Addition of metformin to exogenous glucagon-like peptide-1 results in increased serum glucagon-like peptide-1 concentrations and greater glucose lowering in type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that lowers blood glucose after meals in type 2 diabetes mellitus The therapeutic potential of GLP-1 in diabetes is limited by rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP-4) Metformin has been reported to inhibit DPP-4 Here we investigated the acute effects of metformin and GLP 1 alone or in combination on plasma DPP-4 activity active GLP-1 concentrations, and glucose lowering in type 2 diabetes mellitus Ten subjects with type 2 diabetes mellitus (8 male and 2 female age 687 +/- 26 years [mean +/- SEM], body mass index, 296 +/- 1 7 kg/m(2), hemoglobin A(1c), 70% +/- 0 1%) received 1 of 3 combinations after an overnight fast in a randomized crossover design metformin 1 g orally plus subcutaneous injection saline (Metformin), GLP-1 (1 5 nmol/kg body weight subcutaneously) plus placebo tablet (GLP-1), or metformin 1 g plus GLP 1(Metformin + GLP-1) At 15 minutes, glucose was raised to 15 mmol/L by rapid intravenous infusion of glucose, and responses were assessed over the next 3 hours This stimulus does not activate the enteroinsular axis and secretion of endogenous GLP-1, enabling the effect of exogenously administered GLP-1 to be examined Mean area under curve (AUC) (0 1 80 minutes) plasma glucose responses were lowest after Metformin + GLP-1 (mean +/- SEM, 1629 +/- 90 mmol/[L mm]) compared with GLP-1 (1885 +/- 86 mmol/[L min], P < 002) and Metformin (2045 +/- 115 mmol/[L min], P < 001) Mean AUC serum insulin responses were similar after either Metformin + GLP-1 (5426 +/- 498 mU/[L min]) or GLP-1 (5655 +/- 854 mU/[L min]) treatment, and both were higher than Metformin (3521 +/- 410 mU/[L min], P < 001 and P < 05, respectively) Mean AUC for plasma DPP-4 activity was lower after Metformin + GLP-1 (1505 +/- 2 mu mol/[mL min], P < 001) and Metformin (1508 +/- 2 mu mol/[mL min], P < 002) compared with GLP-1 (1587 +/- 3 mu mol/[mL min]) Mean AUC measures for plasma active GLP-1 concentrations were higher after Metformin + GLP-1 (820 x 10(4) +/- 51 x 10(4) pmol/[L min]) compared with GLP-1 (484 X 10(4) +/- 31 x 10(4) pmol/[L min], P < 001) and Metformin (419 x 10(4) +/- 34 x 10(4) pmol/[L min], P < 001), respectively In patients with type 2 diabetes mellitus, metformin inhibits DPP-4 activity and thus increases active GLP-1 concentrations after subcutaneous injection In combination with GLP-1, metformin significantly lowers plasma glucose concentrations in type 2 diabetes mellitus subjects compared with GLP-1 alone, whereas insulin responses were similar Metformin enhances serum concentrations of injected active GLP-1(7-36)amide, and the combination results in added glucose-lowering potency (C) 2011 Elsevier Inc All rights reserved