Andreas Brønden1, Anders Albér1, Ulrich Rohde1, Jens F Rehfeld2, Jens J Holst3,4, Tina Vilsbøll1,5,6, Filip K Knop1,4,5. 1. Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark. 2. Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 2100 Copenhagen Ø, Denmark. 3. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark. 4. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark. 5. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark. 6. Steno Diabetes Center Copenhagen, University of Copenhagen, 2820 Gentofte, Denmark.
Abstract
Context: Despite a position as the first-line pharmacotherapy in type 2 diabetes, the glucose-lowering mechanisms of metformin remain to be fully clarified. Gut-derived modes of action, including suppression of bile acid reabsorption and a resulting increase in glucagon-like peptide-1 (GLP-1) secretion, have been proposed. Objective: The aim of this study was to assess the GLP-1 secretory and glucometabolic effects of endogenously released bile, with and without concomitant single-dose administration of metformin in patients with type 2 diabetes. Design: Randomized, placebo-controlled, and double-blinded crossover study. Setting: This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark. Patients: Fifteen metformin-treated patients with type 2 diabetes; all participants completed the study. Interventions: Four experimental study days in randomized order with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg-1 × min-1) or saline. Main Outcome Measure: Plasma GLP-1 excursions as measured by baseline-subtracted area under the curve. Results: Single-dose metformin further enhanced bile acid-mediated induction of GLP-1 secretion (P = 0.02), whereas metformin alone did not increase plasma GLP-1 concentrations compared with placebo (P = 0.17). Metformin, both with (P = 0.02) and without (P = 0.02) concomitant cholecystokinin-induced gallbladder emptying, elicited reduced plasma glucose excursions compared with placebo. No GLP-1-mediated induction of insulin secretion or suppression of glucagon was observed. Conclusions: Metformin elicited an enhancement of the GLP-1 response to cholecystokinin-induced gallbladder emptying in patients with type 2 diabetes, whereas no derived effects on insulin or glucagon secretion were evident in this acute setting.
RCT Entities:
Context: Despite a position as the first-line pharmacotherapy in type 2 diabetes, the glucose-lowering mechanisms of metformin remain to be fully clarified. Gut-derived modes of action, including suppression of bile acid reabsorption and a resulting increase in glucagon-like peptide-1 (GLP-1) secretion, have been proposed. Objective: The aim of this study was to assess the GLP-1 secretory and glucometabolic effects of endogenously released bile, with and without concomitant single-dose administration of metformin in patients with type 2 diabetes. Design: Randomized, placebo-controlled, and double-blinded crossover study. Setting: This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark. Patients: Fifteen metformin-treated patients with type 2 diabetes; all participants completed the study. Interventions: Four experimental study days in randomized order with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg-1 × min-1) or saline. Main Outcome Measure: Plasma GLP-1 excursions as measured by baseline-subtracted area under the curve. Results: Single-dose metformin further enhanced bile acid-mediated induction of GLP-1 secretion (P = 0.02), whereas metformin alone did not increase plasma GLP-1 concentrations compared with placebo (P = 0.17). Metformin, both with (P = 0.02) and without (P = 0.02) concomitant cholecystokinin-induced gallbladder emptying, elicited reduced plasma glucose excursions compared with placebo. No GLP-1-mediated induction of insulin secretion or suppression of glucagon was observed. Conclusions: Metformin elicited an enhancement of the GLP-1 response to cholecystokinin-induced gallbladder emptying in patients with type 2 diabetes, whereas no derived effects on insulin or glucagon secretion were evident in this acute setting.
Authors: Alexey V Zilov; Sulaf Ibrahim Abdelaziz; Afaf AlShammary; Ali Al Zahrani; Ashraf Amir; Samir Helmy Assaad Khalil; Kerstin Brand; Nabil Elkafrawy; Ahmed A K Hassoun; Adel Jahed; Nadim Jarrah; Sanaa Mrabeti; Imran Paruk Journal: Diabetes Metab Res Rev Date: 2019-07-24 Impact factor: 4.876
Authors: Anila K Madiraju; Yang Qiu; Rachel J Perry; Yasmeen Rahimi; Xian-Man Zhang; Dongyan Zhang; João-Paulo G Camporez; Gary W Cline; Gina M Butrico; Bruce E Kemp; Gregori Casals; Gregory R Steinberg; Daniel F Vatner; Kitt F Petersen; Gerald I Shulman Journal: Nat Med Date: 2018-07-23 Impact factor: 53.440