Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1

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E M Migoya, R Bergeron, J L Miller, R N K Snyder, M Tanen, D Hilliard, B Weiss, P Larson, M Gutierrez, G Jiang, F. Liu, K A Pryor, J Yao, L Zhu, Jens Juul Holst, C Deacon, G Herman, N Thornberry, J Amatruda, D Williams-Herman & 2 more J A Wagner, R SinhaRoy

The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon-like peptide 1 (GLP-1) (9-36) and glucagon. In healthy subjects, a DPP-4 inhibitor elevated both active GLP-1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP-1 (but not GIP), and the combination resulted in additive increases in active GLP-1 plasma concentrations. Metformin did not inhibit plasma DPP-4 activity either in vitro or in vivo. The study results show that metformin is not a DPP-4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP-1 concentrations. DPP-4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP-1 in plasma.
Original languageEnglish
JournalClinical Pharmacology and Therapeutics
Issue number6
Pages (from-to)801-8
Number of pages8
Publication statusPublished - 1 Dec 2010

    Research areas

  • Adolescent, Adult, Animals, Cross-Over Studies, Dipeptidyl-Peptidase IV Inhibitors, Double-Blind Method, Drug Therapy, Combination, Female, Glucagon-Like Peptide 1, Humans, Male, Metformin, Mice, Mice, Inbred C57BL, Middle Aged, Obesity, Young Adult

ID: 33938724