IMPAIRED INSULIN-SECRETION AND EXCESSIVE HEPATIC GLUCOSE-PRODUCTION ARE BOTH EARLY EVENTS IN THE DIABETIC GK RAT

Adult Goto-Kakisaki Wistar (GK) rats exhibit a spontaneous non-insulin -dependent diabetes characterized by impaired glucoseinduced insulin s ecretion, decreased beta-cell mass, hepatic glucose overproduction, an d moderate insulin resistance in muscles and adipose tissues. To eluci date the pathogenesis of hyperglycemia in this animal model, we have s tudied insulin secretion and insulin action in 4-wk-old GK pups, just before weaning. In the postabsorptive state, their basal plasma glucos e level was elevated (P <0.001), and their tolerance to intravenous gl ucose was impaired. Their kinetics of insulin release in response to g lucose was impaired, with a low acute phase of insulin release in vivo and in vitro (perfused pancreas). Basal glucose production was increa sed in the GK pups by 40% (P <0.05). During euglycemic clamp performed at submaximal hyperinsulinemia, suppression of liver glucose producti on was less effective (P <0.01) in the GK rats, whereas their overall glucose utilization was similar to that of the control group. This was correlated with a normal insulin-stimulated glucose utilization by ep itrochlearis, soleus, and extensor digitorum longus muscles, diaphragm , and white adipose tissues. These data give body to the primacy of th e beta-cell defects in the etiology of non-insulin-dependent diabetes mellitus in the GK rat. They also highlight a possible primary role of the liver defect. Peripheral insulin resistance does not contribute t o the development of postnatal glucose intolerance in this diabetes mo del.