Acute dipeptidyl peptidase-4 inhibition rapidly enhances insulin-mediated suppression of endogenous glucose production in mice.
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.
Duez
Hélène
H
Department of Medicine and Physiology, Division of Endocrinology and Metabolism, University of Toronto,Toronto, Ontario, Canada.
Smith
Angela C
AC
Xiao
C
C
Giacca
Adria
A
Szeto
Linda
L
Drucker
Daniel J
DJ
Lewis
Gary F
GF
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D000077270:Exenatide; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000097:blood; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D011719:Pyrazines; D014230:Triazoles; D014688:Venoms; D000077270:Exenatide; D000068900:Sitagliptin Phosphate