Insulin sensitivity and response in eviscerated obese Zucker rats

In order to examine the contribution of the skeletal muscles to insulin resistance in obesity, fatty (fa/fa) or lean Zucker rats were functionally hepatectomized/nephrectomized by an evisceration procedure. Glucose loads, adjusted to produce plasma levels of about 500 mg/100 ml, were given IV postoperatively, and during the next four hours the uptake and utilization of glucose by peripheral tissues (muscles) was estimated from the rate of fall in the plasma glucose concentration. Glucose utilization in the fa/fa rats was similar to that in the lean, despite plasma insulin levels that were ten times higher. Furthermore, a marked reduction in uptake was revealed when plasma insulin in the fa/fa rats was normalized (by waiting one hour after evisceration) before the glucose load was administered. Glucose uptake was resistant to insulin over a range of submaximal plasma insulin concentrations, indicating a shift to the right of the dose-response relationship. The maximal response in the fatty rats was markedly depressed compared with that in the lean rats, and even large doses of insulin (up to 1000 mU, IV) failed to restore it. The results suggest that the skeletal muscles isolated by evisceration from fa/fa Zucker rats are less responsive as well as sensitive to insulin than the muscles of lean rats and that the muscles contribute significantly to the insulin resistance found in intact obese animals.