A strong genetic component of the beta-cell defect of type 2 diabetes is undisputed. We recently developed a modification of the classic hyperglycemic clamp to assess beta-cell function in response to various stimuli (10 mmol/l glucose, additional glucagon-like peptide [GLP]-1, and arginine). Subjects at risk for developing type 2 diabetes (impaired glucose-tolerant individuals, women with gestational diabetes, and individuals with a family history of type 2 diabetes) clearly showed a significantly decreased mean secretory response to all secretagogues compared with controls. We also showed that normal glucose-tolerant carriers of the Gly972Arg polymorphism in the insulin receptor substrate 1 have significantly reduced insulin secretion in response to glucose and arginine but not to GLP-1. More remarkably, however, the relative impairment of the different secretory phases varied greatly in the same individual, indicating a substantial heterogeneity of beta-cell dysfunction. Specific prominence of this heterogeneity may reflect a specific cellular defect of the beta-cell. In subjects sharing this pattern of heterogeneity, any underlying genetic variant may be enriched and thus more likely not only to be identified but also to be related to a pathophysiological mechanism. In conclusion, we believe that careful clinical characterization of beta-cell function (and dysfunction) is one way of identifying and understanding the genetic factors leading to the insulin secretory failure of type 2 diabetes.