Evolution of insulin resistance in isolated soleus muscle of the NZO mouse

In order to delineate the sequence of development of the metabolic changes in the obese-hyperglycaemic syndrome in the NZO mouse, the uptake of 2-deoxyglucose, glucose utilization and glycogen synthesis by isolated soleus muscle in the absence and presence of graded doses of insulin was measured, and related to the gain in body weight and development of hyperinsulinaemia and hyperglycaemia. It was found that the NZO mice were hyperglycaemic and hyperinsulinaemic compared to an unrelated control strain (Balb c) from the earliest age studied (4 weeks). At 4-6 weeks, 2-deoxyglucose uptake and glucose utilization in the absence of insulin were decreased but the sensitivity and responsiveness to added insulin were comparable to those in the control strain. By 11 weeks, the responsiveness to added insulin was markedly impaired, an abnormality also seen at 52 weeks. Abnormal binding of insulin to its receptors was insufficient explanation for the observed changes. It is concluded that hyperinsulinaemia and hyperglycaemia develop early in NZO mice. Basal glucose transport and glucose utilization by isolated soleus muscle are also decreased from an early age, but decreased responsiveness to insulin in the soleus muscle is secondary and to insulin in the soleus muscle is secondary and relatively late manifestations of the syndrome.