Received for publication November 27, 2006.
Revised February 13, 2007.
Accepted for publication February 13, 2007.

A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog

Abstract

Elevated glucagon is associated with fasting hyperglycemia in Type 2 diabetes. We assessed the effects of a glucagon receptor antagonist, NNC 25-0926, on hepatic glucose production in vivo, using arterio-venous difference and tracer techniques in conscious dogs. The experiments consisted of equilibration (-140 to -40 min), control (40-0 min) and experimental (0-180 min, divided into P1 [0-60 min] and P2 [60-180 min]) periods. In P1, NNC 25-0926 was given intragastrically at 0 (veh), 10, 20, 40 or 100 mg/kg and euglycemia was maintained. In P2, somatostatin, basal intraportal insulin and 5-fold basal intraportal glucagon (2.5ng/kg/min) were infused. Arterial plasma insulin levels remained basal throughout the study in all groups. Arterial plasma glucagon levels remained basal during the control period and P1 and then increased to ~70 pg/ml in P2 in all groups. Arterial plasma glucose levels were basal in the control period and P1 in all groups. In P2, the arterial glucose level increased to 245±22 and 172±15 mg/dl in the veh and 10 mg/kg groups respectively, whereas in the 20, 40 and 100 mg/kg groups there was no rise in glucose. Net hepatic glucose output was ~2 mg/kg/min in all groups during the control period. In P2, it increased by 9.4±2 mg/kg/min in the veh group. In the 10, 20, 40 and 100 mg/kg groups the rise was only 4.1±0.9, 1.6±0.6, 2.4±0.7 and 1.5±0.3 mg/kg/min respectively due to inhibition of glycogenolysis. In conclusion, NNC 25-0926 effectively blocked the ability of glucagon to increase HGP in the dog.

Key words: antagonist, dog, glucagon, glucose production, glycogenolysis, hyperglycemia