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Acute Dipeptidyl Peptidase-4 Inhibition Rapidly Enhances Insulin-Mediated Suppression of Endogenous Glucose Production in Mice

Departments of Medicine and Physiology (H.D., A.C.S., C.X., A.G., L.S., G.F.L.), Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada M5G 2C4; and Department of Medicine (D.J.D.), Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada M5G 1X5

Address all correspondence and requests for reprints to: Dr. Gary F. Lewis, Toronto General Hospital, 200 Elizabeth Street, EN12-218, Toronto, Ontario, Canada M5G 2C4. E-mail: gary.lewis{at}uhn.on.ca.

Pharmacological approaches that enhance incretin action for the treatment of type 2 diabetes mellitus have recently been developed, i.e. injectable glucagon-like peptide-1 receptor (GLP-1R) agonists with prolonged plasma half-lives and orally available inhibitors of dipeptidyl peptidase (DPP)-4, the main enzyme responsible for the rapid degradation of circulating glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. The mechanism(s) underlying the glucose-lowering effect of these two pharmacotherapies differs and is not yet fully understood. Here we investigated whether acute GLP-1R activation (exendin-4) or DPP-4 inhibition (des-F-sitagliptin) modulates insulin action in mice using a hyperinsulinemic euglycemic clamp. A single iv bolus of des-F-sitagliptin (11 mg/kg) was administered to mice 15 min after the start of the clamp, and its effect was compared with a 50-ng bolus of exendin-4 or the same volume of saline. Despite matched levels of plasma glucose and insulin, within 15 min the glucose infusion rate required to maintain euglycemia was significantly greater after des-F-sitagliptin compared with saline or exendin-4. This difference was entirely due to enhancement of insulin-mediated suppression of endogenous glucose production by des-F-sitagliptin, with no difference in glucose disposal rate. These findings illustrate that DPP-4 inhibition modulates glucose homeostasis through pathways distinct from those used by GLP-1R agonists in mice.