INSULIN-RESISTANCE IN THE GK RAT - DECREASED RECEPTOR NUMBER BUT NORMAL KINASE-ACTIVITY IN LIVER

We have previously shown that the glucose intolerance and the hyperglycemic state in the GK rat, a new spontaneous model of non-insulin-dependent (type II) diabetes without obesity, are partly accounted for by an alteration of the pancreatic B cell response. On the other hand, the hyperglycemic-hyperinsulinemic pattern in these rats suggests a decrease of response to insulin in the basal state. In the present study, in vivo insulin action was assessed in 8-wk-old GK females at basal and submaximal (euglycemic clamp) insulin levels. Overall glucose utilization (OGU), individual tissue glucose utilization (ITGU, in vivo uptake of the glucose analogue 2-deoxy-D-glucose as the relative index of glucose metabolism), as well as hepatic glucose production (GP) and liver insulin receptor properties were determined under these two conditions. The basal OGU was significantly higher in the GK females, compared with that in control Wistar females. The hyperinsulinemic-euglycemic clamp experiments indicated that peripheral insulin resistance was installed at 8 wk of age in the GK females because 1) OGU was significantly lower and 2) in some peripheral tissues (epitrochlearis muscle, periovarian, and inguinal white adipose tissues), but not all, ITGU was significantly lower compared with corresponding ITGU in control rats. In the basal state GP was significantly higher in the GK rats. At submaximal hyperinsulinemia (and euglycemia), it was less effectively suppressed than in the controls, thus demonstrating liver insulin resistance. Under both basal state and clamp condition, binding of I-125-A14-insulin to liver membranes of GK rats was significantly decreased by 20-30%. Membranes and solubilized wheat germ agglutinin-purified liver receptors of GK and control rats exhibited similar affinity for insulin. The kinase activity of liver receptors [autophosphorylation and phosphorylation of the artificial substrate poly(Glu-Tyr)] was also similar in both groups, thus suggesting that liver insulin resistance in the GK rat is mainly accounted for by postreceptor defect(s). The nonobese GK rat should prove a valuable tool for dissecting the pathogenesis of insulin resistance and its cellular basis.