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 at 4 mg . 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 microU/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.

FIG. 1.

Arterial and portal plasma DPP-4 activity in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with vehicle (○) or vildagliptin (▪) (means ± SE; n = 6 per group; *P < 0.05).

FIG. 2.

Arterial and portal plasma GLP-1 levels in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with vehicle (○) or vildagliptin (▪) (means ± SE; n = 6 per group; *P < 0.05).

FIG. 3.

Arterial plasma glucose level and peripheral GIR in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with vehicle (○) or vildagliptin (▪) (means ± SE; n = 6 per group; *P < 0.05). Glucose was infused into the portal vein at 4 mg · kg⁻¹ · min⁻¹ in both groups during the experimental period.

FIG. 4.

Arterial and hepatic sinusoidal plasma insulin levels in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with vehicle (○) or vildagliptin (▪) (means ± SE; n = 6 per group).

FIG. 5.

Arterial plasma C-peptide and hepatic sinusoidal plasma glucagon levels in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with vehicle (○) or vildagliptin (▪) (means ± SE; n = 6 per group).

FIG. 6.

Net hepatic glucose balance and nonhepatic glucose uptake in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with vehicle (○) or vildagliptin (▪) (means ± SE; n = 6 per group).

FIG. 7.

Net hepatic glucose fractional extraction (A), net hepatic glucose uptake–to–hepatic sinusoidal plasma insulin ratio (B), and nonhepatic glucose uptake–to–arterial plasma insulin ratio (C) during the last 3 h of the experimental period (60–240 min) in conscious dogs treated with vehicle (□) or vildagliptin (▪) (means ± SE; n = 6 per group; P < 0.05).