Individuals that are predisposed to develop type 2 diabetes inherit a set of genes that make their tissues resistant to insulin. However, in spite of this genetic background, the increasing global prevalence of diabetes is strongly associated with obesity and chronic physical inactivity.
Insulin sensitive organs such as skeletal muscle and liver uniquely respond differently in the insulin resistance state. In the liver, there is an overproduction of glucose during the fasting state in the presence of hypersecretion of insulin by the pancreatic beta cells. Additionally, this increase in plasma insulin also fails to prevent the liver from continuing glucose production following a meal in spite of high glucose levels from ingested food.
The muscle is the largest insulin sensitive organ and responsible for 60-70% plasma glucose disposal. However, following a carbohydrate meal, in the insulin resistance state, the muscle shows impaired glucose uptake with reduced expression of glucose “gates or doors” called transporter-4 on the surface of muscle cells. Therefore, this results in further increases in blood glucose or postprandial hyperglycemia.
The combination of excessive glucose production by the liver during fasting and fed states and poor glucose uptake by skeletal muscle kick the pancreatic beta cells into overdrive. The pancreas, therefore, responds by increasing secretion of insulin in order to compensate for impaired insulin action. The blood glucose will remain within normal range as long as the beta cells continue to sufficiently augment their insulin secretion to overcome insulin resistance. At this stage individuals still have normal glucose tolerance but the insulin-producing beta cells are under stress with decreasing beta cells. It, therefore, follows that normal glucose tolerance does not account for pathological process underway in insulin resistance.