Type 2 diabetes mellitus is characterized by 4 major metabolic abnormalities: obesity, impaired insulin action, insulin secretory dysfunction, and increased endogenous glucose output (EGO) (1-3). Although there is substantial evidence that the first 3 of these abnormalities are present in most individuals before the onset of diabetes, the sequence with which they develop and their relative contributions to the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), and ultimately to type 2 diabetes (4-6), remain unknown in the absence of a detailed longitudinal study (7)(8)(9)(10)(11)(12). Current understanding of the pathogenesis of type 2 diabetes is based on a large number of cross-sectional (13-25) and prospective (26-40) studies.In cross-sectional studies, subjects with IGT were on average more obese and more insulin-resistant than those with NGT. Basal EGO, largely reflecting hepatic glucose production, was not increased (3,7,8,(13)(14)(15). Whether insulin secretion is impaired in individuals with IGT is controversial. Some studies have found a lower early insulin secretory response (occurring within minutes of an intravenous or oral glucose load) in individuals with IGT compared with those with . Lower early insulin responses have also been demonstrated in first-degree relatives of individuals with type 2 diabetes, a population at high risk for developing diabetes (20)(21)(22). However, others have reported normal or increased early insulin secretion in both groups of individuals (13,14,23,24). Similarly, both lower (18) and higher (25) late insulin responses (2 hours after an oral glucose load) have been reported in subjects with IGT compared with those with NGT. With respect to the pathogenesis of diabetes, such cross-sectional findings must be interpreted with caution, because many individuals with IGT will never develop diabetes, and their metabolic characteristics may well differ from those who do.In recent years, several prospective studies, in which nondiabetic individuals are metabolically characterized on a single occasion and then followed for several years to determine who develops diabetes, have helped to identify metabolic abnormalities that predispose to diabetes. These studies have shown that obesity (27-29, 33-35, 39) and insulin resistance (30-35) predict the development of diabetes in many populations, whereas basal EGO was not predictive in the only study in which it was measured (30). A low early insulin response predicted diabetes in most (30,(35)(36)(37)(38)(39) but not all (31, 32) studies. Together, these results indicate that defects in both insulin action and insulin secretion predispose some individuals with NGT to diabetes, but they give little information about the time course with which these abnormalities change as glucose tolerance worsens.To determine the natural history of insulin secretory dysfunction and insulin resistance during the development of diabetes, and to understand how these factors interact with one another during the developm...