Evolution of beta-cell dysfunction in impaired glucose tolerance and diabetes

Patients with overt Type 2 diabetes consistently have alterations in insuli n secretion, including reduced insulin secretory responses to glucose, dela yed and blunted meal-induced insulin secretion, increased pro-insulin and a bnormal insulin secretory oscillations. More recently, it has become eviden t that abnormal insulin secretion antedates the onset of overt hyperglycaem ia and is present in people with impaired glucose tolerance, i.e. normal fa sting glucose and glycohaemoglobin concentrations. These defects are subtle and include shifts to the right in the dose-response curves that relate to glucose and insulin secretion, reduced ability of the beta-cell to detect and respond to oscillatory changes in the plasma glucose concentration and impaired beta-cell compensation for insulin resistance. In order to define the factors responsible for these defects in secretion, we have infused hum an patients with a lipid emulsion and heparin to raise plasma free fatty ac id concentrations. This is associated with reduced ability of the beta-cell to detect and respond to small changes in the plasma glucose concentration . In summary, defects in insulin secretion are consistently present in pati ents with impaired glucose tolerance and play a critical role in the progre ssion from impaired glucose tolerance to diabetes.