Impaired Glucagon-like Peptide-1 Secretion Research Articles

Efficacy of treatment with glucagon-like peptide receptor agonists-1 in Asian patients with type 2 diabetes mellitus

The projected 68% increase in patients with type 2 diabetes mellitus (T2D) in the upcoming decades and the specific pathophysiological course of the disease are critical factors for the development of optimal disease management tactics in the Asian population. It is now known that β-cell dysfunction is dominant in the pathogenesis of T2D in Asians. In a number of Asian countries, incretin therapy is the leading therapy. To review literature on glucagon-like peptide-1 (GLP-1) secretion and clinical trial results of GLP-1 receptor agonist class (GLP-1RA) drugs as well as to evaluate their effectiveness in Asian population with T2D. A review of studies on pathophysiological aspects of GLP-1 secretion and evaluation of the efficacy of therapy with GLP-1RA preparations registered and used in clinical practice in Asian regions. Several studies in Asian countries have shown that intact GLP-1 levels were significantly lower in both T2D patients and healthy Japanese volunteers; as well as in patients with impaired glucose tolerance. It is suggested that either impaired secretion of GLP-1 in the gut, accelerated processing by dipeptidyl peptidase-4, or a combination of both are responsible for the decrease in GLP-1. The greater efficacy of GLP-1RA treatment in achieving glycemic control in Asian T2D patients was presented by Kim Y.G. et al. in a meta-analysis of 15 randomised controlled trials, the reduction in HbA1c on GLP-1RA treatment averaged -1.16% in Asian-dominated studies and -0.83% in non-Asian-dominated studies. In the PIONEER 9 clinical programme, similar results were obtained, with oral semaglutide having a more pronounced effect on glycaemic control in Japanese patients. Thus, the mean change in HbA 1c was -1.1%, 7 mg -1.5%, and 14 mg -1.7% at the 3 mg dose; whereas in the PIONEER 1 study in the global population, the mean change in HbA1c was -0.6%, -0.9% and -1.1% for 3, 7, 14 mg semaglutide, respectively. The PIONEER 10 study concluded that oral semaglutide was well tolerated by Japanese patients with T2D. Oral semaglutide reduced HbA1c (14 mg dose) and body weight (7 and 14 mg doses) more significantly compared to dulaglutide at 0.75 mg dose. Results of a pooled analysis of long-acting GLP-1RA showed a more significant reduction in cardiovascular event risk in the Asian subpopulation. The presented review describes benefits in glycemic control as well as in the reduction of relative cardiovascular event risks with GLP-1RA treatment in the Asian population, which requires further in-depth research and implies optimal management tactics in patients with T2DM.

Essential Role of Syntaxin-Binding Protein-1 in the Regulation of Glucagon-Like Peptide-1 Secretion.

Circadian secretion of the incretin, glucagon-like peptide-1 (GLP-1), correlates with expression of the core clock gene, Bmal1, in the intestinal L-cell. Several SNARE proteins known to be circadian in pancreatic α- and β-cells are also necessary for GLP-1 secretion. However, the role of the accessory SNARE, Syntaxin binding protein-1 (Stxbp1; also known as Munc18-1) in the L-cell is unknown. The aim of this study was to determine whether Stxbp1 is under circadian regulation in the L-cell and its role in the control of GLP-1 secretion. Stxbp1 was highly-enriched in L-cells, and STXBP1 was expressed in a subpopulation of L-cells in mouse and human intestinal sections. Stxbp1 transcripts and protein displayed circadian patterns in mGLUTag L-cells line, while chromatin-immunoprecipitation revealed increased interaction between BMAL1 and Stxbp1 at the peak time-point of the circadian pattern. STXBP1 recruitment to the cytosol and plasma membrane within 30 minutes of L-cell stimulation was also observed at this time-point. Loss of Stxbp1 in vitro and in vivo led to reduced stimulated GLP-1 secretion at the peak time-point of circadian release, and impaired GLP-1 secretion ex vivo. In conclusion, Stxbp1 is a circadian regulated exocytotic protein in the intestinal L-cell that is an essential regulatory component of GLP-1 secretion.

Impaired secretion of active GLP-1 in patients with hypertriglyceridaemia: A novel lipotoxicity paradigm?

Lipotoxicity plays an important role in the pathogenesis of β-cell dysfunction. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that exerts beneficial effects on the number and function of islet β cells. However, the effect of lipotoxicity on GLP-1 secretion is still unknown. Twenty-five patients who were newly diagnosed with diabetes were recruited from 400 subjects based on 75-g Oral Glucose Tolerance Test. Patients were divided into diabetes (DM) and DM combined with hypertriglyceridaemia (DM+HTG) groups according to their serum triglyceride (TG) levels. Seventy-one normal controls and 17 patients with isolated hypertriglyceridaemia were matched by age and gender. Total and active fasting GLP-1 and 2-hour GLP-1 levels were not significantly altered among the 4 groups. However, total and active ΔGLP-1 levels (the difference between 2-hour GLP-1 and fasting GLP-1 levels) were significantly reduced in the isolated HTG, DM, and DM+HTG groups, particularly the DM+HTG group. The ratio of serum active GLP-1 (AGLP-1) to total GLP-1 (TGLP-1) levels was also decreased in patients with isolated HTG, suggesting that active GLP-1 secretion may be more seriously impaired. Both ΔTGLP-1 and ΔAGLP-1 levels were negatively correlated with serum TG levels, body mass index and fasting plasma glucose (FPG) levels and positively correlated with HDL-C levels. According to the multivariate linear regression analysis, only TG and FPG levels were independently associated with ΔTGLP-1 and ΔAGLP-1 levels. Impaired GLP-1 secretion was associated with hypertriglyceridaemia and diabetes, and a more obvious association was noted in hypertriglyceridaemic patients with diabetes.

Accumulation of intestinal tissue 3-deoxyglucosone attenuated GLP-1 secretion and its insulinotropic effect in rats.

BackgroundOur recent findings support the idea that 3-deoxyglucosone (3DG), a dietary composition, has been suggested as an independent factor for the development of prediabetes. Secretion of glucagon-like peptide-1 (GLP-1) has been suggested to be impaired in T2DM and in conditions associated with hyperglycemia. Since low oral bioavailability of 3DG has been indicated in a single administration study, in the present study we examined if 3DG is capable of accumulating in intestinal tissue of rats after 2-week administration of 3DG, and the 3DG treatment affects GLP-1 secretion and glucose tolerance.MethodsRats were administered by gastric gavage for 2 weeks. We measured 3DG contents of intestinal tissues (by HPLC), plasma levels of total GLP-1 (by ELISA), insulin and glucagon (both by radioimmunoassay) and blood glucose concentrations. The expressions of the sweet receptor subunits (TAS1R2, TAS1R3) and its downstream molecule TRPM5 in duodenum and colon tissues of rats were quantified by WB. We examined GLP-1 secretion in enteroendocrine STC-1 cells exposured to 3DG.Results3DG treatment for 2 weeks increased 3DG content of intestinal tissues, fasting blood glucose concentration, and reduced plasma concentrations of GLP-1 and insulin at fasting and 15 and 180 min after the glucose load and oral glucose tolerance in conjunction with increased plasma glucagon concentrations. The expressions of TAS1R2, TAS1R3 and TRPM5 were shown to be reduced whereas 3DG treatment did not affect plasma dipeptidyl peptidase-4 activity, indicating an impaired GLP-1 secretion in 3DG-treated rats. This idea was further supported by the fact that exposure to 3DG directly decrease GLP-1 secretion in STC-1.ConclusionIt is the first demonstration that 3DG was capable of accumulating in intestinal tissue and thereby decreased secretion of GLP-1 and insulin in a similar manner. 3DG-treated rats developed impaired glucose regulation (IGR) with obviously pancreatic islet cell dysfunction. It is further concluded that a decrease in the biological function of GLP-1 resulting from the decreased GLP-1 secretion is the most likely mechanism for the impaired insulin secretion, which ultimately promoted the development of IGR. These results will also contribute to a better understanding of the significance for restoring physiological GLP-1 secretion.Electronic supplementary materialThe online version of this article (doi:10.1186/s13098-016-0194-9) contains supplementary material, which is available to authorized users.

Chronic Exposure to TNFα Impairs Secretion of Glucagon-Like Peptide-1.

Obesity is associated with systemic inflammation and elevated levels of TNFα, leading to impaired glucose tolerance. In humans, obesity is also associated with reduced nutrient-stimulated secretion of the intestinal incretin hormone, glucagon-like peptide-1 (GLP-1). We hypothesized that TNFα plays a direct role in the impairment of GLP-1 secretion from the enteroendocrine L-cell and that blocking TNFα can restore both GLP-1 secretion and glucose homeostasis. Expression of the TNFα receptor subytpe-1 was detected in the human NCI-H716 and murine GLUTag L-cell models and in mouse ileal sections. Although TNFα acutely increased GLP-1 release from NCI-H716 cells (P < .05-.001), preincubation with TNFα for 24 hours reduced proglucagon mRNA (P < .05) and GLP-1 cellular (P < .05) levels without affecting cell viability. Furthermore, both NCI-H716 and GLUTag cells pretreated with TNFα for 24 hours no longer responded to known GLP-1 secretagogues, an effect that was reversed by coincubation with the Nuclear Factor Kappa B inhibitor, 5-aminosalicylic acid, in the NCI-H716 cells. Mice given a high-fat diet (HFD) for 12 weeks developed impaired glucose tolerance, hyperinsulinemia, and increased TNFα mRNA expression in fat and ileal tissue. Hyperglycemia and hyperinsulinemia were reduced in HFD mice treated with the anti-TNFα biological, etanercept, for 2 weeks. In primary intestinal cultures from these animals, HFD control mice had impaired GLP-1 secretion, and this was not observed in the HFD etanercept-derived cultures (P < .05). In conclusion, chronic exposure to TNFα directly impairs GLP-1 secretion at the level of the intestinal L-cell, an effect that is reversed by anti-TNFα therapy in association with improved glucose tolerance.

Multiple Factors Related to the Secretion of Glucagon-Like Peptide-1.

The glucagon-like peptide-1 is secreted by intestinal L cells in response to nutrient ingestion. It regulates the secretion and sensitivity of insulin while suppressing glucagon secretion and decreasing postprandial glucose levels. It also improves beta-cell proliferation and prevents beta-cell apoptosis induced by cytotoxic agents. Additionally, glucagon-like peptide-1 delays gastric emptying and suppresses appetite. The impaired secretion of glucagon-like peptide-1 has negative influence on diabetes, hyperlipidemia, and insulin resistance related diseases. Thus, glucagon-like peptide-1-based therapies (glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) are now well accepted in the management of type 2 diabetes. The levels of glucagon-like peptide-1 are influenced by multiple factors including a variety of nutrients. The component of a meal acts as potent stimulants of glucagon-like peptide-1 secretion. The levels of its secretion change with the intake of different nutrients. Some drugs also have influence on GLP-1 secretion. Bariatric surgery may improve metabolism through the action on GLP-1 levels. In recent years, there has been a great interest in developing effective methods to regulate glucagon-like peptide-1 secretion. This review summarizes the literature on glucagon-like peptide-1 and related factors affecting its levels.

Is Endogenous GLP-1 the Only Important Enhancer of Glucose-Induced Insulin Secretion in Type 2 Diabetes?

It has been known for over a century that the small intestinal mucosa contains a substance(s) which decreases glucosuria in diabetic patients (1), with the term “incretin” (i.e., the assumption that intestinally derived substances are involved in regulation of postprandial insulin secretion) being first coined by La Barre (2) in 1932. Proof of the incretin concept came with the observation that orally administered glucose gave rise to a much larger insulin response than when the same amount of glucose was given intravenously (3,4). Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the major incretin hormones in humans (5,6). Together, they account for up to 70% of postprandial insulin secretion in healthy subjects (7). In individuals with type 2 diabetes, however, the incretin effect is severely impaired (8). It is now widely accepted that this is largely the result of reductions in the insulinotropic activity of both incretin hormones (9,10), although in some patients an impaired secretion of GLP-1 may also contribute (11). A classic method for establishing the role of a given peptide is to infuse it in such a way as to mimic normal physiological plasma concentrations. By giving GLP-1 and GIP by variable infusion rate to copy their normal postprandial plasma profiles, Vilsboll et al. (12) demonstrated that both incretin hormones contribute almost equally to the incretin effect in healthy subjects. However, …

Impaired Secretion of Total Glucagon-like Peptide-1 in People with Impaired Fasting Glucose Combined Impaired Glucose Tolerance

Objective: We assessed the serum glucagon-like peptide-1 (GLP-1) levels for Chinese adults with pre-diabetes (PD) and newly-diagnosed diabetes mellitus (NDDM) during oral glucose tolerance test (OGTT). The relationships between total GLP-1 level and islet β cell function, insulin resistance (IR) and insulin sensitivity (IS) were also investigated.Methods: A 75g glucose OGTT was given to 531 subjects. Based on the results, they were divided into groups of normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), IFG combined IGT (IFG+IGT) and NDDM. Total GLP-1 levels were measured at 0- and 2-hour during OGTT. Homeostasis model assessment of β cell function (HOMA-β), HOMA of insulin resistance (HOMA-IR), Gutt and Matsuda indexes were calculated. The relationships between GLP-1 level and β cell function, IR and IS were analyzed.Results: The levels of total fasting GLP-1 (FGLP-1), 2h GLP-1 (2hGLP-1) and 2hGLP-1 increments (∆GLP-1) following OGTT reduced significantly in IFG+IGT and NDDM groups (P<0.005). HOMA-β , HOMA-IR, Gutt and Matsuda indexes demonstrated various patterns among NGT, isolated IFG, isolated IGT, IFG+IGT and NDDM groups (P<0.05). Spearman rank correlation analysis and multivariable linear regression model suggested that some levels of correlation between GLP-1 levels, ∆GLP-1 and β cell function, IR (P<0.05).Conclusions: The total GLP-1 levels and its response to glucose load decreased significantly in IFG+IGT group, compared to isolated IFG or IGT group. They were even similar to that of NDDM group. Moreover, there were observable correlations between impaired GLP-1 secretion and β cell function, IR and IS.

Gastric Emptying, Incretin Hormone Secretion, and Postprandial Glycemia in Cystic Fibrosis—Effects of Pancreatic Enzyme Supplementation

Postprandial hyperglycemia is an important clinical problem in cystic fibrosis (CF), but the contribution of fat malabsorption, rapid gastric emptying, and the incretin axis has not been widely considered. The aim of this study was to evaluate these aspects of gut function in nondiabetic CF patients. We conducted a randomized, double-blind, placebo-controlled crossover study at a clinical research laboratory. Five nondiabetic CF patients (three males; age, 25.8 ± 1.0 yr; body mass index, 20.2 ± 1.1 kg/m(2)) with exocrine pancreatic insufficiency and six healthy subjects of similar age and body mass index participated in the study. CF patients consumed a radiolabeled mashed potato meal on 2 separate days, together with four capsules of Creon Forte (100,000 IU lipase) or placebo. Healthy subjects consumed the meal once, without pancreatic enzymes. Gastric emptying was measured using scintigraphy, and blood was sampled frequently for blood glucose and plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon concentrations. CF patients had more rapid gastric emptying (P < 0.001), impaired secretion of GLP-1 (P < 0.01) and GIP (P < 0.001), and greater postprandial glycemic excursions (P < 0.001) than healthy subjects. Pancreatic enzyme supplementation normalized gastric emptying and GLP-1 secretion and tended to increase glucagon (P = 0.08), but did not completely restore GIP secretion or normalize postprandial blood glucose. There was an excellent correlation between gastric emptying and blood glucose concentration at 60 min (R = 0.75; P = 0.01). Pancreatic enzyme supplementation plays an important role in incretin secretion, gastric emptying, and postprandial hyperglycemia in CF.

Insulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell

Insulin resistance and type 2 diabetes mellitus are associated with impaired postprandial secretion of glucagon-like peptide-1 (GLP-1), a potent insulinotropic hormone. The direct effects of insulin and insulin resistance on the L cell are unknown. We therefore hypothesized that the L cell is responsive to insulin and that insulin resistance impairs GLP-1 secretion. The effects of insulin and insulin resistance were examined in well-characterized L cell models: murine GLUTag, human NCI-H716, and fetal rat intestinal cells. MKR mice, a model of chronic hyperinsulinemia, were used to assess the function of the L cell in vivo. In all cells, insulin activated the phosphatidylinositol 3 kinase-Akt and MAPK kinase (MEK)-ERK1/2 pathways and stimulated GLP-1 secretion by up to 275 +/- 58%. Insulin resistance was induced by 24 h pretreatment with 10(-7) m insulin, causing a marked reduction in activation of Akt and ERK1/2. Furthermore, both insulin-induced GLP-1 release and secretion in response to glucose-dependent insulinotropic peptide and phorbol-12-myristate-13-acetate were significantly attenuated. Whereas inhibition of phosphatidylinositol 3 kinase with LY294002 potentiated insulin-induced GLP-1 release, secretion was abrogated by inhibiting the MEK-ERK1/2 pathway with PD98059 or by overexpression of a kinase-dead MEK1-ERK2 fusion protein. Compared with controls, MKR mice were insulin resistant and displayed significantly higher fasting plasma insulin levels. Furthermore, they had significantly higher basal GLP-1 levels but displayed impaired GLP-1 secretion after an oral glucose challenge. These findings indicate that the intestinal L cell is responsive to insulin and that insulin resistance in vitro and in vivo is associated with impaired GLP-1 secretion.

Normal secretion of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 during gestational diabetes mellitus

Background and aim. Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM2) are suggested to be caused by the same metabolic disorder. Defects in gut hormone-dependent regulation of β-cell function (entero-insular axis) have been proposed to contribute to the pathogenesis of DM2. The aim of study was to evaluate whether an impaired secretion of glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) could play a role in the development of carbohydrate disorders during pregnancy.Subjects and methods. The study group (GDM) consisted of 13 gestational women with diabetes mellitus in whom GDM was diagnosed according to the World Health Organization criteria (75-g oral glucose tolerance test (OGTT)). The control group consisted of 13 pregnant women with normal glucose tolerance (NGT), matched according to age and duration of pregnancy. For all patients, plasma glucose, insulin, GLP-1 and GIP concentrations were evaluated after an OGTT, i.e. at 0, 30, 60, 90 and 120 min after glucose load.Results. Fasting plasma glucose concentrations were similar in both groups, but the 0–120 min area under the curve (AUC) for glucose was significantly greater in the GDM group than in the NGT group (p < 0.0005). Fasting insulin concentration was higher (p < 0.05) and the 2-h insulin response (AUCtotal) was significantly greater (p = 0.01) in the GDM group than in the NGT group. Insulin resistance was significantly higher in GDM compared with control women (homeostasis model assessment, p = 0.003). Fasting GLP-1 concentrations were higher in the GDM group (p = 0.05), but no differences were observed in GLP-1 response (AUC) between the studied groups. Fasting and stimulated GIP response did not differ between groups at any time of the study (p > 0.05). Positive correlations were observed between fasting GLP-1 and insulin concentration (r = 0.56, p < 0.004) and between fasting GLP-1 and insulin resistance (r = 0.43, p < 0.029).Conclusion. An impaired secretion of GLP-1 and GIP does not seem to play a major role in the pathogenesis of GDM.

Incretins, insulin secretion and Type 2 diabetes mellitus

When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown to be able to near-normalize both fasting and postprandial glycaemic concentrations in the patients, perhaps because the treatment compensates for both the impaired secretion of GLP-1 and the impaired action of GIP. Several GLP-1 analogues are currently in clinical development and the reported results are, so far, encouraging.

Gastric inhibitory polypeptide analogues: do they have a therapeutic role in diabetes mellitus similar to that of glucagon-like Peptide-1?

Gastric inhibitory polypeptide (GIP, also called glucose-dependent insulinotropic polypeptide) and glucagon-like peptide-1 (GLP-1) are peptide hormones from the gut that enhance nutrient-stimulated insulin secretion (the 'incretin' effect). Judging from experiments in mice with targeted deletions of GIP and GLP-1 receptors, the incretin effect is essential for normal glucose tolerance. In patients with type 2 diabetes mellitus it turns out that the incretin effect is severely impaired or abolished. The explanation seems to be that both the secretion of GLP-1 and the effect of GIP are impaired (whereas both the secretion of GIP and the effect of GLP-1 are near normal). The impaired GLP-1 secretion is probably a consequence of diabetic metabolic disturbances. The known genetic variations in the GIP receptor sequence are not associated with type 2 diabetes mellitus, but a defective insulinotropic effect of GIP may be found in first degree relatives of the patients, suggesting a genetic background for the defect. The molecular nature of the defect is not known and given the close similarity of the two receptors and their signalling, the dissociation of their effects is remarkable. Whereas GLP-1 and its analogues are attractive as therapeutic agents for type 2 diabetes mellitus, analogues of GIP are unlikely to be effective. On the other hand, GIP seems to play an important role in lipid metabolism, promoting the disposal of ingested lipids, and mice with a targeted deletion of the GIP receptor do not become obese when exposed to a high-fat diet. Therefore, antagonistic analogues of GIP may be speculated to have a role in the pharmaceutical management of obesity.

Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients

Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients

Incretin hormones - an update

Incretin hormones are insulinotropic hormones from the intestinal mucosa, which after being released in response to ingestion of a meal, enhance insulin secretion in excess of that elicited by the absorbed nutrients (glucose, amino acids etc) themselves. To day it is well established that the most important incretin hormones are glucose-dependent insulinotropic polypeptide (GIP, previously known as gastric inhibitory polypeptide) and glucagon-like peptide-1 (GLP-1) from the upper and lower small intestinal mucosa, respectively. It has been shown that interference with the incretin function causes glucose intolerance and it has also been shown that the incretin function is greatly impaired in type 2 diabetes mellitus. The reason for this seems to be twofold: an impaired secretion of GLP-1 and a severely impaired insulinotropic effect of GIP in these patients. In agreement with this, administration of the active incretin, GLP-1, to patients with type 2 diabetes may nearly normalise their fasting and postprandial hyperglycaemia. In addition to its insulinotropic effects, GLP-1 has been shown to stimulate the formation of new beta cells in rodents, partly by enhanced beta cell proliferation and partly by enhancing differentiation of duct progenitor cells to mature beta cells. GLP-1 also inhibits glucagon secretion, inhibits gastric emptying and reduces appetite and food intake. During the last years, therefore, several most promising attempts have been made to develop GLP-1 into a clinically useful therapeutic agent for the treatment of type 2 diabetes.