EFFECTS OF INCREASED GLUCOKINASE GENE COPY NUMBER ON GLUCOSE-HOMEOSTASIS AND HEPATIC GLUCOSE-METABOLISM

The relationship between glucokinase (GK) gene copy number and glucose homeostasis was studied in transgenic mice with additional copies of the entire GK gene locus (Niswender, K. D., Postic, C., Jetton, T. L., Bennett, B. D., Piston, D. W., Efrat, S., and Magnuson, M. A. (1997) J. Biol. Chem. 272, 22564-22569). The plasma glucose concentration was reduced by 25 +/- 3% and 37 +/- 4% in mice with one or two extra copi es of the gene locus, respectively. The basis for the hypoglycemic phe notype was determined using metabolic tracer techniques in chronically cannulated, conscious mice with one extra GK gene copy. Under basal c onditions (6-h fasted) transgenic mice had a lower blood glucose conce ntration (-12 +/- 1%) and a slightly higher glucose turnover rate (+8 +/- 3%), resulting in a significantly higher glucose clearance rate (21 +/- 2%). Plasma insulin levels were not different, suggesting that increased glucose clearance was due to augmented hepatic, not islet, G K gene expression. Under hyperglycemic clamp conditions the transgenic mice had glucose turnover and clearance rates similar to the controls , but showed a lower plasma insulin response (-48 +/- 5%). Net hepatic glycogen synthesis was markedly elevated (+360%), whereas skeletal mu scle glycogen synthesis was decreased (-40%). These results indicate t hat increased GK gene dosage leads to increased hepatic glucose metabo lism and, consequently, a lower plasma glucose concentration. Increase d insulin secretion was not observed, even though the transgene is exp ressed in islets, because hypoglycemia causes a down-regulation in isl et GK content (Niswender, K. D., Postic, C., Jetton, T. L., Bennett, B . D., Piston, D. W., Efrat, S., and Magnuson, M. A. (1997) J. Biol. Ch em. 272, in press).