Glucagon-Like Peptide-1 Is a Significant Determinant of the Second-Meal Effect in Patients with Type 2 Diabetes

Abstract

Background and Aim: The mechanisms behind the second-meal effect, i.e., the capability of a small premeal to reduce plasma glucose excursions during a main meal in type 2 diabetes, remain unknown. We investigated the involvement of the gut-derived hormone glucagon-like peptide-1 (GLP1) in the second-meal effect in patients with type 2 diabetes. Methods: In a randomized, double-blinded, placebo-controlled, double-dummy, cross-over study, the second-meal effect was investigated in 15 male patients with metformin-treated type 2 diabetes over two days by administering a premeal (30 g of whey protein in 100 ml water) or a non-caloric flavor-controlled drink 30 minutes before a standardized liquid main meal. During both conditions, the second-meal effect was evaluated twice: with concomitant iv infusion of the GLP1 receptor antagonist exendin[9-39] and saline (placebo), respectively. Results: A second-meal effect was observed in 9 out of 15 participants, defined as responders, in whom the premeal significantly reduced postprandial glucose excursions during the main meal by 11% (assessed by area under the plasma glucose curve). The second-meal effect was completely abolished by iv infusion of exendin[9-39], during which the premeal resulted in a 5% exacerbation of postprandial glucose excursions. Significant GLP1-mediated second-meal effects on postprandial insulin (56%) and C-peptide responses (86%) were also observed. Conclusions: By antagonizing the GLP1 receptor, premeal-induced beta cell secretion is significantly reduced and the glucose-lowering effect of a premeal on a subsequent main meal, the second-meal effect, is annulled in patients with type 2 diabetes. This suggests that premeal-induced GLP1 secretion constitutes a significant determinant of the second-meal effect in type 2 diabetes patients. Disclosure S. Bergmann: None. N.C. Bergmann: Employee; Self; Zealand Pharma A/S. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.