Abnormal regulation of hepatic glucose production by hyperglycemia in mice with a disrupted glucokinase allele. Rossetti, Luciano, Wei Chen, Meizhu Hu, Meredith Hawkins, Nir Barzilai, and Shimon Efrat. Diabetes Research and Training Center, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461
APStracts 4:0149E, 1997.
Glucokinase (GK) catalyzes the phosphorylation of glucose in beta cells and hepatocytes and mutations in the GK gene have been implicated in a form of human diabetes. To investigate the relative role of partial deficiencies in the hepatic versus pancreatic GK activity, we examined insulin secretion, glucose disposal, and hepatic glucose production (HGP) in response to hyperglycemia in transgenic mice a) with one disrupted GK allele, which manifest decreased GK activity in both liver and beta cells (GK+/-), and b) with decreased GK activity selectively in beta cells (RIP-GKRZ). Liver GK activity (Vmax) was decreased by 35-50% in the GK+/- but not in the RIP-GKRZ mice, compared with wild type (WT) mice. Hyperglycemic clamp studies were performed in conscious mice with or without concomitant pancreatic clamp. In all studies [3-3H]-glucose was infused to measure the rate of appearance of glucose (Ra) and HGP during 80 min of euglycemia (Glc 5 mM), followed by 90 min of hyperglycemia (Glc 17 mM). During hyperglycemic clamp studies, the steady-state plasma insulin concentration, the rate of glucose infusion (GIR), and the rate of glucose disappearance (Rd) were decreased in both GK+/- and RIP-GKRZ, compared with WT mice. However, while the basal HGP (at euglycemia) averaged 22 mg/Kg[beta]min in all groups, during hyperglycemia HGP was suppressed by only 48% in GK+/-, compared with 70% and 65% in the WT and RIP-GKRZ mice, respectively. Thus, HGP was higher in the GK+/- (12.22.0) than in WT (7.51.8) or RIP-GKRZ (7.11.7 mg/Kg[beta]min) mice. During the pancreatic clamp studies, the ability of hyperglycemia per se to increase Rd was similar in all groups. However, hyperglycemia inhibited HGP by only 12% in GK+/-, versus 42% and 45%, respectively, in the WT and RIP -GKRZ mice. Thus, HGP was higher in the GK+/- (15.41.2; p<0.01) than in WT (10.61.6) and RIP-GKRZ (9.61.3 mg/Kg[beta]min) mice. We conclude that while impaired glucose-induced insulin secretion is common to both models of decreased pancreatic GK activity, the marked impairment in the ability of hyperglycemia to inhibit HGP is due to the specific decrease in hepatic GK activity. 

Received 11 April 1997; accepted in final form 3 July 1997.
APS Manuscript Number E164-7.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 24 July 1997