The Role of Glucagon-Like Peptide-1 for the Postprandial Effects of Metformin in Type 2 Diabetes

Abstract

Metformin is the most widely used plasma glucose-lowering drug for the treatment of type 2 diabetes. It has been shown that metformin increases plasma concentrations of glucagon-like peptide-1 (GLP-1), but it remains unknown whether metformin-induced GLP-1 secretion plays any role for the beneficial effects of metformin on postprandial glucose metabolism. We investigated the effect of metformin-induced GLP-1 secretion during meal ingestion in patients with type 2 diabetes using the GLP-1 receptor antagonist exendin[9-39]. In a double-blinded, double dummy, placebo-controlled, randomized, cross-over study, 15 participants with type 2 diabetes (medians: age 71 years, BMI 30.07 kg/m2, HbA1c 50 mmol/mol) were subjected to 14 days’ metformin and placebo treatment, respectively, in randomized order with at least a 2-week washout period between treatments. At the end of each treatment period, two randomized 4-hour mixed meal tests with either concomitant exendin[9-39] (450 pmol/kg/min) or saline infusion, were carried out. Metformin treatment significantly lowered fasting plasma glucose and postprandial plasma glucose excursions compared to placebo. We observed equal metformin-induced reductions in postprandial plasma glucose excursions during saline and exendin[9-39] infusions. Based on postprandial plasma glucose excursions, using the GLP-1 receptor antagonist exendin[9-39], we cannot confirm that GLP-1 secretion is involved in the beneficial postprandial glucose-lowering effects of metformin in patients with type 2 diabetes. Disclosure L.S. Hansen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. A. Brønden: None. N.B. Dalsgaard: None. E. Bahne: None. P.H. Sørensen: None. 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.