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 hypergly cemic state in the GK rat, a new spontaneous model of non-insulin-depe ndent (type II) diabetes without obesity, are partly accounted for by an alteration of the pancreatic B cell response. On the other hand, th e hyperglycemic-hyperinsulinemic pattern in these rats suggests a decr ease 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 an d submaximal (euglycemic clamp) insulin levels. Overall glucose utiliz ation (OGU), individual tissue glucose utilization (ITGU, in vivo upta ke of the glucose analogue 2-deoxy-D-glucose as the relative index of glucose metabolism), as well as hepatic glucose production (GP) and li ver insulin receptor properties were determined under these two condit ions. The basal OGU was significantly higher in the GK females, compar ed with that in control Wistar females. The hyperinsulinemic-euglycemi c clamp experiments indicated that peripheral insulin resistance was i nstalled at 8 wk of age in the GK females because 1) OGU was significa ntly lower and 2) in some peripheral tissues (epitrochlearis muscle, p eriovarian, 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 sub maximal hyperinsulinemia (and euglycemia), it was less effectively sup pressed than in the controls, thus demonstrating liver insulin resista nce. Under both basal state and clamp condition, binding of I-125-A14- insulin to liver membranes of GK rats was significantly decreased by 2 0-30%. Membranes and solubilized wheat germ agglutinin-purified liver receptors of GK and control rats exhibited similar affinity for insuli n. The kinase activity of liver receptors [autophosphorylation and pho sphorylation of the artificial substrate poly(Glu-Tyr)] was also simil ar in both groups, thus suggesting that liver insulin resistance in th e GK rat is mainly accounted for by postreceptor defect(s). The nonobe se GK rat should prove a valuable tool for dissecting the pathogenesis of insulin resistance and its cellular basis.