TY - JOUR

T1 - Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1

AU - Migoya, E M

AU - Bergeron, R

AU - Miller, J L

AU - Snyder, R N K

AU - Tanen, M

AU - Hilliard, D

AU - Weiss, B

AU - Larson, P

AU - Gutierrez, M

AU - Jiang, G

AU - Liu, F.

AU - Pryor, K A

AU - Yao, J

AU - Zhu, L

AU - Holst, Jens Juul

AU - Deacon, C

AU - Herman, G

AU - Thornberry, N

AU - Amatruda, J

AU - Williams-Herman, D

AU - Wagner, J A

AU - SinhaRoy, R

PY - 2010/12/1

Y1 - 2010/12/1

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Animals

KW - Cross-Over Studies

KW - Dipeptidyl-Peptidase IV Inhibitors

KW - Double-Blind Method

KW - Drug Therapy, Combination

KW - Female

KW - Glucagon-Like Peptide 1

KW - Humans

KW - Male

KW - Metformin

KW - Mice

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Obesity

KW - Young Adult

U2 - 10.1038/clpt.2010.184

DO - 10.1038/clpt.2010.184

M3 - Journal article

C2 - 21048706

VL - 88

SP - 801

EP - 808

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 6

ER -