The pathogenesis of type 2 diabetes is complex and in most instances clearly requires defects in both ß-cell function and insulin sensitivity (1). Together, these abnormalities result in increased rates of glucose release by the liver and kidney as well as decreased clearance from the circulation (2, 3). For the last decade, a great deal of attention has been directed at further understanding the role of insulin resistance as an important contributor to the development and maintenance of the hyperglycemia of type 2 diabetes. During this same period, the well described vital role of the pancreatic islet, and specifically the ß-cell, in this process has been largely neglected.

Perhaps one of the most striking and sobering findings of the United Kingdom Prospective Diabetes Study (UKPDS) was the reaffirmation of the clinically recognized progressive nature of type 2 diabetes (4). Every day clinicians all over the world find themselves struggling to maintain good glycemic control in subjects with type 2 diabetes, and the results of this study clearly confirm that, even with the use of algorithmic approaches aimed at maintaining superb glucose control, it is very difficult to maintain individuals at the desired levels of glycemia. In fact, in the UKPDS after 9 yr only 25% of the subjects in the intensive treatment arm were achieving a HbA1c less than 7% with monotherapy alone (5). When one examines the outcome in the different groups based on their initial assignment, this goal was attained in 8% of subjects given dietary therapy, 13% receiving metformin, 24% taking sulfonylureas, and 42% of individuals using insulin. The reason (s) for the progressive deterioration in glycemic control observed in the UKPDS have been addressed using the Homeostasis Model Assessment (HOMA). This model provides a simple approach for estimating insulin sensitivity and ß-cell function and lends itself to use in large studies such as the UKPDS. With this approach, the UKPDS has clearly demonstrated that the progressive nature of diabetes in this cohort of individuals with recently diagnosed type 2 diabetes is an ongoing decline in ß-cell function without a change in insulin sensitivity (6, 7). It is of interest that a similar observation was made in the Belfast diet intervention study in which the progressive deterioration of glycemic