HYPERINSULINEMIA INDUCES A REVERSIBLE IMPAIRMENT IN INSULIN-RECEPTOR FUNCTION LEADING TO DIABETES IN THE SAND RAT MODEL OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS

The insulin receptor was evaluated at different disease stages in the sand rat (Psammomys obesus), a model for nutrition induced diabetes. N ondiabetic sand rats showed markedly low receptor number in liver comp ared with albino rats. Their receptor had an intact tyrosine kinase ac tivity but a higher K-m for ATP in the phosphorylation reaction of exo genous substrates. The initial effects of overeating (i.e., developmen t of hyperinsulinemia without hyperglycemia) were associated in the sa nd rat with a dramatic decrease in in vitro and in vivo insulin-induce d receptor tyrosine kinase activity in both liver and muscle. In muscl e, this coincided with a decrease in receptor number and an increase i n basal tyrosine kinase activity. Similar changes were observed upon d evelopment of hyperinsulinemia with hyperglycemia. Upon recovery from the diabetic state by diet restriction, the impaired receptor kinase a ctivation was corrected. Complete restoration occurred only in animals that fully recovered from the diabetic state and became normoinsuline mic. These observations indicate that loss and gain of receptor tyrosi ne kinase activity were dependent on insulin levels. Thus, overeating may lead to the development of hyperinsulinemia through ineffective ex traction of excess insulin by the scarce liver receptors. Hyperinsulin emia, in turn, causes a reversible reduction in receptor kinase activi ty, leading to insulin resistance. This sequence of events may be rele vant to diet-related changes in human non-insulin-dependent diabetes m ellitus.