate novel roles of 14-3-3ζ in the regulation of glucose homeostasis and suggest that modulating 14-3-3ζ levels in intestinal L cells may have beneficial metabolic effects through GLP-1-dependent mechanisms.

Topics: 14-3-3 Proteins; Animals; Blood Glucose; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Insulin; Insulin-Secreting Cells; Mice; Mice, Knockout; Phosphorylation; Proto-Oncogene Proteins c-akt

The intestinal G protein-coupled receptor GPR119 is a novel metabolic target involving glucagon-like peptide-1 (GLP-1)-derived insulin-regulated glucose homeostasis. Endogenous and diet-derived lipids, including N-acylethanolamines and 2-monoacylglycerols (2-MAG) activate GPR119. The purpose of this work is to evaluate whether 2-oleoyl glycerol (2-OG) improves glucose tolerance through GPR119, using wild type (WT) and GPR 119 knock out (KO) mice. We here show that GPR119 is essential for 2-OG-mediated release of GLP-1 and CCK from GLUTag cells, since a GPR119 specific antagonist completely abolished the hormone release. Similarly, in isolated primary colonic crypt cultures from WT mice, GPR119 was required for 2-OG-stimulated GLP-1 release while there was no response in crypts from KO mice. In vivo, gavage with 2-oleyl glyceryl ether ((2-OG ether), a stable 2-OG analog with a potency of 5.3 µM for GPR119 with respect to cAMP formation as compared to 2.3 µM for 2-OG), significantly (P < 0.05) improved glucose clearance in WT littermates, but not in GPR119 KO mice. Finally, deletion of GPR119 in mice resulted in lower glucagon levels, whereas the levels of insulin and GIP were unchanged. In the present study we show that 2-OG stimulates GLP-1 secretion through GPR119 activation in vitro, and that fat-derived 2-MAGs are potent candidates for mediating fat-induced GLP-1 release through GPR119 in vivo. © 2016 BioFactors, 42(6):665-673, 2016.

Topics: Administration, Oral; Animals; Cell Line; Cholecystokinin; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glycerides; Male; Mice, Inbred C57BL; Mice, Knockout; Receptors, G-Protein-Coupled

The aim of this study was to evaluate the antidiabetic properties of collagen hydrolysates (CHs). CHs exhibited dipeptidyl peptidase-IV inhibitory activity and stimulated glucagon-like-peptide-1 (GLP-1) secretion in vitro. We also determined whether CHs improve glucose tolerance in normal mice. Oral administration of CHs suppressed the glycemic response during the oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT), but the effects were weaker in IPGTT than in OGTT. CHs had no effect on the gastric emptying rate. A pretreatment with the GLP-1 receptor antagonist, exendin 9-39 (Ex9), partially reversed the glucose-lowering effects of CHs, but only when coadministered with glucose. CHs administered 45 min before the glucose load potentiated the glucose-stimulated insulin secretion. This potentiating effect on insulin secretion was not reversed by the pretreatment with Ex9, it appeared to be enhanced. These results suggest that CHs improve glucose tolerance by inhibiting intestinal glucose uptake and enhancing insulin secretion, and also demonstrated that GLP-1 was partially involved in the inhibition of glucose uptake, but not essential for the enhancement of insulin secretion.

Topics: Administration, Oral; Animals; Blood Glucose; Cichlids; Collagen; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Fish Proteins; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin; Insulin Secretion; Intestinal Absorption; Male; Mice, Inbred C57BL; Protein Hydrolysates; Reference Values

Plasminogen (Plg), which is the inactive form of plasmin, deficiency enhanced insulin secretion, and was associated with improved oral glucose tolerance in mice. Additionally, Plg deficiency was associated with lower dipeptidyl peptidase-4 (DPP-4) activity, and enhanced glucagons-like peptide-1 (GLP-1) expression. Plg may regulate the DPP-4 activity and the glucose metabolism.

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Secretion; Male; Mice; Mice, Knockout; Plasminogen

A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone--and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology.. The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice.. Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively.. As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy.. This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.

Topics: Adolescent; Animals; Biomechanical Phenomena; Bone Density; Femur; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Mice, Knockout; Stress, Mechanical; X-Ray Microtomography

Glucagon-like peptide-1 (GLP-1)-based medicines have recently been widely used to treat type 2 diabetic patients, whereas adverse effects of nausea and vomiting have been documented. Inhibition of voltage-gated K(+) channel subtype Kv2.1 in pancreatic β-cells has been suggested to contribute to mild depolarization and promotion of insulin release. This study aimed to determine whether the blockade of Kv2.1 channels potentiates the insulinotropic effect of GLP-1 agonists. Kv2.1 channel blocker guangxitoxin-1E (GxTx) and GLP-1 agonist exendin-4 at subthreshold concentrations, when combined, markedly increased the insulin release and cytosolic Ca(2+) concentration ([Ca(2+)]i) in a glucose-dependent manner in mouse islets and β-cells. Exendin-4 at subthreshold concentration alone increased islet insulin release and β-cell [Ca(2+)]i in Kv2.1(+/-) mice. The [Ca(2+)]i response to subthreshold exendin-4 and GxTx in combination was attenuated by pretreatment with protein kinase A inhibitor H-89, indicating the protein kinase A dependency of the cooperative effect. Furthermore, subthreshold doses of GxTx and GLP-1 agonist liraglutide in combination markedly increased plasma insulin and improved glucose tolerance in diabetic db/db mice and NSY mice. These results demonstrate that a modest suppression of Kv2.1 channels dramatically raises insulinotropic potency of GLP-1-based drugs, which opens a new avenue to reduce their doses and associated adverse effects while achieving the same glycemic control in type 2 diabetes.

Topics: Animals; Arthropod Proteins; Cells, Cultured; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Insulin; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Peptides; Shab Potassium Channels; Spider Venoms; Venoms

GLP-1 is a gastrointestinal L-cell hormone that enhances glucose-stimulated insulin secretion. Hence, strategies that prevent GLP-1 degradation or activate the GLP-1 receptor are used to treat patients with type 2 diabetes. GLP-1 secretion occurs after a meal and is partly regulated by other circulating hormones. Ghrelin is a stomach-derived hormone that plays a key role in whole-body energy metabolism. Because ghrelin levels peak immediately before mealtimes, we hypothesized that ghrelin plays a role in priming the intestinal L-cell for nutrient-induced GLP-1 release. The intraperitoneal injection of ghrelin into mice 15 min before the administration of oral glucose enhanced glucose-stimulated GLP-1 release and improved glucose tolerance, whereas the ghrelin receptor antagonist D-Lys GHRP-6 reduced plasma levels of GLP-1 and insulin and diminished oral glucose tolerance. The ghrelin-mediated improvement in glucose tolerance was lost in mice coinjected with a GLP-1 receptor antagonist as well as in Glp1r(-/-) mice lacking the GLP-1 receptor. The impaired oral glucose tolerance in diet-induced obese mice was also improved by ghrelin preadministration. Importantly, ghrelin directly stimulated GLP-1 release from L-cell lines (murine GLUTag, human NCI-H716) through an extracellular signal-related kinase 1/2-dependent pathway. These studies demonstrate a novel role for ghrelin in enhancing the GLP-1 secretory response to ingested nutrients.

Topics: Animals; Cell Line; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Homeostasis; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Glucagon

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

Quantification of changes in glucose and lipid concentrations in women with intrahepatic cholestasis of pregnancy (ICP) and uncomplicated pregnancy and study of their influence on fetal growth.. A prospective study comparing metabolic outcomes in cholestastic and uncomplicated singleton pregnancies was undertaken at two university hospitals in the U.K. and U.S. from 2011-2014. A total of 26 women with ICP and 27 control pregnancies with no prior history of gestational diabetes mellitus were recruited from outpatient antenatal services and followed until delivery. Alterations in glucose, incretins, cholesterol, and triglycerides were studied using a continuous glucose monitoring (CGM) system and/or a standard glucose tolerance test (GTT) in conjunction with GLP-1 and a fasting lipid profile. Fetal growth was quantified using adjusted birth centiles.. Maternal blood glucose concentrations were significantly increased in ICP during ambulatory CGM (P < 0.005) and following a GTT (P < 0.005). ICP is characterized by increased fasting triglycerides (P < 0.005) and reduced HDL cholesterol (P < 0.005), similar to changes observed in metabolic syndrome. The offspring of mothers with ICP had significantly larger customized birth weight centiles, adjusted for ethnicity, sex, and gestational age (P < 0.005).. ICP is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. These findings may have implications regarding the future health of affected offspring.

Topics: Adult; Birth Weight; Blood Glucose; Cholestasis, Intrahepatic; Cholesterol; Diabetes, Gestational; Dyslipidemias; Female; Fetal Development; Fetal Macrosomia; Gestational Age; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Lipids; Male; Metabolic Syndrome; Metabolome; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Triglycerides

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

Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity.

Topics: Animals; Blood Glucose; Body Composition; Body Fat Distribution; Cholecystokinin; Diet; Diet, High-Fat; Gastric Emptying; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Obesity; Postprandial Period; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sucrose

To assess the impact of concomitant inhibition of sodium-glucose cotransporter (SGLT) 2 and dipeptidyl peptidase IV (DPP4) for the treatment of type 2 diabetes mellitus (T2DM), the effect of combined treatment with canagliflozin, a novel SGLT2 inhibitor, and teneligliptin, a DPP4 inhibitor, on glucose intolerance was investigated in Zucker diabetic fatty (ZDF) rats. Canagliflozin potently inhibited human and rat SGLT2 and moderately inhibited human and rat SGLT1 activities but did not affect DPP4 activity. In contrast, teneligliptin inhibited human and rat DPP4 activities but not SGLT activities. A single oral treatment of canagliflozin and teneligliptin suppressed plasma glucose elevation in an oral glucose tolerance test in 13 week-old ZDF rats. This combination of agents elevated plasma active GLP-1 levels in a synergistic manner, probably mediated by intestinal SGLT1 inhibition, and further improved glucose intolerance. In the combination-treated animals, there was no pharmacokinetic interaction of the drugs and no further inhibition of plasma DPP4 activity compared with that in the teneligliptin-treated animals. These results suggest that the inhibition of SGLT2 and DPP4 improves glucose intolerance and that combined treatment with canagliflozin and teneligliptin is a novel therapeutic option for glycemic control in T2DM.

Topics: Administration, Oral; Animals; Canagliflozin; Cells, Cultured; Cricetinae; Cricetulus; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemic Agents; Male; Pyrazoles; Rats, Zucker; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidines

β-Cell insufficiency plays an important role in the development of diabetes. Environmental factors, including lifestyle, play a critical role in β-cell dysfunction. Modern lifestyles affect the inherent circadian clock in central and peripheral organs. Recent studies have demonstrated that the normal intrinsic circadian clock in islets was essential for the viability of β cells and their insulin secretory function. Overall, however, the data are inconclusive. Our study demonstrated that the disrupted circadian rhythm of islets in streptozotocin induced type1 diabetic mice may be associated with impaired β-cell function and glucose intolerance. Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, could partially restore the normal circadian rhythm and activate the 5' AMP-activated protein kinase (AMPK) signaling pathway. Our study provided evidence demonstrating that Liraglutide might restore β-cell function and protect against the development of diabetes in a mouse model by attenuating the disruption of the intrinsic circadian rhythm in islets and by activating AMPK signaling.

Topics: AMP-Activated Protein Kinases; Animals; Circadian Rhythm; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Liraglutide; Male; Mice, Inbred C57BL; Phosphorylation; Signal Transduction

The G protein-coupled receptor TGR5 is a membrane receptor for bile acids. Its agonism increases energy expenditure and controls blood glucose through secretion of glucagon-like peptide-1 in enteroendocrine cells. In this study, we explored the therapeutic potential of WB403, a small compound activating TGR5 which was identified by combining TGR5 targeted luciferase assay and active GLP-1 assay, in treating type 2 diabetes. After confirmation of TGR5 and GLP-1 stimulating activities in various cell systems, WB403 was examined in oral glucose tolerance test, and tested on different mouse models of type 2 diabetes for glycemic control and pancreatic β-cell protection effect. As a result, WB403 exhibited a moderate TGR5 activation effect while promoting GLP-1 secretion efficiently. Interestingly, gallbladder filling effect, which was reported for some known TGR5 agonists, was not detected in this novel compound. In vivo results showed that WB403 significantly improved glucose tolerance and decreased fasting blood glucose, postprandial blood glucose and HbA1c in type 2 diabetic mice. Further analysis revealed that WB403 increased pancreatic β-cells and restored the normal distribution pattern of α-cell and β-cell in islets. These findings demonstrated that TGR5 activator WB403 effectively promoted GLP-1 release, improved hyperglycemia and preserved the mass and function of pancreatic β-cells, whereas it did not show a significant side effect on gallbladder. It may represent a promising approach for future type 2 diabetes mellitus drug development.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Insulin-Secreting Cells; Mice; Postprandial Period; Receptors, G-Protein-Coupled

Small protein or lipid preloads are able to improve glucose tolerance to a different extent and through different and poorly defined mechanisms. We aimed at quantifying the effect of a mixed protein and lipid preload and at evaluating the underlying mechanisms.. Volunteers with normal (NGT, n = 12) or impaired (IGT, n = 13) glucose tolerance and patients with type 2 diabetes (n = 10) underwent two OGTTs coupled to the double glucose tracer protocol, preceded by either 50 g of parmesan cheese, a boiled egg and 300 ml of water, or 500 ml of water. We measured plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP), NEFA and glucose tracers, and calculated glucose fluxes, beta cell function variables, insulin sensitivity and clearance.. After the nutrient preload, the OGTT-induced rise of plasma glucose was lower than after water alone in each study group. This reduction—more pronounced across classes of glucose tolerance (NGT -32%, IGT -37%, type 2 diabetes -49%; p < 0.002)—was the result of different combinations of slower exogenous glucose rate of appearance, improved beta cell function and reduced insulin clearance, in this order of relevance, which were associated with an only mild stimulation of GIP and GLP-1.. After a non-glucidic nutrient preload, glucose tolerance improved in proportion to the degree of its baseline deterioration through mechanisms that appear particularly effective in type 2 diabetes. Exploiting the physiological responses to nutrient ingestion might reveal, at least in the first stages of the diabetic disease, a potent tool to improve daily life glycaemic control.. ClinicalTrials.gov NCT02342834 FUNDING: This work was supported by grants from the University of Pisa (Fondi di Ateneo) and by FCT grant (PIC/IC/82956/2007).

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dietary Fats; Dietary Proteins; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Young Adult

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L cells in response to nutrient ingestion. Dipeptidyl peptidase-4 (DPP-4) rapidly degrades the active form of GLP-1 to an inactive form in the bloodstream. The present study aimed to investigate the role of serotonin (5-HT)1B receptors in the regulation of plasma active GLP-1 levels and glucose tolerance under DPP-4 inhibition.. C57BL6J mice treated with or without alogliptin, a highly selective DPP-4 inhibitor, for 4 days were intraperitoneally injected with either saline, the 5-HT1B/2C receptor agonist meta-chlorophenylpiperazine (mCPP) at 2.5mg/kg and 5mg/kg or the selective 5-HT1B receptor agonist CP94253 at 2.5mg/kg and 5mg/kg, and food-deprived after treatment. An hour later, plasma active GLP-1 levels were determined. Also, a glucose tolerance test was done by injecting D-glucose (2g/kg) following the injection of saline or CP94253 (5mg/kg) in mice treated with alogliptin.. Intraperitoneal injection of mCPP (2.5 and 5mg/kg) or CP94253 (2.5 and 5mg/kg) in mice treated with alogliptin for 4 days significantly increased plasma active GLP-1 levels compared with saline controls in mice that were food-deprived after the injections. While intraperitoneal injection of either mCPP or CP94253 alone had no significant effect on plasma active GLP-1 levels, the injection of CP94253 improved glucose tolerance in mice treated with alogliptin compared with saline.. These findings suggest that pharmacological stimulation of 5-HT1B receptors enhances the increases in plasma active GLP-1 induced by DPP-4 inhibition independently of feeding and also improves glucose tolerance in mice.

Topics: Administration, Oral; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Food-Drug Interactions; Glucagon-Like Peptide 1; Glucose Intolerance; Injections, Intraperitoneal; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Piperazines; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1B; Serotonin 5-HT1 Receptor Agonists; Up-Regulation; Uracil

Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) when activated by short-chain fatty acids (SCFAs). Functionally GLP-1 and PYY inhibit gut transit, increase glucose tolerance, and suppress appetite; thus, FFA2 has therapeutic potential for type 2 diabetes and obesity. However, FFA2-selective agonists have not been characterized in vivo. Compound 1 (Cpd 1), a potent FFA2 agonist, was tested for its activity on the following: GLP-1 release, modulation of intestinal mucosal ion transport and transit in wild-type (WT) and FFA2(-/-) tissue, and food intake and glucose tolerance in lean and diet-induced obese (DIO) mice. Cpd 1 stimulated GLP-1 secretion in vivo, but this effect was only detected with dipeptidyl peptidase IV inhibition, while mucosal responses were PYY, not GLP-1, mediated. Gut transit was faster in FFA2(-/-) mice, while Cpd 1 slowed WT transit and reduced food intake and body weight in DIO mice. Cpd 1 decreased glucose tolerance and suppressed plasma insulin in lean and DIO mice, despite FFA2(-/-) mice displaying impaired glucose tolerance. These results suggest that FFA2 inhibits intestinal functions and suppresses food intake via PYY pathways, with limited GLP-1 contribution. Thus, FFA2 may be an effective therapeutic target for obesity but not for type 2 diabetes.

Topics: Animals; Appetite; Cells, Cultured; Eating; Gastrointestinal Transit; Glucagon-Like Peptide 1; Glucose Intolerance; Intestinal Mucosa; Intestines; Mice; Mice, Obese; Obesity; Peptide YY; Receptors, Cell Surface

Homozygous glucagon-GFP knock-in mice (Gcggfp/gfp) lack proglucagon derived-peptides including glucagon and GLP-1, and are normoglycemic. We have previously shown that Gcggfp/gfp show improved glucose tolerance with enhanced insulin secretion. Here, we studied glucose and energy metabolism in Gcggfp/gfp mice fed a high-fat diet (HFD). Male Gcggfp/gfp and Gcggfp/+ mice were fed either a normal chow diet (NCD) or an HFD for 15-20 weeks. Regardless of the genotype, mice on an HFD showed glucose intolerance, and Gcggfp/gfp mice on HFD exhibited impaired insulin secretion whereas Gcggfp/+ mice on HFD exhibited increased insulin secretion. A compensatory increase in β-cell mass was observed in Gcggfp/+mice on HFD, but not in Gcggfp/gfp mice on the same diet. Weight gain was significantly lower in Gcggfp/gfp mice than in Gcggfp/+mice. Oxygen consumption was enhanced in Gcggfp/gfp mice compared to Gcggfp/+ mice on an HFD. HFD feeding significantly increased uncoupling protein 1 mRNA expression in brown adipose and inguinal white adipose tissues of Gcggfp/gfp mice, but not of Gcggfp/+mice. Treatment with the glucagon-like peptide-1 receptor agonist liraglutide (200 mg/kg) improved glucose tolerance in Gcggfp/gfp mice and insulin content in Gcggfp/gfp and Gcggfp/+ mice was similar after liraglutide treatment. Our findings demonstrate that Gcggfp/gfp mice develop diabetes upon HFD-feeding in the absence of proglucagon-derived peptides, although they are resistant to diet-induced obesity.

Topics: Animals; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Obesity; Peptides; Proglucagon; Weight Gain

We assessed the acute impact of laparoscopic Roux-en-Y gastric bypass (GBP) or sleeve gastrectomy (SG) compared to caloric-matched control group without surgery on glucose excursion in obese patients with type 2 diabetes, and examined if this was mediated by changes in insulin resistance, early insulin response or glucagon-like peptide (GLP)-1 levels.. Six-day subcutaneous continuous glucose monitoring (CGM) recordings were obtained from patients beginning 3 days before GBP (n = 11), SG (n = 10) or fasting in control group (n = 10). GLP-1, insulin and glucose were measured during 75 g oral glucose tolerance testing at the start and end of each CGM.. Post-operative hyperglycaemia occurred after both surgeries in the first 6 h, with a more rapid decline in glycaemia after GBP (p < 0.001). Beyond 24 h post-operatively, continuous overlapping of net glycaemia action reduced from baseline after GBP (median [interquartile range]) 1.6 [1.2-2.4] to 1.0 [0.7-1.3] and after SG 1.4 [0.9-1.8] to 0.7 [0.7-1.0]; p < 0.05), similar to controls (2.2 [1.7-2.5] to 1.3 [0.8-2.8] p < 0.05). Higher log GLP-1 increment post-oral glucose occurred after GBP (mean ± SE, 0.80 ± 0.12 vs. 0.37 ± 0.09, p < 0.05), but not after SG or control intervention. Among subgroup with baseline hyperglycaemia, a reduction in HOMA-IR followed GBP. Reduction in time and level of peak glucose and 2-h glucose occurred after both surgeries but not in controls.. GBP and SG have a similar acute impact on reducing glycaemia to caloric restriction; however, with a superior impact on glucose tolerance.

Topics: Adult; Bariatric Surgery; Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Female; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Laparoscopy; Male; Middle Aged; Obesity, Morbid

Low GLP-1 has been implicated in obesity and type 2 diabetes. Some studies reported reduced post-prandial GLP-1 levels in type 2 diabetics, whereas others reported GLP-1 levels not reduced in patients with impaired glucose tolerance (IGT) or type 2 diabetes. We undertook this study to evaluate the effect of obesity and pre-diabetes on GLP-1 levels in response to 75 g oral glucose.. Eighty subjects comprised four groups: 20 control subjects (normal weight and normal glucose tolerance (NGT)), 20 obese with NGT, 20 obese with impaired fasting glucose (IFG) and 20 obese with both IFG and impaired glucose tolerance (IGT). Laboratory tests included fasting blood glucose (FBG), 75 g glucose OGTT, fasting insulin and glucose-stimulated GLP-1 (30 min after 75 g glucose). Insulin resistance was quantified using HOMA-IR.. GLP-1 levels were significantly decreased in obese subjects compared to controls (571.17 ± 170.37 vs. 908.50 ± 169.90 pg/mL, p <0.001) and it was negatively correlated with body mass index (BMI) and waist circumference in all studied groups. Levels of GLP-1 were negatively correlated with HOMA-IR in all obese groups (r = -0.75, p <0.001). No significant difference was found in GLP-1 levels between all obese subjects (611.50 ± 187.96, 577.50 ± 150.85, 524.50 ± 167.35 pg/mL respectively, p >0.05). Morbidly obese cases (n = 15) had a significantly higher fasting insulin (25.20 ± 2.49 vs. 14 ± 3.81 μIU/ml), higher HOMA-IR (6.69 ± 1.2 vs. 3.48 ± 1.20), and lower GLP- 1 (212.0 ± 35.64 vs. 603.82 ± 136.35 pg/mL) (p <0.001) compared to non-morbid obese cases (n = 45).. Obesity reduces the GLP-1 levels. In insulin resistance, GLP-1 levels were reduced and it was related to the degree of insulin resistance.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Prediabetic State

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

Glucagon-like peptide-1 (GLP-1), an insulinotropic gut peptide released after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β cells, we developed mice with β cell-specific knockdown of Glp1r. β cell Glp1r knockdown mice had impaired GT after intraperitoneal (i.p.) glucose and did not secrete insulin in response to i.p. or intravenous GLP-1. However, they had normal GT after oral glucose, a response that was impaired by a GLP1R antagonist. β cell Glp1r knockdown mice had blunted responses to a GLP1R agonist but intact glucose lowering with a dipeptidylpeptidase 4 (DPP-4) inhibitor. Thus, in mice, β cell Glp1rs are required to respond to hyperglycemia and exogenous GLP-1, but other factors compensate for reduced GLP-1 action during meals. These results support a role for extraislet GLP1R in oral glucose tolerance and paracrine regulation of β cells by islet GLP-1.

Topics: Animals; Blood Glucose; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Knockout; Receptors, Glucagon; Signal Transduction; Tamoxifen

G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic β-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes.

Topics: Animals; Blood Glucose; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Exenatide; Gene Knockout Techniques; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Indans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice; Peptides; Phenylpropionates; Propionates; Rats; Receptors, G-Protein-Coupled; Receptors, Glucagon; Venoms

Functional dyspepsia is predominantly attributed to gastric sensorimotor dysfunctions. The contribution of intestinal chemosensitivity to symptoms is not understood. We evaluated symptoms and plasma hormones during enteral nutrient infusion and the association with impaired glucose tolerance and quality-of-life (QOL) scores in patients with functional dyspepsia vs. healthy controls.. Enteral hormonal responses and symptoms were measured during isocaloric and isovolumic dextrose and lipid infusions into the duodenum in 30 patients with functional dyspepsia (n=27) or nausea and vomiting (n=3) and 35 healthy controls. Infusions were administered in randomized order over 120 min each, with a 120-min washout. Cholecystokinin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1 (GLP1), and peptide YY were measured during infusions.. Moderate or more severe symptoms during lipid (4 controls vs. 14 patients) and dextrose (1 control vs. 12 patients) infusions were more prevalent in patients than controls (P≤0.01), associated with higher dyspepsia symptom score (P=0.01), worse QOL (P=0.01), and greater plasma hormone concentrations (e.g., GLP1 during lipid infusion). Moderate or more severe symptoms during enteral infusion explained 18%, and depression score explained 21%, of interpatient variation in QOL. Eight patients had impaired glucose tolerance, associated with greater plasma GLP1 and peptide YY concentrations during dextrose and lipid infusions, respectively.. Increased sensitivity to enteral dextrose and lipid infusions was associated with greater plasma enteral hormone concentrations, more severe daily symptoms, and worse QOL in functional dyspepsia. These observations are consistent with the hypothesis that enteral hormones mediate increased intestinal sensitivity to nutrients in functional dyspepsia.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Cholecystokinin; Duodenum; Dyspepsia; Enteral Nutrition; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Lipids; Male; Peptide YY; Quality of Life; Severity of Illness Index

Glucagon-like peptide-1 (GLP-1) analogues have emerged as insulin secretagogues and are widely used in type 2 diabetic patients. GLP-1 analogues also demonstrate a promotion of beta cell proliferation and reduction of apoptosis in rodents. In the present study, we investigated the protection of pancreatic beta cells by early use (at the age of 2 weeks) of GLP-1 analogue, liraglutide in Gato-Kakizaki (GK) rats and explored the underlying mechanisms.. The effects of liraglutide on glucose tolerance were evaluated by intraperitoneal glucose tolerance test (IPGTT) and insulin release tests (IRT). Ki67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) immunostaining, Western blots and real-time polymerase chain reaction were applied to evaluate cell proliferation, apoptosis and related gene expressions.. Our results demonstrated that early use of liraglutide improved glucose tolerance during liraglutide treatment in GK rats. Liraglutide increased pancreatic insulin contents and markedly reduced beta cell apoptosis. Liraglutide also downregulated pro-apoptotic gene expressions and reduced intra-islet macrophage infiltration.. This experiment reported for the first time that early use of liraglutide could protect beta cell failure in pre-diabetic GK rats through reduction of beta cell apoptosis and ameliorating islet inflammation.

Topics: Animals; Apoptosis; Cytoprotection; Diabetes Mellitus, Experimental; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin-Secreting Cells; Liraglutide; Macrophages; Male; Rats; Time Factors

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates the insulin secretion depending on blood glucose level. Recent studies show that the unsaturated fatty acids can promote GLP-1 secretion from intestinal L-cells. We have shown previously that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) administered into a mouse closed intestinal loop, especially into the colonic segment, stimulate GLP-1 and insulin secretion and have a hypoglycemic effect, suggesting that DHA and EPA have potential as antidiabetic agents. The present study examined the antidiabetic effect of DHA following long-term in vivo delivery to the colon using normal ddY and diabetic KK-A(y) mice. The plasma GLP-1 concentration of KK-A(y) mice increased after long-term DHA administration, and this had a significant hypoglycemic effect. In contrast, although GLP-1 secretion in ddY mice tended to increase after DHA administration, blood glucose concentration did not differ between vehicle- and DHA-treated ddY mice. Immunostaining of the pancreas after long-term DHA administration showed that continuous DHA treatment stimulated β-cell apoptosis and accordingly suppressed islet cell growth in KK-A(y) mice. Colon targeting of DHA may provide a new strategy for improving impaired glucose tolerance in type 2 diabetes mellitus by stimulating GLP-1 secretion, which may subsequently suppress the compensatory hyperplasia of pancreatic islets.

Topics: Animals; Blood Glucose; Colon; Diabetes Mellitus, Type 2; Docosahexaenoic Acids; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperplasia; Hypoglycemic Agents; Islets of Langerhans; Male; Mice; Mice, Transgenic

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

It is still an important question whether sleeve gastrectomy (SG) is appropriate only in the context of obesity-the condition for which it was originally developed-or whether lean people with insulin-deficient diabetes might also benefit. The aim of this study is to evaluate the effects of SG in Goto-Kakizaki (GK) and diet-induced obese (DIO) rats that have distinct characteristics in beta-cell function and fat mass.. SG was performed in GK and DIO rats. Body weight, food intake, and fasting blood glucose were monitored after surgery. Des-acyl ghrelin in fasting condition and blood glucose, insulin, and glucagon-like peptide-1 levels during meal test were measured. Homeostatic model assessment and insulinogenic index were examined.. In both GK and DIO rats, SG improved glucose tolerance with increased glucagon-like peptide-1 and insulin secretion during meal test, and reduced fasting des-acyl ghrelin levels. Insulin sensitivity was enhanced after SG in DIO rats. The improvement in glucose tolerance after SG was shown earlier in DIO rats than in GK rats and weight regain after SG occurred faster and was more prominent in GK rats than in DIO rats.. In both DIO and GK rats, SG could improve glucose tolerance with increased insulin secretion and/or action. The improvement in glucose tolerance was shown earlier in DIO rats than in GK rats.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Eating; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hormones; Insulin; Male; Obesity; Rats; Rats, Mutant Strains; Rats, Wistar

Parenteral delivery of long-acting glucagon-like peptide-1 (GLP-1) mimetics has received much attention as a therapeutic option for diabetes. However, cell therapy-based GLP-1 treatments may provide a more physiological regulation of blood glucose. The present study assessed the effects of chronic GLP-1 delivery by cell therapy, using the GLP-1-secreting GLUTag cell line, in normoglycemic and streptozotocin-induced diabetic mice. GLUTag cell aggregates were transplanted into the subscapular region of mice. Over 30 days, cellular transplantation gave rise to encapsulated and well-vascularized growths, which contained immunoreactive GLP-1. Cell implantation was well tolerated and had no appreciable metabolic effects in normal mice. However, transplantation significantly (P<0.001) countered excessive food and fluid intake in diabetic mice and maintained normal body weight. Circulating glucose (P<0.01) and glucagon (P<0.05) were significantly reduced and plasma insulin and GLP-1 dramatically increased. This was associated with significantly (P<0.01) improved glucose tolerance in diabetic mice. Histological examination of the pancreata of these mice revealed elevations (P<0.001) in islet and β-cell area, with reduced (P<0.001) α-cell area. Increased β-cell mass reflected the enhanced proliferation relative to apoptosis. These studies emphasize the potential of chronic GLP-1 delivery by cell therapy as a potential therapeutic option for diabetes.

Topics: Animals; Blood Glucose; Body Weight; Cell Line; Cell Transplantation; Diabetes Mellitus, Experimental; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin-Secreting Cells; Male; Mice; Mice, SCID; Streptozocin

Type 2 diabetes is a chronic metabolic disorder characterized by hyperglycemia with insulin resistance and impaired insulin secretion. DPP-4 inhibitors have attracted attention as a new class of anti-diabetic agents for the treatment of type 2 diabetes. We investigated the effects of anagliptin, a highly selective DPP-4 inhibitor, on insulin secretion and insulin resistance in high-fat diet-fed mice with haploinsufficiency of glucokinase (GckKO) as animal models of type 2 diabetes.. Wild-type and GckKO mice were administered two doses of anagliptin by dietary admixture (0.05% and 0.3%) for 10weeks.. Both doses of anagliptin significantly inhibited the plasma DPP-4 activity and increased the plasma active GLP-1 levels in both the wild-type and GckKO mice to a similar degree. After 10weeks of treatment with 0.3% anagliptin, body weight gain and food intake were significantly suppressed in both wild-type and GckKO mice. In addition, 0.3% anagliptin ameliorated insulin resistance and glucose intolerance in both genotypes of mice. On the other hand, treatment with 0.05% anagliptin was not associated with any significant change of the body weight, food intake or insulin sensitivity in either genotype of mice, but it did improve the glucose tolerance by enhancing insulin secretion and increasing the β-cell mass in both genotypes of mice.. High-dose anagliptin treatment improved glucose tolerance by suppression of body weight gain and amelioration of insulin resistance, whereas low-dose anagliptin treatment improved glucose tolerance by enhancing insulin secretion.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Energy Intake; Glucagon-Like Peptide 1; Glucokinase; Glucose Intolerance; Haploinsufficiency; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Pyrimidines; Weight Gain

Pharmacological and surgical interventions that increase glucagon-like peptide 1 (GLP-1) action are effective to improve glucose homeostasis in type 2 diabetes mellitus. In light of this, nutritional strategies to enhance postprandial GLP-1 secretion, particularly in the context of diet-induced obesity, may provide an alternative therapeutic approach. Importantly, recent evidence suggests the amino acid L-arginine, a well-known insulin secretagogue, can also stimulate release of GLP-1 from isolated rat intestine. Here we tested the hypothesis that oral L-arginine acts as a GLP-1 secretagogue in vivo, to augment postprandial insulin secretion and improve glucose tolerance. To test this, we administered L-arginine or vehicle by oral gavage, immediately prior to an oral glucose tolerance test in lean and diet-induced obese mice. In both lean and obese mice oral L-arginine increased plasma GLP-1 and insulin and substantially improved glucose clearance. To directly assess the contribution of GLP-1 receptor (GLP-1R)-signaling to these improvements, L-arginine was given to Glp1r knockout mice and their wild-type littermates. In this experiment oral l-arginine significantly augmented insulin secretion and improved glucose clearance in WT mice, but not in Glp1r knockout littermates. Taken together these findings identify L-arginine as a GLP-1 secretagogue in vivo and demonstrate that improvement of glucose tolerance by oral L-arginine depends on GLP-1R-signaling. These findings raise the intriguing possibility that L-arginine-based nutritional and/or pharmaceutical therapies may benefit glucose tolerance by improving the postprandial GLP-1 response in obese individuals.

Topics: Animals; Arginine; Dietary Fats; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Glucagon

Roux-en-Y gastric bypass (RYGB) is effective in controlling blood glucose in obese patients with type 2 diabetes (T2DM). The alterations of gut hormones involving in glucose metabolism may play an important role. Our aim was to explore the short-term effects of Billroth II gastrojejunostomy (a similar type of RYGB) on glucose metabolism and gut hormone modulations in nonobese patients with different levels of blood glucose tolerance.. Twenty one nonobese gastric cancer patients with different levels of blood glucose tolerance were submitted to Billroth II gastrojejunostomy. Among them, seven had T2DM, seven with impaired glucose tolerance (IGT) and the other seven had normal glucose tolerance (NGT). Body weight, glucose parameters, responses of plasma glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) to 75 g glucose were measured at baseline and 3 months after surgery.. Similar weight losses were observed in all groups. Blood glucose was reduced in T2DM and IGT patients. Fasting and 30-min plasma glucose were increased significantly in NGT. GLP-1 showed insignificant alterations in all groups. PYY was evaluated in T2DM and IGT but remained unchanged in the NGT group. Decreased fasting and AUC GIP were observed in patients with T2DM; however, fasting and 30-min GIP were increased in NGT patients.. Billroth II gastrojejunostomy is effective in reducing blood glucose in nonobese patients with T2DM and IGT but could deteriorate early blood glucose in nonobese NGT in a 3-month time period. Variations of glucose and gut hormone changes in the three groups suggest a role of proximal intestine in the pathophysiology of T2DM.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Obesity; Peptide YY; Postoperative Period; Stomach Neoplasms; Weight Loss

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Male; Peptide YY

Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart.. Goto-Kakizaki (GK) rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin) or vehicle (n=10, each). After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays.. Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36), alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells.. Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36) promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.

Topics: Animals; Apoptosis; Cardiomegaly; Cardiotonic Agents; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Drug Evaluation, Preclinical; Fibroblasts; Fibronectins; Fibrosis; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin; Male; Metformin; Myocardium; Myocytes, Cardiac; PPAR delta; Protein Isoforms; Pyrazines; Rats; Sitagliptin Phosphate; Triazoles

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

EXf is a C-terminally truncated fragment of Exendin-4 with two amino acid substitutions. Previous studies showed that EXf controls plasma glucose level acting as a glucagon-like peptide 1 (GLP-1) receptor agonist. The purpose of this study was to evaluate the effects of EXf on β-cell function and survival in diabetic KKAy mice. EXf treatment significantly improved the glucose intolerance and reduced non-fasting and fasting plasma glucose levels, as well as plasma triglyceride levels in diabetic KKAy mice. In hyperglycemic clamp test, EXf-treated mice displayed an increased glucose infusion rate and first-phase insulin secretion. Treatment with EXf also led to a significant restoration of islet morphology, an increase in Ki67 expression in β-cells, and a reduction in the number of TUNEL positive β-cells. In the pancreas, comparative transcription analysis showed up-regulation of Akt1. The up-regulation of phosphorylated Akt1 was confirmed by Western blot, and changes in the protein levels of members of the Akt1 pathway, such as PI3K, Bim, Bcl-2, Bax, Caspase-3, and Caspase-9, PDX-1, were observed as well. Therefore, EXf treatment could improve β-cell function and survival in diabetic KKAy mice, likely as a result of islet morphology restoration, stimulation of β-cell proliferation, and inhibition of β-cell apoptosis.

Topics: Animals; Apoptosis; Blood Glucose; Exenatide; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Secretion; Insulin-Secreting Cells; Ki-67 Antigen; Mice; Mice, Inbred NOD; Peptide Fragments; Peptides; Proto-Oncogene Proteins c-akt; Triglycerides; Venoms

Recent studies have provided new evidence that alterations in the composition of the gut microbiota--known as dysbiosis--participate in the development of obesity. The aim of the present study was to investigate the ability of chitin-glucan (CG) from a fungal source to modulate both the gut microbiota and glucose and lipid metabolism in high-fat (HF) diet-induced obese mice. Supplementation of the HF diet with fungal CG (10% w/w) induced caecal enlargement with prominent changes in gut microbiota: it restored the number of bacteria from clostridial cluster XIVa including Roseburia spp., which were decreased due to HF feeding. Furthermore, CG treatment significantly decreased HF-induced body weight gain, fat mass development, fasting hyperglycemia, glucose intolerance, hepatic triglyceride accumulation and hypercholesterolemia, independently of the caloric intake. All those parameters were negatively correlated with specific bacteria of clostridial cluster XIVa, i.e., Roseburia spp. (Pearson's correlations analysis). In contrast to prebiotics that more specifically target the bifidobacteria species, CG effects on obesity appear to be independent of the incretin glucagon-like peptide 1 (GLP-1) production, since portal GLP-1 and proglucagon (its precursor) expression were not modified by the dietary intervention. In conclusion, our findings support the view that chronic consumption of CG has potential beneficial effects with respect to the development of obesity and associated metabolic diabetes and hepatic steatosis, through a mechanism related to the restoration of the composition and/or the activity of gut bacteria, namely, bacteria from clostridial cluster XIVa.

Topics: Animals; Chitin; Diet, High-Fat; Dietary Fiber; Dietary Supplements; Fatty Liver; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucans; Glucose; Glucose Intolerance; Gram-Positive Bacteria; Hyperglycemia; Lipid Metabolism; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Proglucagon; Triglycerides; Weight Gain

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Calcium Signaling; Cell Differentiation; Diet, High-Fat; DNA Mutational Analysis; Energy Metabolism; Europe; Exons; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Lipogenesis; Liver; Macrophages; Mice; Mutation; Obesity; Receptors, G-Protein-Coupled; Signal Transduction; White People

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

Reduced β cell mass is a characteristic feature of type 2 diabetes and incretin therapy is expected to prevent this condition. However, it is unknown whether dipeptidyl peptidase-4 inhibitors influence β and α cell mass in animal models of diabetes that can be translated to humans. Therefore, we examined the long-term effects of treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet morphology in Goto-Kakizaki (GK) rats, a spontaneous, non-obese model of type 2 diabetes, and explored the underlying mechanisms. Four-week-old GK rats were orally administered with vildagliptin (15 mg/kg) twice daily for 18 weeks. Glucose tolerance was monitored during the study. After 18 weeks, β and α cell morphology and the expression of molecules involved in cell proliferation and cell death were examined by immunohistochemistry and morphometric analysis. We found that vildagliptin improved glucose tolerance and insulin secretion, and suppressed hyperglucagonemia by increasing plasma active glucagon-like peptide-1 concentrations. β cell mass was reduced in GK rats to 40% of that in Wistar rats, but was restored to 80% by vildagliptin. Vildagliptin enhanced β and α cell proliferation, and increased the number of small neogenetic islets. Vildagliptin also reduced the number of 8-hydroxy-2'-deoxyguanosine-positive cells and forkhead box protein O1 expression, inhibited macrophage infiltration, and enhanced S6 ribosomal protein, molecule of target of rapamycin, and pancreatic duodenal homeobox 1 expression. These results indicate that starting vildagliptin treatment from an early age improved glucose tolerance and preserved islet β cell mass in GK rats by facilitating the proliferation of islet endocrine cells.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adamantane; Animals; Apoptosis; Cell Proliferation; Deoxyguanosine; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Eating; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Nitriles; Pyrrolidines; Rats; Time Factors; Vildagliptin

Insulin-like factor 5 (INSL5), a member of the insulin superfamily, is expressed in the colorectum and hypothalamus. To facilitate studies into the role of INSL5, we generated Insl5(-/-) mice by gene targeting. Insl5(-/-) mice were born in the expected Mendelian ratio, reached normal body weight, but displayed impaired male and female fertility that are due to marked reduction in sperm motility and irregular length of the estrous cycle. Furthermore, Insl5(-/-) mice showed impairment in glucose homeostasis with characteristic elevation of serum glucose levels at an advanced age. Glucose and insulin tolerance tests revealed that the increased blood glucose in Insl5(-/-) mice was due to glucose intolerance resulting from reduced insulin secretion. Morphometric and immunohistological analyses revealed that the Insl5(-/-) mice had markedly reduced average islets area and β-cell numbers. Furthermore, immunohistochemistry showed the expression of INSL5 in enteroendocrine cells in the colorectal epithelium and the presence of its putative receptor relaxin family peptide receptor 4 in pancreatic islet cells. These results suggest the potential role of INSL5 signaling in the regulation of insulin secretion and β-cell homeostasis.

Topics: Animals; Cell Proliferation; Estrous Cycle; Female; Fertility; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Homeostasis; Infertility; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Knockout; Peptide Hormones; Receptors, G-Protein-Coupled; Receptors, Peptide; Sperm Motility

Bariatric surgery alters the gastrointestinal hormonal milieu leading to improved glucose homeostasis, though the mechanism leading to these changes is poorly understood. Ileal transposition (IT) is a procedure that is neither restrictive nor malabsorptive but nevertheless produces profound improvements in glucose regulation. Ileal transposition involves a short segment of distal ileum being transposed to the proximal jejunum in an isoperistaltic direction, thereby avoiding any gastric resection or intestinal bypass.. Diet-induced obese rats underwent either ileal transposition (IT) or Sham procedures. The Sham operated rats were pair-fed to the IT surgical group to control for the effects of reduced food intake. Body composition data were recorded at specific time points, and glucose tolerance tests were performed at 5 and 6 wk, both in the presence and absence of Exendin 9-39, a known glucose-like peptide 1 (GLP-1) receptor antagonist. A subset of naïve rats were also maintained for comparison.. IT and Sham operated rats had no differences in food intake and body weight, however, IT rats had a significant decrease in their body fat composition (P < 0.05). No difference existed in glucose tolerance when exposed to an intraperitoneal glucose load, however, IT rats showed markedly improved glucose tolerance when submitted to an oral glucose tolerance test (P < 0.001). Blocking GLP-1 receptors reversed these important improvements in rats with IT surgery.. The present work recapitulates what is seen in rodents and humans that IT improves glucose tolerance and body composition. The present data provide compelling evidence that these improvements are a product of increased GLP-1 secretion that results from placing the key GLP-1 secreting cells closer to chyme coming from the stomach. Such data support the notion that rather than restriction or malabsorption, the underling molecular mechanisms that mediate the potent improvements produced by bariatric procedures involve increased activation of GLP-1 signaling.

Topics: Animals; Bariatric Surgery; Body Composition; Body Weight; Eating; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Ileum; Jejunum; Male; Obesity; Random Allocation; Rats; Rats, Long-Evans; Signal Transduction

In this study, we combined the dipeptidyl peptidase-4 inhibitor sitagliptin with the antidiabetic drug mangiferin to examine the effects on active glucagon-like peptide-1 (GLP-1) and glucose tolerance in streptozotocin-diabetic rats. Active GLP-1 levels were measured by an ELISA kit. Insulin levels were measured by an RIA kit. Islet morphology was determined by double immunolabeling. Sitagliptin (1 mg/kg) or mangiferin (20 mg/kg) single treatment improved glucose tolerance during an oral glucose tolerance test. In addition, the combination therapy improved glucose tolerance with an increase in plasma insulin level and active GLP-1 levels. Islets from combination-treated diabetic rats had markedly increased β-cell/islet area ratio compared with islets from the diabetic or single-treatment rats. In conclusion, these results indicate that the combination therapy is useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Experimental; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Islets of Langerhans; Male; Pyrazines; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Streptozocin; Triazoles; Xanthones

Low birthweight (BW) is associated with increased risk of type 2 diabetes. We compared glucose metabolism in adult BW-discordant monozygotic (MZ) twins, thereby controlling for genetic factors and rearing environment.. Among 77,885 twins in the Danish Twin Registry, 155 of the most BW-discordant MZ twin pairs (median BW difference 0.5 kg) were assessed using a 2 h oral glucose tolerance test with sampling of plasma (p-)glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. HOMA for beta cell function (HOMA-β) and insulin resistance (HOMA-IR), and also insulin sensitivity index (BIGTT-SI) and acute insulin response (BIGTT-AIR), were calculated. Subgroup analyses were performed in those with: (1) double verification of BW difference; (2) difference in BW >0.5 kg; and (3) no overt metabolic disease (type 2 diabetes, hyperlipidaemia or thyroid disease).. No intra-pair differences in p-glucose, insulin, C-peptide, incretin hormones, HOMA-β, HOMA-IR or BIGTT-SI were identified. p-Glucose at 120 min was higher in the twins with the highest BW without metabolic disease, and BIGTT-AIR was higher in those with the highest BW although not in pairs with a BW difference of >0.5 kg.. BW-discordant MZ twins provide no evidence for a detrimental effect of low BW on glucose metabolism in adulthood once genetic factors and rearing environment are controlled for.

Topics: Adult; Aged; Analysis of Variance; Birth Weight; Blood Glucose; C-Peptide; Denmark; Diabetes Mellitus, Type 2; Disease Susceptibility; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Infant, Low Birth Weight; Infant, Newborn; Insulin Resistance; Logistic Models; Male; Middle Aged; Risk Factors; Surveys and Questionnaires; Twins, Monozygotic

We studied the effect of a novel dipeptidyl peptidase IV (DPP IV) inhibitor, DA-1229, on blood glucose profile and pancreatic β-cell mass in established diabetes after streptozotocin (STZ) treatment. Mice that developed diabetes after administration of STZ 100mg/kg were treated with DA-1229 for 13 weeks. DA-1229 significantly reduced plasma DPP IV activity, and enhanced glucagon-like peptide 1 (GLP-1) levels. In STZ-treated mice fed DA-1229 (STZ-DA), blood glucose levels were significantly lower than those in diabetic mice fed normal chow (STZ-NC). Basal and glucose-stimulated insulin secretion and glucose tolerance assessed by intraperitoneal glucose tolerance test were significantly improved by DA-1229 administration. Volume density of β-cell was significantly increased in STZ-DA mice compared to STZ-NC mice, suggesting that DA-1229-mediated amelioration of established diabetes was due to beneficial effect of DA-1229 on β-cell mass. The number of replicating β-cells and that of scattered small β-cell unit representing β-cell neogenesis were significantly increased in STZ-DA mice compared to STZ-NC mice, explaining increased β-cell mass by DA-1229. The expression of PDX-1, a downstream mediator of GLP-1 action, was increased in islets of STZ-DA mice compared to STZ-NC mice. These results suggest a therapeutic potential of DA-1229 in diabetes, particularly that associated with decreased β-cell mass.

Topics: Animals; Blood Glucose; Cell Count; Cell Differentiation; Cell Proliferation; Cell Size; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose Intolerance; Homeodomain Proteins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Piperazines; Regeneration; Streptozocin; Trans-Activators

Microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT-130, a novel intestine-specific MTP inhibitor, on high fat diet-induced obesity and glucose intolerance.. Male Sprague-Dawley rats were fed a 3.1% fat diet or a 35% fat diet with or without JTT-130 as a food admixture (0.029%). Food intake, body weight, abdominal fat, hepatic triglyceride, faecal free fatty acids and plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were assessed. Plasma levels of glucose and insulin were measured during intraperitoneal glucose tolerance tests. In addition, indirect calorimetry was performed on rats fed with a 35% fat diet.. JTT-130 treatment decreased body weights, abdominal fat and hepatic triglyceride with suppression of food intake and elevation of faecal free fatty acids and plasma GLP-1 and PYY levels in rats fed with the 35% fat diet, whereas no significant effects on these parameters except for increased faecal free fatty acids were observed in rats fed with the 3.1% fat diet. JTT-130 treatment decreased plasma levels of glucose and insulin during intraperitoneal glucose tolerance tests on rats fed with the 35% fat diet, but not on rats fed with the 3.1% fat diet. JTT-130-treated rats showed increased O(2) consumption and CO(2) production on a 35% fat diet.. JTT-130 suppresses high fat diet-induced obesity and glucose intolerance with suppression of food intake and fat absorption and could be useful for prevention and treatment of obesity and obesity-related insulin resistance.

Topics: Animals; Benzamides; Biomarkers; Blood Glucose; Carrier Proteins; Diet, High-Fat; Dietary Fats; Eating; Fatty Acids; Feces; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Male; Malonates; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Triglycerides

Laparoscopic adjustable gastric banding (LAGB) provides weight loss in obese individuals and is associated with improved glucose homeostasis and resolution of type 2 diabetes. However, in most available reports, potentially inappropriate methodology has been applied when measuring the impact of LAGB on glucose intolerance. In order to clarify the applicability of the diagnostic 75 g-oral glucose tolerance test (OGTT) to measure the effect of LAGB on glucose metabolism, we investigated the effect of LAGB on gastric emptying for liquids as well as pancreatic and incretin hormone responses.. Eight obese patients (three with normal glucose tolerance, three with impaired glucose tolerance, and two with type 2 diabetes; age 47.5 ± 1.1 years (mean±SEM); body mass index 44 ± 1 kg/m²; HbA(1)c 6.2 ± 0.4%) underwent a 75 g-oral glucose tolerance test with 1 g acetaminophen before and ~6 weeks after LAGB.. A small weight reduction was seen after LAGB (125 ± 8 vs. 121 ± 8 kg, P = 0.014). No differences in determinants of gastric emptying were observed before and after LAGB (area under the serum acetaminophen curve 10.1 ± 0.6 vs. 9.8 ± 0.5 mM x 4 h, P = 0.8; peak acetaminophen concentration 62 ± 3 vs. 61 ± 3 μM, P = 0.8; acetaminophen peak time 98 ± 6 vs. 100 ± 6 min, P = 0.9). No differences in plasma glucose, insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide, or glucagon-like peptide-1 responses to the OGTT were observed before as compared to after LAGB.. OGTT can be used to evaluate glucose tolerance in obese patients before and after LAGB without bias from changes in gastric emptying. LAGB has no direct impact on incretin hormone secretion.

Topics: Acetaminophen; Adult; C-Peptide; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastroplasty; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Laparoscopy; Male; Middle Aged

Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity.

Topics: Adiposity; Analysis of Variance; Animals; Dietary Fats; Energy Metabolism; Feeding Behavior; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperphagia; In Situ Hybridization; Injections, Intraventricular; Islets of Langerhans; Male; Motor Activity; Obesity; Peptide Fragments; Proglucagon; Rats; Rats, Long-Evans; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger; Tissue Culture Techniques

Disturbance of glucose metabolism and diabetes is an increasing complication in adult patients with cystic fibrosis (CF). The aim of the present study was to evaluate the impact of insulin and glucagon-like peptide-1 (GLP-1) secretion on early disturbance of glucose metabolism and clinical status in an unselected cohort of CF patients. 34 adult CF patients and 10 matched healthy subjects underwent an oral glucose tolerance test. Blood samples were taken to measure indices for insulin secretion and insulin sensitivity. Metabolic parameters were correlated with anthropometric and clinical data. In CF patients, there was a decrease in first phase insulin secretion (FPIR) with progressive delay of insulin peak, which was correlated with worsening glucose tolerance (Stumvoll index: normal glucose tolerance: 450±291; impaired fasting glucose: 252±203; impaired glucose tolerance: 309±254; CF related diabetes: 18±41; controls: 950±388) and high early post-challenge glucose peak (p<0.01 vs. controls). However, total insulin secretory capacity was not decreased in CF patients resulting to low glucose levels in the late phase (120-180 min). We found neither a difference in basal or maximal GLP-1 levels nor in insulin resistance between study groups. Maximum glucose levels correlated with impaired FEV1 (rs=-0.5, p=0.002). Our data demonstrate that alteration of FPIR, but not insulinopenia, insulin resistance, or disturbed GLP-1 secretion is present in the prediabetic state in CF patients. Correlation between high glucose levels and worse clinical status suggest that diabetes treatment should be initiated more early in the state of glucose intolerance.

Topics: Adult; Blood Glucose; Cohort Studies; Cystic Fibrosis; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Insulin; Insulin Secretion; Kinetics; Male; Prediabetic State; Young Adult

Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.

Topics: Animals; Blood Glucose; Dietary Fats; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Inflammation; Intestines; Male; Metagenome; Mice; Mice, Inbred C57BL; Receptors, Glucagon; Resveratrol; Stilbenes; Time Factors

To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice.. Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.. In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat-fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters.. We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.

Topics: Animals; Cecum; Colon; Diabetes Mellitus, Type 2; Dietary Fats; Enteroendocrine Cells; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Intolerance; Gram-Negative Bacteria; Gram-Positive Bacteria; Hyperglycemia; Hyperlipidemias; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Typing; Obesity; Prebiotics; Proglucagon; RNA, Messenger

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

Besides the insulinotropic effects of glucagon-like peptide-1 (GLP-1) mimetics, their effects on endothelial dysfunction and myocardial ischaemia are of interest. No previous study has investigated associations between plasma levels of GLP-1 and CHD.. We investigated longitudinal relationships of fasting GLP-1 with the dynamic GLP-1 response after OGTT (difference between 60 min OGTT-stimulated and fasting GLP-1 levels [DeltaGLP-1]) and CHD in a population-based cohort of 71-year-old men. In the same cohort, we also cross-sectionally investigated the association between stimulated GLP-1 levels and: (1) cardiovascular risk factors (blood pressure, lipids, urinary albumin, waist circumference and insulin sensitivity index [M/I] assessed by euglycaemic-hyperinsulinaemic clamp); and (2) impaired glucose tolerance (IGT) and type 2 diabetes mellitus.. During the follow-up period (maximum 13.8 years), of 294 participants with normal glucose tolerance (NGT), 69 experienced a CHD event (13.8 years), as did 42 of 141 with IGT and 32 of 74 with type 2 diabetes mellitus. DeltaGLP-1 did not predict CHD (HR 1.0, 95% CI 0.52-2.28). The prevalence of IGT was associated with DeltaGLP-1, lowest vs highest quartile (OR 0.3, 95% CI 0.12-0.58), with no such association for type 2 diabetes mellitus (OR 1.0, 95% CI 0.38-2.86). M/I was significantly associated with DeltaGLP-1 in the type 2 diabetes mellitus group (r = 0.38, p < 0.01), but not in the IGT (r = 0.11, p = 0.28) or NGT (r = 0.10, p = 0.16) groups.. Impaired GLP-1 secretion is associated with IGT, but not with type 2 diabetes mellitus. This finding in the latter group might be confounded by oral glucose-lowering treatment. GLP-1 does not predict CHD. Although DeltaGLP-1 was associated with insulin sensitivity in the type 2 diabetes mellitus group, GLP-1 does not seem to be a predictor of CHD in insulin-resistant patients.

Topics: Aged; Albuminuria; Blood Pressure; Cardiovascular Diseases; Cholesterol; Cohort Studies; Coronary Disease; Diabetes Mellitus, Type 2; Fasting; Follow-Up Studies; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Male; Survival Analysis; Waist Circumference

The insulinotropic action of the incretin glucose-dependent insulinotropic polypeptide (GIP) is impaired in type 2 diabetes, while the effect of glucagon-like peptide-1 (GLP-1) is preserved. To evaluate the role of impaired GIP function in glucose homeostasis and development of the endocrine pancreas in a large animal model, we generated transgenic pigs expressing a dominant-negative GIP receptor (GIPR(dn)) in pancreatic islets.. GIPR(dn) transgenic pigs were generated using lentiviral transgenesis. Metabolic tests and quantitative stereological analyses of the different endocrine islet cell populations were performed, and beta-cell proliferation and apoptosis were quantified to characterize this novel animal model.. Eleven-week-old GIPR(dn) transgenic pigs exhibited significantly reduced oral glucose tolerance due to delayed insulin secretion, whereas intravenous glucose tolerance and pancreatic beta-cell mass were not different from controls. The insulinotropic effect of GIP was significantly reduced, whereas insulin secretion in response to the GLP-1 receptor agonist exendin-4 was enhanced in GIPR(dn) transgenic versus control pigs. With increasing age, glucose control deteriorated in GIPR(dn) transgenic pigs, as shown by reduced oral and intravenous glucose tolerance due to impaired insulin secretion. Importantly, beta-cell proliferation was reduced by 60% in 11-week-old GIPR(dn) transgenic pigs, leading to a reduction of beta-cell mass by 35% and 58% in 5-month-old and 1- to 1.4-year-old transgenic pigs compared with age-matched controls, respectively.. The first large animal model with impaired incretin function demonstrates an essential role of GIP for insulin secretion, proliferation of beta-cells, and physiological expansion of beta-cell mass.

Topics: Animals; Animals, Genetically Modified; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Glucose Tolerance Test; Immunohistochemistry; Insulin; Insulin Secretion; Insulin-Secreting Cells; Receptors, Glucagon; Swine

In an acute treatment experiment, metformin (150, 300 mg/kg, per os (p.o.)) markedly reduced the consumption of a high-fat diet (HFD) (45 kcal% fat-containing diet) for 2 h after the HFD was given to the fasted male C57BL/6J (B6) mice. In addition, metformin at a higher dose increased plasma active glucagon-like peptide-1 (GLP-1) levels at 1 h after the HFD was given. On the other hand, pioglitazone (12 mg/kg, p.o.) slightly increased the food intake but did not affect active GLP-1 levels when given at 6 and 12 mg/kg, p.o. In a long-team experiment for 9 weeks, metformin treatment (0.25, 0.5% in the HFD) resulted in reduction of body weight gain and HFD intake. When wet weights of various body fat pads of each mouse were measured at 9 weeks after treatment, metformin markedly decreased these weights. However, pioglitazone treatment (0.01, 0.02% in the HFD) did not have obvious effects on these parameters. Oral glucose tolerance test was carried out after 20-h fasting at 4 weeks post-treatment. Whereas metformin treatment (0.25, 0.5%) markedly improved glucose intolerance, pioglitazone treatment (0.02%) slightly improved this parameter. At 9 weeks, both metformin and pioglitazone markedly improved hyperglycemia and hyperinsulinemia. Metformin treatment also improved hyperleptinemia, whereas pioglitazone was ineffective. These results indicate that metformin reduces body weight gain and improves glucose intolerance in HFD-induced obese diabetic B6 mice.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Energy Intake; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Mice; Mice, Inbred C57BL; Obesity; Pioglitazone; Thiazolidinediones; Weight Gain

GLP-1 and GIP are the two key incretin hormones that regulate post-prandial glucose homeostasis. Furthermore, potent enzyme-resistant GIP and GLP-1 receptor agonists such as N-AcGIP and exendin-4 have now been developed. In the present study the effects of stable incretins, exendin-4 and N-AcGIP alone and in combination were examined in mice with high fat feeding induced glucose intolerance. Daily s.c. injections of exendin-4 (50 nmol/kg bw) for 12 days restored glycaemic control and significantly (P<0.05) decreased glucose intolerance compared to saline-treated controls. Food intake was transiently decreased (P<0.05) without effect on body weight. In the following 12 day period, mice either continued the original treatment or were administered an additional dose of N-AcGIP (50 nmol/kg body weight; s.c.). Under these circumstances sub-chronic administration of exendin-4 alone or particularly when combined with N-AcGIP significantly (P<0.05) reduced body weight. Exendin-4, N-AcGIP and combined treatment groups displayed significantly (P<0.05) decreased plasma glucose levels and less severe glucose intolerance. Non-fasting 24-h glycaemic profiles revealed marked (P<0.05 to P<0.01) beneficial effects of all treatment regimes. Insulin resistance was also reduced (P<0.01 to P<0.001) in all exendin-4 treated mice compared to saline controls. Adipose tissue mRNA levels of adiponectin, leptin, resistin, GIP-R, LPL and DGAT-1 were not significantly altered. These results illustrate efficacy of enzyme resistant GIP and GLP-1 analogues for treatment of glucose intolerance induced by high fat feeding.

Topics: Animals; Body Weight; Diabetes Mellitus, Experimental; Dietary Fats; Eating; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin Resistance; Mice; Peptides; Receptors, Gastrointestinal Hormone; Venoms

The present study investigated the antidiabetic effects of the dipeptidyl peptidase (DPP)-IV inhibitors ASP8497 and vildagliptin, and the sulfonylureas glibenclamide and gliclazide in streptozotocin-nicotinamide-induced mildly diabetic mice. A single administration of ASP8497 and vildagliptin significantly improved glucose tolerance by increasing plasma insulin and glucagon-like peptide-1 levels. In addition, a single administration of glibenclamide and gliclazide also caused significant improvement in glucose tolerance with an accompanying increase in the plasma insulin level. Subsequently, the effects of a 1-week chronic daily dosing of DPP-IV inhibitors and sulfonylureas were investigated. All drugs significantly improved glucose tolerance on day 1 of chronic daily dosing. After 1 week of chronic daily dosing, the DPP-IV inhibitors caused a significant improvement in glucose tolerance similar to those observed on day 1 by increasing the plasma insulin and glucagon-like peptide-1 levels. In contrast, the sulfonylureas had no significant improving or insulinotropic effect. Furthermore, ASP8497 also had an antihyperglycemic effect and improved pancreatic histopathologic lesions in a 4-week chronic daily dosing study. These results suggest that chronic daily dosing of sulfonylureas had virtually no antidiabetic effects because of marked attenuation of the insulinotropic action in streptozotocin-nicotinamide-induced mildly diabetic mice. In contrast, the antidiabetic efficacy of DPP-IV inhibitors, including ASP8497, did not change even after chronic daily dosing; therefore, DPP-IV inhibitors are useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes mellitus.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gliclazide; Glucagon-Like Peptide 1; Glucose Intolerance; Glyburide; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred ICR; Niacinamide; Piperidines; Pyrrolidines; Sulfonylurea Compounds

Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (D-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice.. Mice on high-fat diet for 155 days were injected once daily with (D-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (D-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes.. Daily intraperitoneal injections of (D-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p < 0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (D-Ala(8))GLP-1 alone (p < 0.05) or in combination with (Pro(3))GIP (p < 0.01) compared with normal chow-fed controls.. These results illustrate efficacy of (Pro(3))GIP and (D-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.

Topics: Animals; Blood Glucose; Dietary Fats; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Injections, Intraperitoneal; Insulin; Insulin Resistance; Mice; Receptors, Gastrointestinal Hormone; Receptors, Glucagon; Treatment Outcome

The control of glucose metabolism is a complex process, and dysregulation at any level can cause impaired glucose tolerance and insulin resistance. These two defects are well-known characteristics associated with obesity and onset of type 2 diabetes. Here we introduce the N-terminal dipeptidase, DPP2, as a novel regulator of the glucose metabolism. We generated mice with a neurogenin 3 (NGN3)-specific DPP2 knockdown (kd) to explore a possible role of DPP2 in maintaining metabolic homeostasis. These mice spontaneously developed hyperinsulinemia, glucose intolerance, and insulin resistance by 4 months of age. In addition, we observed an increase in food intake in DPP2 kd mice, which was associated with a significant increase in adipose tissue mass and enhanced liver steatosis but no difference in body weight. In accordance with these findings, the mutant mice had a higher rate of respiratory exchange than the control littermates. This phenotype was exacerbated with age and when challenged with a high-fat diet. We report, for the first time, that DPP2 enzyme activity is essential for preventing hyperinsulinemia and maintaining glucose homeostasis. Interestingly, the phenotype of NGN3-DPP2 kd mice is opposite that of DPP4 knockout mice with regard to glucose metabolism, namely the former have normal glucagon-like peptide 1 levels but present with glucose intolerance, whereas the latter have increased glucagon-like peptide 1, which is accompanied by augmented glucose tolerance.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Eating; Fasting; Fatty Liver; Female; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Mice; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Obesity

The current scarcity of high-quality deceased pancreas donors prevents widespread application of islet transplantation for treatment of labile type 1 diabetes mellitus. Opportunities for the improvement of current techniques include optimization of islet isolation and purification, use of culture with pharmacological insulinotropic agents, strategies to reduce graft rejection and inflammation, and the search for alternative insulin producing tissue. Here, we report our findings on the efficacy of the long-acting human glucagon-like peptide 1 analog, liraglutide, in a mouse model of marginal mass islet transplantation. Liraglutide was administered (200 microg/kg sc twice daily) after a marginal mass syngeneic islet transplant in streptozotocin-induced diabetic BALB/c mice. Time-to-normoglycemia was significantly shorter in liraglutide-treated animals (median 1 vs. 7 d; P = 0.0003), even in recipients receiving sirolimus (median 1 vs. 72.5 d; P < 0.0001). Liraglutide-treated animals also demonstrated improved glucose tolerance as assessed by an ip glucose tolerance test. Liraglutide discontinuation at postoperative d 90 resulted in diminished glucose tolerance during the ip glucose tolerance test, whereas a late-start liraglutide therapy 90 d after transplant resulted in no improvement. These findings suggest that liraglutide therapy mediates early and late insulinotropic effects. In accord with this hypothesis, insulin/terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling fluorescence microscopy showed reduced transplanted beta-cell apoptosis in liraglutide-treated recipients 48 h after transplant. In addition, liraglutide resulted in improved glucose-dependent insulin secretion. Overall, our data show that liraglutide has a beneficial impact on the engraftment and function of syngeneic islet transplants in mice, when administered continuously starting on the day of transplant.

Topics: Animals; Apoptosis; Delayed-Action Preparations; Diabetes Mellitus, Experimental; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Graft Rejection; Homeostasis; Islets of Langerhans; Islets of Langerhans Transplantation; Liraglutide; Mice; Mice, Inbred BALB C; Satiety Response; Streptozocin

The effect of high multivitamin intake during pregnancy on the metabolic phenotype of rat offspring was investigated. Pregnant Wistar rats (n=10 per group) were fed the AIN-93G diet with the recommended vitamin (RV) content or a 10-fold increase [high vitamin (HV) content]. In experiment 1, male and female offspring were followed for 12 wk after weaning; in experiment 2, only males were followed for 28 wk. Body weight (BW) was measured weekly. Every 4 wk, after an overnight fast, food intake over 1 h was measured 30 min after a gavage of glucose or water. An oral glucose tolerance test was performed every 3-5 wk. Postweaning fasting glucose, insulin, ghrelin, glucagon-like peptide-1, and systolic blood pressure were measured. No difference in BW at birth or litter size was observed. Food intake was greater in males born to HV dams (P<0.05), and at 28 wk after weaning, BW was 8% higher (P<0.05) and fat pad mass was 27% higher (P<0.05). Food intake reduction after the glucose preload was nearly twofold less in males born to HV dams at 12 wk after weaning (P<0.05). Fasting glucose, insulin, and ghrelin were 11%, 62%, and 41% higher in males from HV dams at 14 wk after weaning (P<0.05). Blood glucose response was 46% higher at 23 wk after weaning (P<0.01), and systolic blood pressure was 16% higher at 28 wk after weaning (P<0.05). In conclusion, high multivitamin intake during pregnancy programmed the male offspring for the development of the components of metabolic syndrome in adulthood, possibly by its effects on central mechanisms of food intake control.

Topics: Adipose Tissue; Animal Nutritional Physiological Phenomena; Animals; Appetite Regulation; Blood Glucose; Blood Pressure; Body Weight; Dietary Supplements; Eating; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Time Factors; Vitamins

Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.

Topics: Animals; Blood Glucose; Body Temperature Regulation; Brain Stem; Carbon Dioxide; Diabetes Mellitus, Type 2; Dietary Fats; Energy Metabolism; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperinsulinism; Insulin Resistance; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Motor Activity; Muscle, Skeletal; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxygen Consumption; Peptide Fragments; Physical Endurance; Proglucagon; RNA, Messenger; Signal Transduction; Uncoupling Protein 2

Therapeutic use of atypical antipsychotic agents is often associated with weight gain and impaired glucose tolerance. The once-daily human GLP-1 analog liraglutide improves glycemic control and reduces body weight. We have investigated the ability of liraglutide to improve olanzapine-induced metabolic effects in female rats. Female Sprague-Dawley rats were implanted with subcutaneous osmotic mini pumps for delivery of olanzapine (1.75 mg/24 h) or vehicle for 28 days (n=20). After 14 days, ten animals from each group were given liraglutide (0.2 mg/kg) or vehicle twice daily for the remainder of the study. Compared to vehicle treated animals, olanzapine infusion for 4 weeks significantly increased end point cumulated food intake (667.3+/-7.0 versus 593.2+/-13.2g, p<0.01), body weight (306.6+/-4.2 versus 276.4+/-3.6 g, p<0.001), subcutaneous inguinal fat (3.4+/-0.3 versus 1.9+/-0.1 g, p<0.001), mesenteric fat (3.1+/-0.2 versus 1.7+/-0.2g, p<0.001), retroperitoneal fat (6.2+/-0.6 versus 2.8+/-0.3 g, p<0.001), and impaired glucose tolerance, measured as total area under the glucose curve during an oral glucose tolerance test (1906+/-66 versus 1770+/-28 mMxmin, p<0.05). These olanzapine-induced elevations were significantly reduced by liraglutide (cumulated food intake: 601.8+/-20.4 g, p<0.01; body weight: 280.2+/-5.6 g, p<0.001; subcutaneous inguinal fat: 2.4+/-0.2 g, p<0.001; mesenteric fat: 1.8+/-0.1 g, p<0.001; retroperitoneal fat: 3.5+/-0.4 g, p<0.001; AUC: 1764+/-32 mMxmin, p<0.05). In conclusion, subcutaneous olanzapine infusion in female rats leads to weight gain and metabolic changes of which several are reversed following liraglutide treatment. It may therefore be relevant to study these effects of liraglutide in patients treated with atypically antipsychotics.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Drug Administration Schedule; Eating; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Intra-Abdominal Fat; Liraglutide; Olanzapine; Rats; Rats, Sprague-Dawley; Subcutaneous Fat, Abdominal; Weight Gain

In this study, streptozotocin-nicotinamide-induced mildly diabetic mice and streptozotocin-induced severely diabetic mice were created to compare their characteristics and to investigate the effects of antidiabetic drugs on glucose tolerance. In severely diabetic mice, the pancreatic insulin content decreased to approximately 10% of levels found in normal mice. These mice also showed a decrease in body weight, a marked increase in nonfasting blood glucose levels and urinary glucose excretion, and a marked decline in glucose tolerance due to insulin secretory deficiency. In contrast, the pancreatic insulin content was approximately 50% of normal levels in mildly diabetic mice. These mice did not show any change in body weight, but displayed a mild increase in nonfasting blood glucose levels and urinary glucose excretion, and a mild decline in glucose tolerance due to loss of early-phase insulin secretion. Administration of antidiabetic drugs, namely voglibose, metformin, glibenclamide, sitagliptin and insulin, significantly improved glucose tolerance in mildly diabetic mice. In severely diabetic mice, voglibose, metformin and insulin significantly improved glucose tolerance, but no significant effect was observed for glibenclamide and sitagliptin due to a decreased insulinotropic effect. These results demonstrate that streptozotocin-nicotinamide-induced mildly diabetic mice have many pathological features resembling type 2 diabetes, and can serve as models for the pharmacological evaluation of many antidiabetic drugs.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Glycosuria; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred ICR; Niacinamide; Pancreas; Vitamin B Complex

The pathogenesis of hepatitis C virus (HCV)-associated glucose intolerance remains unclear. Glucagon-like peptide-1 (GLP-1), a gut hormone, synthesizes hepatic glycogen and is inactivated by dipeptidyl peptidase IV (DPPIV). The aims of this study were to investigate the alterations in the expression of GLP-1 and DPPIV in HCV-associated glucose intolerance.. We enrolled patients with HCV- or hepatitis B virus (HBV)-related liver disease (n = 94 and 37, respectively), patients with inflammatory bowel disease (IBD; n = 14) as disease controls, and healthy controls (n = 48). The serum or tissue GLP-1 and DPPIV expression levels were determined by enzyme immunoassay, immunoblotting, or immunostaining. The hepatic glycogen content was assayed by periodic acid-Schiff staining.. The serum GLP-1 levels were significantly decreased in the HCV group (4.9 +/- 0.3 ng/mL) than those in the controls (7.5 +/- 0.6 ng/mL), the HBV group (7.0 +/- 0.5 ng/mL), or the IBD group (10.8 +/- 1.0 ng/mL, P < 0.01). Although the ileum GLP-1 expression was not significantly different between the controls and the HCV group, the DPPIV expression was significantly increased in the ileum, liver, and serum in the HCV group. Hepatic glycogen content was decreased to a greater extent in the HCV group than that in the HBV group (127.5 +/- 5.3 vs 187.7 +/- 6.6 arbitrary units; n = 19, P < 0.01).. We demonstrated the altered expressions of GLP-1 and DPPIV in patients with HCV-associated glucose intolerance. Since hepatic glycogen synthesis, a GLP-1 action, was impaired, the altered expressions of GLP-1 and DPPIV may be involved in the development of HCV-associated glucose intolerance.

Topics: Adult; Dipeptidyl Peptidase 4; Fasting; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glycogen; Hepatitis B; Hepatitis C; Humans; Ileum; Immunoblotting; Immunohistochemistry; Inflammatory Bowel Diseases; Insulin; Insulin Secretion; Liver; Middle Aged

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

We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance.. Non-diabetic offspring (n=874; mean age 40+/-10.4 years; BMI 26.6+/-4.9 kg/m(2)) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals.. Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0-10 min) and higher second-phase insulin release (10-60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance.. The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.

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

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

Despite important empirical findings, current models of the oral glucose tolerance test (OGTT) do not incorporate the essential contributions of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, to glucose-stimulated insulin secretion. In order to address this deficiency, a model was, therefore, developed in which the incretins, as well as a term reflecting net hepatic glucose balance, were included. Equations modeling the changes in incretins, hepatic glucose balance, insulin and glucose were used to simulate the responses to 50 and 100 g oral glucose loads under normal conditions. The model successfully captures main trends in mean data from the literature using a simple 'lumped-parameter,' single-compartment approach in which the majority of the parameters were matched to known clinical data. The accuracy of the model and its applicability to understanding fundamental mechanisms was further assessed using a variety of glycemic and insulinemic challenges beyond those which the model was originally created to encompass, including hyper- and hypoinsulinemia, changes in insulin sensitivity, and the insulin infusion-modified intravenous glucose tolerance test.

Topics: Administration, Oral; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Hormones; Humans; Insulin; Models, Theoretical

High fat diet or insulin deficiency is commonly seen in Type II diabetes, while the mechanism remains unclear. To test our hypothesis that DPP-IV contributes to Type II diabetes, we examined the expression and activity of DPP-IV in rats (n=8 to each group) treated for 12 weeks with 3 separate diets: a) normal control; b) a high fat diet; and c) a high fat diet plus streptozotocin, a chemical for induction of insulin-deficient diabetes. Compared to rats on the normal diet, the rats with a high fat diet significantly increased DPP-IV's expression and activity about 142-152% in the intestine (P<0.05) and 153-240% in kidneys (P<0.05), but there was no change in the liver. Administration of streptozotocin to the rats treated with the high fat diet showed an insufficient insulin secretion and higher blood glucose in response to glucose/insulin tolerance test, and an increase in expression of DPP-IV and activity by 188-242% in the intestine (P<0.01); 191-225% in liver (P<0.01); and 211-321% in the kidneys (P<0.01). Immunohistochemistry studies confirmed the above results, showing increased DPP-IV immunostaining localized primarily in intestinal epithelium, hepatocytes and renal tubular cells. This study, for the first time reports an increase in DPP-IV associated with a high fat diet, as well as in the combination of a high fat diet with an insulin deficiency. Since both high fat diet and insulin deficiency are closely linked with etiology of Type II diabetes, the evidence in this study suggests a role of DPP-IV in development of Type II diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Dipeptidyl Peptidase 4; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Immunohistochemistry; Insulin; Intestines; Kidney; Lipids; Liver; Rats; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that is secreted during meal absorption and is essential for normal glucose homeostasis. However, the relatively low plasma levels and rapid metabolism of GLP-1 raise questions as to whether direct endocrine action on target organs, such as islet cells, account for all of its effects on glucose tolerance. Recently, an alternative neural pathway initiated by sensors in the hepatic portal region has been proposed to mediate GLP-1 activity. We hypothesized that visceral afferent neurons in the portal bed express the GLP-1 receptor (GLP-1r) and regulate glucose tolerance. Consistent with this hypothesis, GLP-1r mRNA was present in the nodose ganglia, and nerve terminals innervating the portal vein contained the GLP-1r. Rats given an intraportal infusion of the GLP-1r antagonist, [des-His(1),Glu(9)] exendin-4, in a low dose, had glucose intolerance, with a 53% higher glucose excursion compared with a vehicle-infused control group. Infusion of [des-His(1),Glu(9)] exendin-4 at an identical rate into the jugular vein had no effect on glucose tolerance, demonstrating that this dose of GLP-1r antagonist did not affect blood glucose due to spillover into the systemic circulation. These studies demonstrate that GLP-1r are present on nerve terminals in the hepatic portal bed and that GLP-1 antagonism localized to this region impairs glucose tolerance. These data are consistent with an important component of neural mediation of GLP-1 action.

Topics: Animals; Blood Glucose; Cell Line; Dose-Response Relationship, Drug; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Glucose Tolerance Test; Infusions, Intravenous; Liver; Male; Nerve Endings; Nodose Ganglion; Peptides; Portal Vein; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms

Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes and reduced insulin secretion. The transcription factor TCF7L2 is an essential factor for glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells. We studied whether a defect in the enteroinsular axis contributes to impaired insulin secretion in carriers of TCF7L2 polymorphisms.. We genotyped 1,110 non-diabetic German participants for five single nucleotide polymorphisms in TCF7L2. All participants underwent an OGTT; GLP-1 secretion was measured in 155 participants. In 210 participants, an IVGTT combined with a hyperinsulinaemic-euglycaemic clamp was performed. In another 160 participants from the Netherlands and 73 from Germany, a hyperglycaemic clamp (10 mmol/l) was performed. In 73 German participants this clamp was combined with a GLP-1 infusion and an arginine bolus.. The OGTT data confirmed that variants in TCF7L2 are associated with reduced insulin secretion. In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 concentrations during the OGTT were not influenced by the TCF7L2 variants. However, GLP-1-infusion combined with a hyperglycaemic clamp showed a significant reduction in GLP-1-induced insulin secretion in carriers of the risk allele in two variants (rs7903146, rs12255372, p < 0.02).. Variants of TCF7L2 specifically impair GLP-1-induced insulin secretion. This seems to be rather the result of a functional defect in the GLP-1 signalling in beta cells than a reduction in GLP-1 secretion. This defect might explain the impaired insulin secretion in carriers of the risk alleles and confers the increased risk of type 2 diabetes.

Topics: Adult; Arginine; Blood Glucose; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Heterozygote; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Polymorphism, Single Nucleotide; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins secreted in response to oral glucose ingestion by intestinal L and K cells, respectively. The molecular mechanisms responsible for intestinal cell glucose sensing are unknown but could be related to those described for beta-cells, brain and hepatoportal sensors. We determined the role of GLUT2, GLP-1 or GIP receptors in glucose-induced incretins secretion, in the corresponding knockout mice. GLP-1 secretion was reduced in all mutant mice, while GIP secretion did not require GLUT2. Intestinal GLP-1 content was reduced only in GIP and GLUT2 receptors knockout mice suggesting that this impairment could contribute to the phenotype. Intestinal GIP content was similar in all mice studied. Furthermore, the impaired incretins secretion was associated with a reduced glucose-stimulated insulin secretion and an impaired glucose tolerance in all mice. In conclusion, both incretins secretion depends on mechanisms involving their own receptors and GLP-1 further requires GLUT2.

Topics: Animals; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 2; Intestinal Mucosa; Intestines; Mice; Mice, Knockout; Models, Biological; Portal System; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

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

The mechanisms by which the enteroinsular axis influences beta-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate beta-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 +/- 0.18, P = 0.004] amounted to 18 +/- 2 nmol/m(2) (32 +/- 4% of oral response), and its time course matched that of total insulin secretion. The beta-cell glucose sensitivity (OGTT/IV ratio = 1.52 +/- 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 +/- 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, beta-cell glucose sensitivity (75 +/- 14 vs. 156 +/- 28 pmol.min(-1).m(-2).mM(-1) of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of beta-cell glucose sensitivity (OGTT/IV ratio = 1.73 +/- 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of beta-cell function, particularly beta-cell glucose sensitivity. In IGT, beta-cell function is inherently impaired, whereas the incretin effect is only partially affected.

Topics: Adult; Blood Glucose; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hormones; Humans; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Models, Statistical; Radioimmunoassay

This study evaluates the antidiabetic potential of an enzyme-resistant analog, (Val8)GLP-1. The effects of daily administration of a novel dipeptidyl peptidase IV-resistant glucagon-like peptide-1 (GLP-1) analog, (Val8)GLP-1, on glucose tolerance and pancreatic beta-cell function were examined in obese-diabetic (ob/ob) mice. Acute intraperitoneal administration of (Val8)GLP-1 (6.25-25 nmol/kg) with glucose increased the insulin response and reduced the glycemic excursion in a dose-dependent manner. The effects of (Val8)GLP-1 were greater and longer lasting than native GLP-1. Once-daily subcutaneous administration of (Val8)GLP-1 (25 nmol/kg) for 21 days reduced plasma glucose concentrations, increased plasma insulin, and reduced body weight more than native GLP-1 without a significant change in daily food intake. Furthermore, (Val8)GLP-1 improved glucose tolerance, reduced the glycemic excursion after feeding, increased the plasma insulin response to glucose and feeding, and improved insulin sensitivity. These effects were consistently greater with (Val8)GLP-1 than with native GLP-1, and both peptides retained or increased their acute efficacy compared with initial administration. (Val8)GLP-1 treatment increased average islet area 1.2-fold without changing the number of islets, resulting in an increased number of larger islets. These data demonstrate that (Val8)GLP-1 is more effective and longer acting than native GLP-1 in obese-diabetic ob/ob mice.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Eating; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Immunohistochemistry; Injections, Intraperitoneal; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Obese

7-But-2-ynyl-9-(6-methoxy-pyridin-3-yl)-6-piperazin-1-yl-7,9-dihydro-purin-8-one (ER-319711) is a novel dipeptidyl peptidase (DPP)-IV inhibitor discovered in our laboratories. In this study, we have characterized this DPP-IV inhibitor in vitro and in vivo as an antidiabetic agent. The trifluoroacetate salt form of ER-319711, ER-319711-15, inhibited human DPP-IV with an IC(50) value of 0.089 microM, whereas its IC(50) values toward human DPP8 and DPP9 were >100 microM. Inhibition kinetic pattern analysis indicated that ER-319711-15 inhibited DPP-IV in a competitive manner. ER-319711-15 (1 mg/kg) reduced glucose excursion in an oral glucose tolerance test (OGTT) using Zucker fa/fa rats, with significant increases in plasma insulin and active glucagon-like peptide-1 levels. In an OGTT using mice fed a high-fat diet in which ER-319711-15 (0.1-10 mg/kg) was orally administered at 0 h, and glucose was loaded at 0 and 5 h, this compound improved glucose tolerance dose dependently at both 0- and 5-h glucose loading. Next, we compared efficacy of ER-319711-15, E3024, a competitive DPP-IV inhibitor having an imidazopyridazinone structure, or vildagliptin, a slow-binding and long-acting DPP-IV inhibitor, at the same dose, 10 mg/kg, in the same procedures. At the first glucose challenge, all compounds lowered area under the curve (AUC) values of delta blood glucose between 0 and 2 h significantly to the same degree. At the second glucose load, the AUC values between 5 and 7 h were significantly decreased by ER-319711-15 and vildagliptin, but not by E3024. Therefore, ER-319711 might be a potent, competitive, and selective DPP-IV inhibitor with an antihyperglycemic activity.

Topics: Adamantane; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Fats; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Imidazoles; Insulin; Kinetics; Mice; Mice, Inbred C57BL; Nitriles; Piperazines; Protease Inhibitors; Purines; Pyridazines; Pyrrolidines; Rats; Rats, Zucker; Tosyl Compounds; Vildagliptin

To investigate early secretory defects in prediabetes, we evaluated beta-Cell function and insulin sensitivity (M value, by euglycemic clamp) in 26 normotolerant first-degree relatives of type 2 diabetic patients (FDR) and 17 age- and weight-matched control subjects. beta-Cell function was assessed by modeling analysis of glucose and C-peptide concentrations measured during 24 h of standardized living conditions. Fasting and total insulin secretion (ISR) were increased in FDR, as was ISR at a reference 5 mM glucose level (ISR5, 107 +/- 6 vs. 87 +/- 6 pmol x min(-1) x m(-2), P < 0.05). ISR5 was inversely related to M in controls (ISR5 = k/M1.23, rho = -0.74, P < 0.005) but not in FDR; when M was accounted for (by calculating a compensation index ISR5 x M1.23), compensation for insulin resistance was impaired in FDR (10.8 +/- 1.0 vs. 13.4 +/- 0.6 units, P < 0.05). Potentiation of ISR, expressing relative transient increases in glucose-stimulated ISR during meals, was impaired in FDR (1.29 +/- 0.08 vs. 1.62 +/- 0.08 during 1st meal, P < 0.02). Moreover, the potentiation time course was related to glucose-dependent insulin-releasing polypeptide (GIP) concentrations in both groups, and the sensitivity of potentiation to GIP derived from this relationship tended to be impaired in FDR. Compensation index, potentiation, and sensitivity to GIP were interrelated parameters (P < 0.05 or less). beta-Cell function parameters were also related to mean 24-h glucose levels (r2 = 0.63, P < 0.0001, multivariate model). In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, beta-cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a beta-cell defect in the amplifying pathway of insulin secretion.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet; Energy Intake; Family; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Linear Models; Male; Models, Biological; Multivariate Analysis; Peptide Fragments; Protein Precursors

We investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV-infected patients on highly active antiretroviral therapy (HAART).. Eighteen HIV-infected male patients (six lipodystrophic and 12 nonlipodystrophic) with normal glucose tolerance (NGT) were compared with 10 HIV-infected male patients (eight lipodystrophic and two nonlipodystrophic) with IGT. Plasma concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations.. The incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared with NGT patients (1455+/-422 vs. 409+/-254 pmol/L/180 min, respectively; P<0.05), whereas the incrAUC for GIP did not differ between the study groups (7689+/-1097 vs. 8041+/-998 pmol/L/180 min, respectively; not significant). In pooled study groups, the GIP incrAUC correlated positively with the ISR incrAUC without adjustment (r=0.38, P<0.05) and following adjustment for glucose incrAUC (r=0.49, P<0.01).. Our data suggest: (1) that glucose-intolerant, HIV-infected male patients may display enhanced GLP-1 responses to oral glucose compared with normal glucose-tolerant HIV-infected male patients, which may represent a compensatory mechanism rather than explain the IGT; (2) that the GIP response may be associated with ISR independently of plasma glucose in nondiabetic HIV-infected males on HAART.

Topics: Adult; Analysis of Variance; Antiretroviral Therapy, Highly Active; Antiviral Agents; Area Under Curve; Blood Glucose; Body Composition; C-Peptide; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Peptide Fragments; Protein Precursors

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.

Topics: Adamantane; Animals; Area Under Curve; Blood Glucose; Dietary Fats; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Oxidase; Glucose Tolerance Test; Insulin Resistance; Male; Nitriles; Pyrrolidines; Rats; Rats, Zucker; Tachyphylaxis; Time Factors; Vildagliptin; Weight Gain

Surgical operations which shorten the intestinal tract between the stomach and the terminal ileum result in an early improvement in type 2 diabetes, and one possible explanation is the arrival of undigested food in the terminal ileum. This study was designed to evaluate the role of the distal ileum in the improvement of glucose control in type 2 diabetic patients who underwent bariatric surgery.. An ileal transposition (IT) to the jejunum was performed in lean diabetic Goto-Kakizaki (GK) rats. The IT was compared to sham-operated diabetic rats and a control group of diabetic rats. Non-diabetic controls were age-matched Sprague-Dawley (SD) rats, which underwent IT and no operation. Food intake and body weight were measured. An oral glucose tolerance test (OGTT) was performed 10 days before the operation and 10 days, 30 days and 45 days after the surgery. GLP-1 and insulin were measured during the OGTT 45 days after surgery. An insulin tolerance test (ITT) was performed 50 days after surgery.. Glucose tolerance improved in the IT diabetic group compared with both the sham-operated animals and control diabetic group 30 days and 45 days after surgery (P=0.029 and P=0.023, respectively). Insulin sensitivity, as measured by an ITT, was not significantly different between diabetic groups and the normal groups respectively after surgery. No differences in basal glucose and glucose tolerance were noted between non-diabetic operated animals and control non-diabetic rats. No differences were recorded between the diabetic rat groups and the non-diabetic rats in terms of weight and food intake. GLP-1 levels were significantly higher in the IT diabetic group compared with the sham-operated rats (P=0.05).. Ileal transposition is effective in inducing an improvement in glucose tolerance in lean diabetic rats without affecting weight and food intake. The possible mechanism underlying the early improvement of diabetes after bariatric surgery may be due to the action of the terminal ileum through an insulin-independent action.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Ileum; Insulin; Insulin Resistance; Jejunum; Male; Rats; Rats, Sprague-Dawley; Weight Gain

Type 2 diabetic patients pass through a phase of impaired glucose tolerence and/or impaired fasting glucose known as 'prediabetic state'. Prediabetic state form a part of syndrome X, other components being obesity, hypertension, dyslipidaemia, hyperinsulinaemia and insulin resistance. The pathophysiology of prediabetes is similar to type 2 diabetes mellitus, two basic defects are insulin resistance and early beta cell failure. In prediabetes, the rapid oscillations of insulin secretion are lost and amplitude of large pulses are decreased. When insulin is delivered in a pulsatile fashion that mimics the normal rapid oscillation, its hypoglycaemic effects are greater. In prediabetes, the glycaemic excursions after each meal are high and early insulin responses to meals tend to be lower than normal but the second phase of insulin secretion is delayed and prolonged.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Metabolic Syndrome; Prediabetic State

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P =.018) and lower OGIS (397 +/- 21 v 463 +/- 12 mL/min/m(2); P =.005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 +/- 51 v 774 +/- 91 nmol/min/m(2), P =.001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P <.001). In contrast, TIS over the whole 180-minute period was higher in IGT (26.2 +/- 2.4 v 20.0 +/- 2.0 nmol/L; P =.035). Hepatic insulin extraction correlated linearly with OGIS (r = 0.71; P <.001), but was not significantly different between the groups although there was a trend with lower extraction in IGT (P =.055). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT (P =.036). We conclude that also in non-obese subjects with IGT, when adiposity is controlled for in relation to NGT, defective early insulin secretion after oral glucose is a key factor. This defective beta-cell function is associated with, and may be caused by, a reduced early GLP-1 response.

Topics: Administration, Oral; Area Under Curve; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Liver; Middle Aged; Peptide Fragments; Protein Precursors; Regression Analysis; Time Factors

The incretin hormone GLP1 promotes islet-cell survival via the second messenger cAMP. Here we show that mice deficient in the activity of CREB, caused by expression of a dominant-negative A-CREB transgene in pancreatic beta-cells, develop diabetes secondary to beta-cell apoptosis. Remarkably, A-CREB severely disrupted expression of IRS2, an insulin signaling pathway component that is shown here to be a direct target for CREB action in vivo. As induction of IRS2by cAMP enhanced activation of the survival kinase Akt in response to insulin and IGF-1, our results demonstrate a novel mechanism by which opposing pathways cooperate in promoting cell survival.

Topics: Animals; Apoptosis; Cell Line; Cell Survival; Colforsin; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Mice; Mice, Transgenic; Peptide Fragments; Phosphoproteins; Phosphorylation; Promoter Regions, Genetic; Protein Precursors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; Transfection; Transgenes; Tumor Cells, Cultured

Glucagon-like peptide-1 (GLP-1) is an effective anti-diabetic agent, but its metabolic instability makes it therapeutically unsuitable. This study investigated the pharmacodynamics of a long-acting GLP-1 derivative (NN2211: (Arg(34)Lys(26)-(N- epsilon -(gamma-Glu(N-alpha-hexadecanoyl)))-GLP-1(7-37)), after acute and chronic treatment in hyperglycaemic minipigs. During hyperglycaemic glucose clamps, NN2211 (2 micrograms kg(-1) i.v.) treated pigs required more (P < 0.005) glucose than control animals (5.8 +/- 2.1 vs. 2.9 +/- 1.8 mg kg(-1) min(-1)). Insulin excursions were higher (P < 0.01) after NN2211 (15,367 +/- 5,438 vs. 9,014 +/- 2,952 pmol l(-1) min), and glucagon levels were suppressed (P < 0.05). Once-daily injections of NN2211 (3.3 micrograms kg(-1) s.c.) reduced the glucose excursion during an oral glucose tolerance test, to 59 +/- 15% of pre-treatment values by 4 weeks (P < 0.05), without measurable changes in insulin responses. Fructosamine concentrations were unaltered by vehicle, but decreased (from 366 +/- 187 to 302 +/- 114 micromol l(-1), P = 0.14) after 4 weeks of NN2211. Gastric emptying was reduced (P < 0.05) by NN2211. NN2211 acutely increases glucose utilization during a hyperglycaemic glucose clamp and chronic treatment results in better daily metabolic control. Therefore, NN2211, a GLP-1 derivative that can be administered once daily, holds promise as a new anti-diabetic drug with a minimal risk of hypoglycaemia.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin; Liraglutide; Male; Peptide Fragments; Protein Precursors; Swine, Miniature

Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet.. In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 micromol/g body weight) was administered in the drinking water for an 8 week period.. DPPIV inhibition reduced plasma DPPIV activity to 0.01+/-0.03 mU/ml vs 3.26+/-0.19 mU/ml in controls (P<0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P=0.029) and in mice fed a high-fat diet (P=0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P<0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7+/-2.6 x 10(3) microm(2) in controls to 7.6+/-1.0 x 10(3) microm(2) (P=0.0019).. Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Dipeptidyl Peptidase 4; Drinking; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Insulin; Insulin Resistance; Intubation, Gastrointestinal; Islets of Langerhans; Mice; Mice, Inbred C57BL; Nitriles; Organ Size; Peptide Fragments; Protease Inhibitors; Protein Precursors; Pyrrolidines; Time Factors

Diets enriched in monounsaturated fatty acids (MUFA)s have been shown to benefit glycemic control. Furthermore, MUFAs specifically stimulate secretion of the antidiabetic hormone, Glucagon-like peptide-1 (GLP-1) in vitro. To determine whether the MUFA-induced benefit in glycemic tolerance in vivo is due to increased GLP-1 release, lean Zucker rats were pair-fed a synthetic diet containing 5% fat derived from either olive oil (OO; 74% MUFA) or coconut oil (CO; 87% saturated fatty acids; SFA) for 2 weeks. Food intake and body weight gain were similar for both groups over the feeding period. The OO group had improved glycemic tolerance compared with the CO group in both oral and duodenal glucose tolerance tests [area under curve (AUC) 121 +/- 61 vs. 290 +/- 24 mM.120 min, P < 0.05; and 112 +/- 28 vs. 266 +/- 65 mM.120 min, P < 0.05, respectively]. This was accompanied by increased secretion of gut glucagon-like immunoreactivity (gGLI; an index of GLP-1 levels) in the OO rats compared with the CO rats (402 +/- 96 vs. 229 +/- 33 pg/ml at t = 10 min, P < 0.05). Tissue levels of GLP-1 and plasma insulin and glucagon levels were not different between the two groups. To determine the total contribution of GLP-1 to the enhanced glycemic tolerance in OO rats, the GLP-1 receptor antagonist exendin(9-39) (Ex(9-39)) was infused 3 min before a duodenal glucose tolerance test. Ex(9-39) abolished the benefit in glycemic tolerance conferred by OO feeding (OO+Ex(9-39) vs. CO+Ex(9-39), P = NS), and resulted in a deterioration of glycemic tolerance in the OO+Ex(9-39) group when compared with the OO controls (AUC 331 +/- 21 vs. 112 +/- 28 mM.120 min, P < 0.05). To probe the mechanism by which the OO diet enhanced GLP-1 secretion, a GLP-1-secreting L cell line was incubated for 24 h with either 100 microM oleic acid (MUFA) or 100 microM palmitic acid (SFA) and subsequently challenged with GIP, a known stimulator of the L cell. Preexposure to oleic acid but not to palmitic acid significantly increased GIP-induced GLP-1 secretion when compared with controls (55 +/- 12% vs. 34 +/- 9%, P < 0.01). These results demonstrate that the benefit in glycemic tolerance obtained with MUFA diets occurs in association with increased GLP-1 secretion, through a mechanism of enhanced L cell sensitivity. These results suggest that diet therapy with MUFAs may be useful for the treatment of patients with impaired glucose tolerance and/or type 2 diabetes through increased GLP-1 secretion.

Topics: Administration, Oral; Animals; Body Weight; Cell Line; Dietary Fats; Duodenum; Eating; Fatty Acids; Fatty Acids, Monounsaturated; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Male; Oleic Acid; Palmitic Acid; Peptide Fragments; Protein Precursors; Rats; Rats, Zucker

In subjects with impaired glucose tolerance (IGT) insulin secretion is impaired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ratio in the insulin secretory granule is ideally assessed by plasma measurements in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretion results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in 11 normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hyperglycemic clamp, 10 mmol/L), glucagon-like peptide-1 (GLP-1; primed-continuous infusion), and arginine given during the continued GLP-1 infusion. In IGT, insulin levels were significantly lower during the first phase (144 +/- 20 vs. 397 +/- 119 pmol/L; P = 0.02), at the end of the GLP infusion (2142 +/- 350 vs. 5430 +/- 1091 pmol/L; P: = 0.002), and in response to arginine (3983 +/- 375 vs. 8663 +/- 1430 pmol/L; P = 0.005). In response to glucose, the minimum PI/I ratio was significantly higher in IGT (3.4 +/- 0.6%) than in NGT (1.4 +/- 0.5%; P = 0.02), suggesting defective proinsulin processing in this condition. In subjects with IGT, the PI/I ratio decreased significantly after GLP-1 priming (1.7 +/- 0.2%; P = 0.02) and after arginine given during GLP-1 (1.4 +/- 0.2%; P = 0.007) and was not significantly different from those values in NGT (1.3 +/- 0.2% and 1.3 +/- 0.2%, respectively; both P = NS). In conclusion, during maximal stimulation of insulin secretion in subjects with IGT, the PI/I ratio in plasma decreased significantly and was not different from that in normal controls. This strongly argues against the hypothesis that defective processing of proinsulin to insulin represents a major component of the beta-cell dysfunction in IGT.

Topics: Adult; Arginine; Blood Glucose; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Middle Aged; Peptide Fragments; Proinsulin; Protein Precursors

To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investigated the secretion of the incretin hormones, glucagon-like peptide-1 and glucose- dependent insulinotropic polypeptide and measured nonesterified fatty acids, and plasma concentrations of insulin, C peptide, pancreatic polypeptide, and glucose during a 4-h mixed meal test in 54 heterogeneous type 2 diabetic patients, 33 matched control subjects with normal glucose tolerance, and 15 unmatched subjects with impaired glucose tolerance. The glucagon-like peptide-1 response in terms of area under the curve from 0-240 min after the start of the meal was significantly decreased in the patients (2482 +/- 145 compared with 3101 +/- 198 pmol/liter.240 min; P = 0.024). In addition, the area under the curve for glucose-dependent insulinotropic polypeptide was slightly decreased. In a multiple regression analysis, a model with diabetes, body mass index, male sex, insulin area under the curve (negative influence), glucose-dependent insulinotropic polypeptide area under the curve (negative influence), and glucagon area under the curve (positive influence) explained 42% of the variability of the glucagon-like peptide-1 response. The impaired glucose tolerance subjects were hyperinsulinemic and generally showed the same abnormalities as the diabetic patients, but to a lesser degree. We conclude that the meal-related glucagon-like peptide-1 response in type 2 diabetes is decreased, which may contribute to the decreased incretin effect in type 2 diabetes.

Topics: Analysis of Variance; Autoantibodies; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glutamate Decarboxylase; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Pancreatic Polypeptide; Peptide Fragments; Peptides; Protein Precursors; Reference Values

Our studies were undertaken to characterise the defective insulin secretion of impaired glucose tolerance (IGT).. We studied 13 normal glucose tolerant subjects (NGT) and 12 subjects with IGT carefully matched for age, sex, BMI and waist-to-hip ratio. A modified hyperglycaemic clamp (10 mmol/1) with a standard 2-h square-wave hyperglycaemia, an additional glucagon-like-peptide (GLP)-1 phase (1.5 pmol x kg(-1) x min(-1) over 80 min) and a final arginine bolus (5 g) was used to assess various phases of insulin secretion rate.. Insulin sensitivity during the second phase of the hyperglycaemic clamp was low in both groups but not significantly different (0.12 +/- 0.021 in NGT vs 0.11 +/- 0.013 micromol x kg(-1) x min(-1) x pmol(-1) in IGT, p = 0.61). First-phase insulin secretion was lower in IGT (1467 +/- 252 vs 3198 +/- 527 pmol x min(-1), p = 0.008) whereas the second phase was not (677 +/- 61 vs 878 +/- 117 pmol x min(-1), p = 0.15). The acute insulin secretory peak in response to GLP-1 was absent in IGT subjects who only produced a late phase of GLP-1-induced insulin secretion rate which was lower (2228 +/- 188 pmol x min(-l)) than in NGT subjects (3056 +/- 327 pmol x min(-1), p = 0.043). Insulin secretion in response to arginine was considerably although not significantly lower in IGT subjects. The relative impairment (per cent of the mean rate for NGT subjects) was greatest for the GLP-1 peak (19 +/- 9%).. In this Caucasian cohort a defective insulin secretion rate is essential for the development of IGT. The variable degrees of impairment of different phases of the insulin secretion rate indicate that several defects contribute to its abnormality in IGT. Defects in the incretin signalling pathway of the beta cell could contribute to the pathogenesis of beta-cell dysfunction of IGT and thus Type II (non-insulin-dependent) diabetes mellitus.

Topics: Adult; Arginine; Blood Glucose; C-Peptide; Fasting; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Glucose Intolerance; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Peptide Fragments; Reference Values

By applying a newly developed ELISA technique for determining biologically active intact glucagon-like peptide [GLP-1, GLP-1-(7-36)amide] in mouse, plasma baseline GLP-1 in normal NMRI mice was found to be normally distributed (4.5 +/- 0.3 pmol/l; n = 72). In anesthetized mice, gastric glucose (50 or 150 mg) increased plasma GLP-1 levels two- to threefold (P < 0.01). The simultaneous increase in plasma insulin correlated to the 10-min GLP-1 levels (r = 0.36, P < 0.001; n = 12). C57BL/6J mice deleted of the gastrin-releasing peptide (GRP) receptor by genetic targeting had impaired glucose tolerance (P = 0.030) and reduced early (10 min) insulin response (P = 0.044) to gastric glucose compared with wild-type controls. Also, the GLP-1 response to gastric glucose was significantly lower in the GRP receptor-deleted mice than in the controls (P = 0.045). In conclusion, this study has shown that 1) plasma levels of intact GLP-1 increase dose dependently on gastric glucose challenge in correlation with increased insulin levels in mice, and 2) intact GRP receptors are required for normal GLP-1 and insulin responses and glucose tolerance after gastric glucose in mice.

Topics: Animals; Blood Glucose; Enzyme-Linked Immunosorbent Assay; Female; Gastric Lavage; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Protein Precursors; Receptors, Bombesin

Glucose homeostasis in mammals is maintained by insulin secretion from the beta-cells of the islets of Langerhans. Type 2 diabetes results either from primary beta-cell failure alone and/or a failure to secrete enough insulin to overcome insulin resistance. Here, we show that continuous infusion of glucagon-like peptide-1 (7-36) (GLP-1; an insulinotropic agent), to young and old animals, had effects on the beta-cell of the pancreas other than simply on the insulin secretory apparatus. Our previous studies on a rodent model of glucose intolerance, the aging Wistar rat, show that a plateau in islet size, insulin content, and beta-cell mass is reached at 13 months, despite a continuing increase in body weight. Continuous sc infusion of GLP-1 (1.5 pM/kg x min), over 5 days, resulted in normal glucose tolerance. Our current results in both young and old rats demonstrate that treatment caused an up-regulation of pancreatic-duodenum homeobox-1 (PDX-1) expression in islets and total pancreas, induced pancreatic cell proliferation, and beta-cell neogenesis. The effects on levels of PDX-1 messenger RNA were abrogated by simultaneous infusion of Exendin (9-39), a specific antagonist of GLP-1. PDX-1 protein levels increased 4-fold in whole pancreata and 6-fold in islets in response to treatment. Beta-cell mass increased to 7.2 +/- 0.58 from 4.88 +/- 0.38 mg, treated vs. control, respectively, P < 0.02. Total pancreatic insulin content also increased from 0.55 +/- 0.02 to 1.32 +/- 0.11 microg/mg total pancreatic protein. Therefore, GLP-1 would seem to be a unique therapy that can stimulate pancreatic cell proliferation and beta-cell differentiation in the pancreas of rodents.

Topics: Aging; Animals; Blood Glucose; Cell Division; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Homeodomain Proteins; Insulin; Islets of Langerhans; Pancreas; Peptide Fragments; Protein Precursors; Rats; Rats, Wistar; Trans-Activators

Mice with a targeted mutation of the gastric inhibitory polypeptide (GIP) receptor gene (GIPR) were generated to determine the role of GIP as a mediator of signals from the gut to pancreatic beta cells. GIPR-/- mice have higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after meal ingestion are not increased by high-fat diet in GIPR+/+ mice because of compensatory higher insulin secretion, they are significantly increased in GIPR-/- mice because of the lack of such enhancement. Accordingly, early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load in vivo, and because GIP plays an important role in the compensatory enhancement of insulin secretion produced by a high insulin demand, a defect in this entero-insular axis may contribute to the pathogenesis of diabetes.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 2; Dietary Fats; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Injections, Intraperitoneal; Insulin; Insulin Resistance; Insulin Secretion; Intestines; Islets of Langerhans; Mice; Mice, Knockout; Models, Biological; Peptide Fragments; Protein Precursors; Receptors, Gastrointestinal Hormone

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establish if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and potent insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h glucose, 10.1 +/- 0.3 mmol/l) and another with seven subjects with diet-treated NIDDM (2-h glucose, 14.5 +/- 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory glucose infusion, a sensitive test of the ability of the beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg x kg(-1) x min(-1), amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or GLP-1 at 0.4 pmol x kg(-1) x min(-1) for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 +/- 0.4 vs. 6.4 +/- 0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 +/- 1.0 vs. 9.3 +/- 0.7 mmol/l in NIDDM subjects (P < 0.0002). Despite this significant reduction in plasma glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/min; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 +/- 122.16 vs. 642.8 +/- 128 pmol/min; P = 0.1). These results were compatible with enhanced insulin secretion in the presence of GLP-1. Spectral power was used as a measure of the ability of the beta-cell to secrete insulin in response to small changes in the plasma glucose concentration during the oscillatory infusion. Spectral power for ISR increased from 2.1 +/- 0.9 during saline infusion to 7.4 +/- 1.3 during GLP-1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM subjects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dosage GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.

Topics: Administration, Oral; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Peptide Fragments; Protein Precursors

Ageing is one of the major risk factors for glucose intolerance including impaired glucose tolerance and Type II (non-insulin-dependent) diabetes mellitus. Reduced insulin secretion has been described as part of normal ageing although there is no information on age-related changes in the secretion of the major insulinotropic hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (7-36 amide) (GLP-1). We assessed the entero-insular axis in 6 young premenopausal and 6 older postmenopausal women following treatment with oral carbohydrate. Insulin and glucose integrated responses were similar in the younger and older groups. Total integrated responses for GIP and GLP-1 were considerably greater in the older subjects. A positive correlation between age and total integrated responses for glucose (r = 0.65; p < 0.02) as well as GLP-1 (r = 0.85; p < 0.001) was seen. We hypothesise that an age-related impairment of insulin secretion to insulinotropic hormones, GIP and GLP-1, contributes to a reduction in glucose tolerance in this age group. The pronounced compensatory increase in postprandial secretion of GIP and GLP-1 provides further evidence not only for the negative feedback relation between incretin and insulin secretion but also for the importance of the entero-insular axis in the regulation of insulin secretion.

Topics: Acetaminophen; Adult; Aged; Aging; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Intolerance; Humans; Insulin; Insulin Secretion; Peptide Fragments; Postmenopause; Premenopause; Risk Factors

The gastrointestinal hormones, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are both released from the gut after oral glucose ingestion and stimulate insulin secretion. This study examined the release of these hormones in subjects with impaired glucose tolerance (IGT), which precedes the development of non-insulin-dependent diabetes.. Six postmenopausal women with IGT, aged 59 years, underwent a 75 g oral glucose tolerance test and plasma levels of GIP and GLP-1 were determined regularly during the following 2 h. The results were compared with those in seven age- and weight-matched women with normal glucose tolerance (NGT).. Basal plasma levels of GIP and GLP-1 were not different between the groups. In response to the oral glucose ingestion, plasma levels of both GIP and GLP-1 increased in both groups. The plasma GIP increase after glucose ingestion was, however, reduced in women with IGT. Thus, the GIP response as determined as the area under the curve for the 60 min after oral glucose was 34.8 +/- 3.2 pmol/l per min in women with IGT versus 56.4 +/- 7.8 pmol/l per min in those with NGT (P = 0.021). In contrast, the GLP-1 response to oral glucose was not different between the groups. By definition, the glucose response to oral glucose was markedly increased in women with IGT, and the insulin response during the second hour after glucose ingestion was exaggerated.. The GIP response to oral glucose is impaired in postmenopausal women with IGT, whereas the plasma GLP-1 response is not affected.

Topics: Administration, Oral; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Middle Aged; Peptides; Postmenopause; Reference Values

Glucagon-like peptide 1 (GLP1) is postulated to regulate blood glucose and satiety, but the biological importance of GLP1 as an incretin and neuropeptide remains controversal. The regulation of nutrient-induced insulin secretion is dependent on the secretion of incretins, gut-derived peptides that potentiate insulin secretion from the pancreatic islets. To ascertain the relative physiological importance of GLP1 as a regulator of feeding behavior and insulin secretion, we have generated mice with a targeted disruption of the GLP1 receptor gene (GLP1R). These GLP1R-/- mice are viable, develop normally but exhibit increased levels of blood glucose following oral glucose challenge in association with diminished levels of circulating insulin. It is surprising that they also exhibit abnormal levels of blood glucose following intraperitoneal glucose challenge. Intracerebroventricular administration of GLP1 inhibited feeding in wild-type mice but not in GLP1R-/- mice; however, no evidence for abnormal body weight or feeding behavior was observed in GLP1R-/- mice. These observations demonstrate that GLP1 plays a central role in the regulation of glycemia; however, disruption of GLP1/GLP1R signaling in the central nervous system is not associated with perturbation of feeding behavior or obesity in vivo.

Topics: Animals; Blood Glucose; Female; Gene Deletion; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Insulin; Male; Mice; Peptide Fragments; Protein Precursors; Rats; Receptors, Glucagon

We investigated the effect of amylin on the glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) induced stimulation of cAMP production in RINm5F cells. Amylin and the structurally related calcitonin gene-related peptide (CGRP) inhibited the stimulatory effect of GLP-1(7-36)amide on cAMP generation while substance P was without effect. Amylin had no effect on the forskolin-induced cAMP-generation. These findings suggest that amylin alters the biological action of the incretin hormone GLP-1(7-36)amide. This could at least partly contribute to an amylin-induced impaired glucose tolerance which has been previously observed.

Topics: Adenylyl Cyclases; Amyloid; Animals; Cell Line; Colforsin; Cyclic AMP; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Intolerance; Insulinoma; Islet Amyloid Polypeptide; Islets of Langerhans; Models, Biological; Peptide Fragments; Peptides; Rats; Substance P