Insulin response in skeletal muscle and fat cells of the genetically obese Zucker rat.

Isolated fat cells derived from 10-wk-old Zucker obese rats utilized substantially greater amounts of glucose per cell in the presence or absence of insulin than those from lean rats. Initial rates of deoxyglucose or 3-0-methylglucose uptake in fat cells from Zucker obese rats were also 5--10 times greater than those observed in cells from lean rats. However, while 240 microU/ml insulin elicited a maximal response in fat cells from lean rats, this dose of hormone was only about 50% as effective as 24 microU/ml insulin in stimulating glucose metabolism or hexose transport in obese rat cells. This apparent rightward shift in the dose response-relationship could not be adequately explained on the basis of decreased insulin receptors since (125I-) insulin binding per fat cell was increased 2.5--3-fold in obesity, while receptor density on the cell surface in obesity was decreased only slightly. Soleus muscles from obese Zucker rats exhibited decreased basal rates of D(5-3H)glucose conversion to glycogen and H2O compared to those of lean controls. While the percent increase in glucose metabolism due to a supermaximal dose of insulin was similar in soleus muscles of lean and obese Zucker rats, a blunted response to a submaximal insulin dose was observed in muscles from the latter animals. This rightward shift in the dose-response relationship was also observed when deoxyglucose uptake was monitored in soleus muscles from obese rats. Binding of (1251-) insulin to soleus muscles at a medium concentration of 57 microU/ml was significantly decreased in obese compared to lean rats. We conclude that (1) fat cells do not contribute to the insulin resistance of 10-wk obese Zucer rats since glucose utilization is higher in these cells at all concentrations of insulin tested, (2) obese Zucker rat soleus muscle metabolism is defective in two respects--imparied basal glucose utilization and a rightward shift in the insulin dose-response relationship with respect to hexose transport, and (3) this latter defect involving decreased sensitivity of muscle to insulin appears to result from a marked decrease in cell surface receptors for the hormone.