Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes?

Insulin is released from the pancreas in a biphasic manner in response to a square-wave increase in arterial glucose concentration. The first phase consists of a brief spike lasting approximately 10 min followed by the second phase, which reaches a plateau at 2-3 h. It is widely thought that diminution of first-phase insulin release is the earliest detectable defect of beta-cell function in individuals destined to develop type 2 diabetes and that this defect largely represents beta-cell exhaustion after years of compensation for antecedent insulin resistance. In this article, the origins of these concepts are reviewed and recent evidence is presented suggesting that reductions in both phases of insulin release are equally early, that they precede insulin resistance other than that simply due to obesity, and that they therefore may represent the primary genetic risk factor predisposing individuals to type 2 diabetes.