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Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects.

ABSTRACT: Lixisenatide is a once-daily, prandial, short-acting glucagon-like peptide-1 receptor agonist. Its main antidiabetic effect is to delay gastric emptying to control postprandial plasma glucose excursions. The dose-response relationship of the integrated insulinotropic and gastrostatic response to lixisenatide in healthy volunteers after a standardized liquid meal was investigated.Twenty healthy subjects received acetaminophen 1000 mg with a standardized liquid meal 60 min after a single subcutaneous injection of placebo or lixisenatide 2.5, 5, 10 or 20 µg in randomized order separated by a 2- to 7-day washout. Acetaminophen pharmacokinetics served as a surrogate to assess rate of gastric emptying. Postprandial plasma glucose, insulin, C-peptide and glucagon were assessed for 5 h after the meal test, and lixisenatide pharmacokinetics were determined for 6 h.After lixisenatide administration and prior to the standardized meal, insulin and C-peptide transiently increased, while fasting plasma glucose decreased in a dose-dependent manner. After the meal, postprandial plasma glucose, insulin and C-peptide were dose proportionally reduced with lixisenatide versus placebo for up to 6 h. Compared with placebo, glucagon levels were transiently lower after any lixisenatide dose, with more sustained reductions after the meal and no apparent dose-related trends. Acetaminophen absorption was significantly reduced and delayed compared with placebo for lixisenatide doses ≥5 µg and demonstrated dose-dependent slowing of gastric emptying. Lixisenatide displayed near dose-proportional exposure, with gastrointestinal events increasing with dose.Lixisenatide reduced fasting plasma glucose via stimulation of glucose-dependent insulin release and controlled postprandial plasma glucose by delaying gastric emptying, demonstrating it to be a valuable option for overall glycaemic control.

SUBMITTER: Becker RH

PROVIDER: S-EPMC4744661 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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Project description:Context:Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear. Objective:To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes. Design:Randomized, double-blind, cross-over study. Setting:Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Patients:Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)]. Interventions:Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies. Main Outcome Measures:Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion. Results:Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60-480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0-360min (P = 0.006) were lower with lixisenatide than with placebo. Conclusions:Lixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.

Project description:Aims/hypothesisThe common muscle-specific TBC1D4 p.Arg684Ter loss-of-function variant defines a subtype of non-autoimmune diabetes in Arctic populations. Homozygous carriers are characterised by elevated postprandial glucose and insulin levels. Because 3.8% of the Greenlandic population are homozygous carriers, it is important to explore possibilities for precision medicine. We aimed to investigate whether physical activity attenuates the effect of this variant on 2 h plasma glucose levels after an oral glucose load.MethodsIn a Greenlandic population cohort (n = 2655), 2 h plasma glucose levels were obtained after an OGTT, physical activity was estimated as physical activity energy expenditure and TBC1D4 genotype was determined. We performed TBC1D4-physical activity interaction analysis, applying a linear mixed model to correct for genetic admixture and relatedness.ResultsPhysical activity was inversely associated with 2 h plasma glucose levels (β[main effect of physical activity] -0.0033 [mmol/l] / [kJ kg-1 day-1], p = 6.5 × 10-5), and significantly more so among homozygous carriers of the TBC1D4 risk variant compared with heterozygous carriers and non-carriers (β[interaction] -0.015 [mmol/l] / [kJ kg-1 day-1], p = 0.0085). The estimated effect size suggests that 1 h of vigorous physical activity per day (compared with resting) reduces 2 h plasma glucose levels by an additional ~0.7 mmol/l in homozygous carriers of the risk variant.Conclusions/interpretationPhysical activity improves glucose homeostasis particularly in homozygous TBC1D4 risk variant carriers via a skeletal muscle TBC1 domain family member 4-independent pathway. This provides a rationale to implement physical activity as lifestyle precision medicine in Arctic populations.Data repositoryThe Greenlandic Cardio-Metabochip data for the Inuit Health in Transition study has been deposited at the European Genome-phenome Archive ( https://www.ebi.ac.uk/ega/dacs/EGAC00001000736 ) under accession EGAD00010001428.

Project description:ContextIn healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP's insulinotropic effect is impaired and effects on bone may be reduced.ObjectiveTo investigate GIP's effect on bone biomarkers in patients with T2D.DesignRandomized, double-blinded, crossover study investigating 6 interventions.PatientsTwelve male patients with T2D.InterventionsA primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with "insulin-induced hypoglycemia" (PG lowered to 3 mmol/L), "fasting hyperglycemia" (mean PG ~8 mmol/L), or "aggravated hyperglycemia" (mean PG ~12 mmol/L).Main outcome measuresBone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH.ResultsOn days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion (P < 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36 ± 15% during GIP administration, compared with 0 ± 9% during placebo infusion (P < 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47 ± 23% during GIP administration compared with 10 ± 9% during placebo infusion (P = 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes.ConclusionsShort-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients.PrécisShort-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.

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Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects.

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