IMPAIRMENT OF INSULIN ACTION ON PERIPHERAL GLUCOSE-UPTAKE AND HEPATICGLUCOSE-PRODUCTION IN TUMOR-BEARING RATS

The present study was performed to determine the time-course for the d evelopment of peripheral and hepatic insulin resistance in rats as a r esult of an increasing tumor burden. Animals were inoculated with Yosh ida ascites hepatoma, and studies were conducted during the early phas e of tumor growth (day 4) at which time there was no change in food in take and at a later time point (day 8) when the tumor burden was incre ased and rats demonstrated anorexia. In vivo insulin action was access ed under euglycemic hyperinsulinemic conditions, in which insulin was infused at rates sufficient to produce arterial insulin levels that re present high physiological (3.5 ng/ml) or maximally stimulating values (180 ng/ml). On day 4, tumor-bearing (TB) rats were euglycemic, and w hole body glucose turnover was elevated 32%. Insulin-mediated glucose uptake (IMGU) in TB rats was similar to control values at the low insu lin infusion rate but reduced by 53% under maximally stimulating condi tions. The insulin-induced suppression of glucose production was simil ar in TB and control animals at this time point. In contrast, on day 8 , TB rats were hypoglycemic and glucose turnover was reduced 35%. The impairment in IMGU was more severe than seen earlier, with glucose upt ake being reduced 39 and 61% at both levels of hyperinsulinemia. At th is time point, the ability of insulin to inhibit glucose production wa s also impaired. These results indicate that the insulin resistance in duced by the Yoshida hepatoma was manifested initially by a reduction in IMGU by peripheral tissues. As the tumor burden increased periphera l insulin resistance became more severe and an impairment in hepatic i nsulin action was observed.