Acute and chronic effects of hyperglycaemia on glucose metabolism: implications for the development of new therapies.

Hyperglycaemia has two effects on glucose metabolism, both of which have implications for the development of new treatments for patients with non-insulin-dependent diabetes mellitus (NIDDM). Acute increases in plasma glucose concentrations promote glucose uptake in a concentration-dependent fashion (the glucose mass-action effect). This increases glucose utilization in proportion to fasting hyperglycaemia. Postprandially, the absolute rate of glucose utilization is normal in patients with NIDDM, because stimulation of glucose utilization by glucose mass-action compensates for any defects in insulin action. These defects in insulin action may themselves have evolved to protect insulin-sensitive tissues from excessive glucose utilization during hyperglycaemia. Because the absolute rate of glucose utilization is normal in NIDDM, excessive postprandial hyperglycaemia can be attributed to diminished suppression of endogenous glucose production. Consequently, suppression of endogenous glucose production, both in the fasting and postprandial states, becomes the primary target for therapy. Chronically, hyperglycaemia impairs both insulin secretion and sensitivity, a phenomenon known as 'glucose toxicity'. This phenomenon explains why any therapeutic intervention, diet, insulin or drugs, improves both insulin secretion and action. Glucose toxicity may also contribute to the progressive worsening of hyperglycaemia that characterizes the natural course of NIDDM.