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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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.
|Journal||Clinical Pharmacology and Therapeutics|
|Number of pages||8|
|Publication status||Published - 1 Dec 2010|
- 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