Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual ?-cell function.
ABSTRACT: To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual ?-cell function.Eight type 1 diabetic patients with (T1D+), eight without (T1D-) residual ?-cell function, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured.Incretin responses did not differ between patients and control subjects. Infusion of GLP-1 decreased peak PG by 45% in both groups of type 1 diabetic patients. In T1D+ patients, postprandial PG decreased below fasting levels and was indistinguishable from control subjects infused with saline. In T1D- patients, postprandial PG remained at fasting levels. GLP-1 infusion reduced GE and glucagon levels in all groups and increased fasting C-peptide in T1D+ patients and control subjects. Blocking endogenous GLP-1 receptor action increased endogenous GLP-1 secretion in all groups and increased postprandial glucose, glucagon, and GE in T1D+ and T1D- patients. The insulinogenic index (the ratio of insulin to glucose) decreased in T1D+ patients during blockade of endogenous GLP-1 receptor action.Type 1 diabetic patients have normal incretin responses to meals. In type 1 diabetic patients, exogenous GLP-1 decreases peak postprandial glucose by 45% regardless of residual ?-cell function. Endogenous GLP-1 regulates postprandial glucose excursions by modulating glucagon levels, GE, and ?-cell responsiveness to glucose. Long-term effects of GLP-1 in type 1 diabetic patients should be investigated in future clinical trials.
Project description:INTRODUCTION:To investigate canagliflozin-induced changes in postprandial total glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels in patients with type 2 diabetes mellitus (T2DM). METHODS:Forty-five patients with T2DM who had inadequate glycemic control (glycated hemoglobin ≥ 6.5%) with diet and exercise alone (n = 15, drug naïve) and in combination with either a stable dose of the α-glucosidase inhibitor acarbose (n = 15) or metformin (n = 15) received canagliflozin, a sodium-glucose cotransporter 2 inhibitor, at 100 mg once daily for 12 weeks. The primary endpoint was the change from baseline to week 12 in postprandial glucose and plasma levels of total GLP-1 and GIP during a meal tolerance test (MTT). RESULTS:Canagliflozin significantly reduced postprandial blood glucose (mean difference - 40.2 mg/mL at 60 min) and increased postprandial total GLP-1 (mean difference 1.8 pg/mL at 60 min) during an MTT. A transient reduction in the postprandial GIP level at only 30 min (mean difference - 80.3 pg/mL) during an MTT was observed. No changes in postprandial GLP-1 or GIP levels were seen after canagliflozin treatment as an add-on to acarbose in patients with T2DM. Acarbose treatment significantly decreased postprandial total GIP levels (P < 0.05) and tended to increase postprandial total GLP-1 levels (P = 0.07) compared to the other two treatments prior to canagliflozin. CONCLUSION:Canagliflozin 100 mg increased postprandial total GLP-1 levels in the absence of acarbose, suggesting that it may upregulate GLP-1 secretion through delayed glucose absorption in the upper intestine, as with the α-glucosidase inhibitor. TRIAL REGISTRATION:University Hospital Medical Information Network, UMIN000018345. FUNDING:Mitsubishi Tanabe Pharma Corporation.
Project description:In type 1 diabetes (T1D), delayed gastric emptying (GE) may predispose to a mismatch between insulin delivery and glucose absorption. Previous studies evaluated, only partly, the relationship between delayed GE and postprandial, but not diurnal, glycemia.To assess the relationship between GE disturbances and glycemic control in T1D and the effects of accelerating GE on glycemic control.This was a randomized placebo-controlled trial in 30 patients with T1D on an insulin pump at an academic medical center.GE was evaluated with a [13C]-Spirulina breath test at baseline (GEbaseline), during intravenous saline or erythromycin (2 or 3 mg/kg; GEiv), and after 7 days of oral erythromycin or placebo (GEoral). Weighed meals were provided throughout the study.These were GE and continuous glucose monitoring (CGM).The baseline glycosylated hemoglobin was 7.6% ± 0.8% (60 ± 8.7 mmol/mol); 12 patients (40%) had delayed GE; faster GE was associated with a greater postprandial CGM-based glucose, but slower GE was not associated with postprandial hypoglycemia (<70 mg/dL). Intravenous (3 mg/kg) but not oral erythromycin accelerated GE. The relationship between GE and glycemia differed between the postprandial periods and the entire day. After adjusting for carbohydrate intake and insulin consumption, faster GE was associated with more hyperglycemia during the postprandial period but lower glucose values across the entire study.In T1D, pharmacologically mediated acceleration of GE increases postprandial CGM-based glucose. In contrast, delayed GE is associated with greater CGM-based glucose values over the entire day.
Project description:<h4>Background</h4>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).<h4>Methods</h4>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).<h4>Key results</h4>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<sub>half</sub> , glucose tolerance and plasma GLP1 levels were not significant.<h4>Conclusions & inferences</h4>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.
Project description:Context:Postprandial hyperglycemia remains a challenge in type 1 diabetes (T1D) due, in part, to dysregulated increases in plasma glucagon levels after meals. Objective:This study was undertaken to examine whether 3 to 4 weeks of therapy with pramlintide or liraglutide might help to blunt postprandial hyperglycemia in T1D by suppressing plasma glucagon responses to mixed-meal feedings. Design:Two parallel studies were conducted in which participants underwent mixed-meal tolerance tests (MMTTs) without premeal bolus insulin administration before and after 3 to 4 weeks of treatment with either pramlintide (8 participants aged 20 ± 3 years, hemoglobin A1c 6.9 ± 0.5%) or liraglutide (10 participants aged 22 ± 3 years, hemoglobin A1c 7.6 ± 0.9%). Results:Compared with pretreatment responses to the MMTT, treatment with pramlintide reduced the peak increment in glucagon from 32 ± 16 to 23 ± 12 pg/mL (P < 0.02). In addition, the incremental area under the plasma glucagon curve from 0 to 120 minutes dropped from 1988 ± 590 to 737 ± 577 pg/mL/min (P < 0.001), which was accompanied by a similar reduction in the meal-stimulated increase in the plasma glucose curve from 11,963 ± 1424 mg/dL/min pretreatment vs 2493 ± 1854 mg/dL/min after treatment (P < 0.01). In contrast, treatment with liraglutide had no effect on plasma glucagon and glucose responses during the MMTT. Conclusions:Adjunctive treatment with pramlintide may provide an effective means to blunt postmeal hyperglycemia in T1D by suppressing dysregulated plasma glucagon responses. In contrast, plasma glucose and glucagon responses were unchanged after 3 to 4 weeks of treatment with liraglutide.
Project description:Sodium-glucose cotransporter 2 inhibitors (SGLT2i) effectively lower plasma glucose (PG) concentration in patients with type 2 diabetes, but studies have suggested that circulating glucagon concentrations and endogenous glucose production (EGP) are increased by SGLT2i, possibly compromising their glucose-lowering ability. To tease out whether and how glucagon may influence the glucose-lowering effect of SGLT2 inhibition, we subjected 12 patients with type 2 diabetes to a randomized, placebo-controlled, double-blinded, crossover, double-dummy study comprising, on 4 separate days, a liquid mixed-meal test preceded by single-dose administration of either <i>1</i>) placebo, <i>2</i>) the SGLT2i empagliflozin (25 mg), <i>3</i>) the glucagon receptor antagonist LY2409021 (300 mg), or <i>4</i>) the combination empagliflozin + LY2409021. Empagliflozin and LY2409021 individually lowered fasting PG compared with placebo, and the combination further decreased fasting PG. Previous findings of increased glucagon concentrations and EGP during acute administration of SGLT2i were not replicated in this study. Empagliflozin reduced postprandial PG through increased urinary glucose excretion. LY2409021 reduced EGP significantly but gave rise to a paradoxical increase in postprandial PG excursion, which was annulled by empagliflozin during their combination (empagliflozin + LY2409021). In conclusion, our findings do not support that an SGLT2i-induced glucagonotropic effect is of importance for the glucose-lowering property of SGLT2 inhibition.
Project description:Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng x kg(-1) x min(-1)) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse alpha-cells. In alphaTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion. CONCLUSIONS; GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes.
Project description:<h4>Background & aims</h4>The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic ?-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.<h4>Methods</h4>N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH) patients) and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.<h4>Results</h4>Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.<h4>Conclusions</h4>Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.
Project description:Many patients with type 2 diabetes mellitus do not achieve target glycosylated hemoglobin A1c levels despite optimally titrated basal insulin and satisfactory fasting plasma glucose levels. Current evidence suggests that HbA1c levels are dictated by both basal glucose and postprandial glucose levels. This has led to a consensus that postprandial glucose excursions contribute to poor glycemic control in these patients. Lixisenatide is a once-daily, prandial glucagon-like peptide 1 (GLP-1) receptor agonist with a four-fold affinity for the GLP-1 receptor compared with native GLP-1. Importantly, lixisenatide causes a significant delay in gastric emptying time, an important determinant of the once-daily dosing regimen. An exendin-4 mimetic with six lysine residues removed at the C-terminal, lixisenatide has pronounced postprandial glucose-lowering effects, making it a novel incretin agent for use in combination with optimally titrated basal insulin. Lixisenatide exerts profound effects on postprandial glucose through established mechanisms of glucose-dependent insulin secretion and glucagon suppression in combination with delayed gastric emptying. This review discusses the likely place that lixisenatide will occupy in clinical practice, given its profound effects on postprandial glucose and potential to reduce glycemic variability.
Project description:BACKGROUND:Enthusiasm for the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as an adjunctive treatment in type 1 diabetes (T1D) has been offset by the possible increased risk of diabetic ketoacidosis (DKA). Since pump-treated T1D patients are susceptible to DKA due to infusion site problems, this study was undertaken to assess how treatment with SGLT2i affects patterns of early metabolic decompensation following suspension of basal insulin. METHODS:Ten T1D participants (age 19-35 years, duration 10?±?8 years, A1c 7.4%?±?0.8%) underwent overnight pump suspension studies before and after treatment with canagliflozin (CANA). On both nights, basal insulin was suspended at 3 AM and plasma glucose (PG), ?-hydroxybutyrate (BHB), free fatty acids (FFA), plasma insulin (PI), and glucagon were measured. Studies were terminated 6?h after suspension or if PG rose to >350?mg/dL or BHB >2.5?mmol/L. RESULTS:PI levels at the start of suspension were reduced by 30% after CANA treatment (44?±?11?uU/mL vs. 31?±?10?uU/mL, P?<?0.01), but baseline PG, BHB, FFA, and glucagon levels were not significantly different. During the suspension, PG rose from 104?±?10 to 301?±?21?mg/dL before treatment, but only from 109?±?8 to 195?±?14?mg/dL after treatment (P?=?0.002 vs. pretreatment values). On the other hand, CANA treatment did not significantly affect the magnitude of increases in FFA, BHB, and glucagon levels during the suspension study. CONCLUSION:These data indicate that SGLT2i do not accelerate the rate of ketogenesis following the interruption of basal insulin infusion in T1D. Rather, the failure of patients to promptly recognize early metabolic decompensation relates to the much more gradual rise in PG levels.
Project description:Background:Interleukin-6 (IL-6) is released from skeletal muscle during exercise and systemic IL-6 levels therefore increase acutely in response to a single bout of exercise. We recently showed that an acute increase in IL-6 delayed gastric emptying rate and improved postprandial glycemia. Here we investigate whether repeated increases in IL-6, induced by exercise training, influence gastric emptying rate and moreover if IL-6 is required for exercise-induced adaptations in glycemic control including secretion of glucagon and glucagon-like peptide-1 (GLP-1). Methods:A total of 52 abdominally obese non-diabetic men and women were randomly assigned into four groups performing 12 weeks of endurance exercise or no exercise with or without IL-6 receptor blockade (tocilizumab). The primary endpoint was change in gastric emptying rate in response to the intervention and other endpoints included changes in glycemic control, glucagon, and GLP-1 secretion. Results:There was no change in gastric emptying rate in any of the four groups following the intervention and comparing differences in change between groups also revealed no difference. Postprandial glucose remained unchanged in all groups but the exercise + tocilizumab group, which improved postprandial glucose in response to the intervention. The area under the curve for meal-stimulated glucagon, active and total GLP-1 increased in response to IL-6 receptor blockade, this effect was independent of exercise. Conclusion:Exercise training and long-term IL-6 receptor blockade did not change gastric emptying rates in obese humans. IL-6 receptor blockade increased glucagon and GLP-1 secretion and implicate IL-6 in the regulation of the human alpha and L cells.