Inhibition of dipeptidyl peptidase-4 by vildagliptin during glucagon-like peptide 1 infusion increases liver glucose uptake in the conscious dog

Abstract

OBJECTIVE-This study investigated the acute effects of treatment with vildagliptin on dipeptidyl peptidase-4 (DPP-4) activity, glucagon-like peptide 1 (GLP-1) concentration, pancreatic hormone levels, and glucose metabolism. The primary aims were to determine the effects of DPP-4 inhibition on GLP-1 clearance and on hepatic glucose uptake. RESEARCH DESIGN AND METHODS-Fasted conscious dogs were studied in the presence (n = 6) or absence (control, n = 6) of oral vildagliptin (1 mg/kg). In both groups, GLP-1 was infused into the portal vein (1 pmol • kg -1 • min -1) for 240 min. During the same time, glucose was delivered into the portal vein at4mg • kg -1 • min -1 and into a peripheral vein at a variable rate to maintain the arterial plasma glucose level at 160 mg/dl. RESULTS-Vildagliptin fully inhibited DPP-4 over the 4-h experimental period. GLP-1 concentrations were increased in the vildagliptin-treated group (50 ±3 vs. 85 ± 7 pmol/l in the portal vein in control and vildagliptin-treated dogs, respectively; P < 0.05) as a result of a 40% decrease in GLP-1 clearance (38 ± 5 and 22 ± 2 ml • kg -1 • min -1, respectively; P < 0.05). Although hepatic insulin and glucagon levels were not significantly altered, there was a tendency for plasma insulin to be greater (hepatic levels were 73 ± 10 vs. 88 ± 15 (μU/ml, respectively). During vildagliptin treatment, net hepatic glucose uptake was threefold greater than in the control group. This effect was greater than that predicted by the change in insulin. CONCLUSIONS-Vildagliptin fully inhibited DPP-4 activity, reduced GLP-1 clearance by 40%, and increased hepatic glucose disposal by means beyond the effects of GLP-1 on insulin and glucagon secretion. © 2009 by the American Diabetes Association.