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 hepatic glucose uptake.

Research Design and Methods. Fasted conscious dogs were studied in the presence (VIL, n=6) or absence (CON, n=6) of oral vildagliptin (1 mg/kg). In both groups, GLP-1 was infused into the portal vein (1 pmol/kg/min) for 240 min. During the same time, glucose was delivered into the portal vein at 4 mg/kg/min 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 4h experimental period. GLP-1 concentrations were increased in the VIL group (50±3 versus 85±7 pM in the portal vein in CON and VIL, respectively; P<0.05) as a result of a 40% decrease in GLP-1 clearance (38±5 and 22±2 ml/kg/min, 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 versus 88±15 μU/ml, respectively). During vildagliptin treatment net hepatic glucose uptake was 3-fold greater than in the CON 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 GLP-1's effects on insulin and glucagon secretion.