UP-REGULATED HEXOKINASE-ACTIVITY IN ISOLATED ISLETS FROM DIABETIC 90-PERCENT PANCREATECTOMIZED RATS

Glucokinase is the beta-cell glucose sensor, i,e,, the site in glucose metabolism that determines the glucose set-point (sensitivity) for insulin secretion, Hexokinase is also present, but it normally contributes Little to glucose metabolism because of end-product inhibition by glucose 6-phosphate, There is a lowered glucose set-point for insulin secretion in 90% pancreatectomized (Pr) diabetic rats, We investigated the mechanism by measuring hexokinase and glucokinase activity in islet extracts, Glucokinase activity was minimally raised in Pr islets (V-max 125% of sham-operated control rats), In contrast, hexokinase V-max was 250% of the control value, suggesting that the increased hexokinase activity caused the beta-cell glucose hypersensitivity. Additional evidence was obtained with a 401-h fast that was performed because of a previous observation that the inhibitory effect of fasting on insulin secretion was impaired in Pr rats, Glucokinase activity fell normally in the Pr rats (32 +/- 4% reduction in sham vs, 37 +/- 4% in Pr rats) as opposed to hexokinase activity which was unaffected in either group, In summary, a feature of hyperglycemia is upregulated islet hexokinase activity, The result is that hexokinase assumes partial control over the glucose set-point for insulin secretion, As such, regulatory effects on insulin secretion, such as fasting, that are mediated through glucokinase activity may be altered.