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Dipeptidyl Peptidase‐4 Inhibitors Administered in Combination With Metformin Result in an Additive Increase in the Plasma Concentration of Active GLP‐1
Author(s) -
Migoya E M,
Bergeron R,
Miller J L,
Snyder R N K,
Tanen M,
Hilliard D,
Weiss B,
Larson P,
Gutierrez M,
Jiang G,
Liu F,
Pryor K A,
Yao J,
Zhu L,
Holst J J,
Deacon C,
Herman G,
Thornberry N,
Amatruda J,
WilliamsHerman D,
Wagner J A,
SinhaRoy R
Publication year - 2010
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.184
Subject(s) - metformin , incretin , glucagon like peptide 1 , in vivo , dipeptidyl peptidase , endocrinology , medicine , chemistry , glucagon , pharmacology , dipeptidyl peptidase 4 , pharmacokinetics , small intestine , type 2 diabetes , diabetes mellitus , hormone , biology , biochemistry , enzyme , microbiology and biotechnology
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. Clinical Pharmacology & Therapeutics (2010) 88 6, 801–808. doi: 10.1038/clpt.2010.184