Insulin resistance in Pima Indians. A combined effect of genetic predisposition and obesity-related skeletal muscle cell hypertrophy.

Obesity and diabetes are epidemic in the Pima Indians of Southwest United States. Recent evidence suggests that a reduced metabolic rate may predispose the obesity and, since metabolic rate appears to be familial, this may predispose to the familial dependence of obesity. Obesity is associated with an increased risk of diabetes. Insulin resistance is associated with obesity, but is also familial, independent of obesity. In this population insulin resistance is a risk factor for the development of diabetes. Diabetes occurs when insulin secretory failure is superimposed on insulin resistance. Reduced glucose storage in muscle, regulated by glycogen synthase, is important in determining insulin resistance especially at high plasma insulin concentrations and it is possible that a specific genetic defect may be the cause of this. Obesity has its major effect on insulin action at lower plasma insulin concentrations and we propose that this may in part be due to abnormalities of insulin action induced by an increased fat-free mass with a consequent enlargement of muscle cells, a reduced capillary supply, and reduced penetration of insulin into muscle in obese subjects. We propose therefore that insulin resistance may be due to a combination of a genetic defect and obesity-induced changes in the biophysical properties of skeletal muscle. These defects, by slightly increasing the plasma glucose concentration and inducing pancreatic glucose insensitivity, may in turn lead to the development of non-insulin-dependent diabetes mellitus.