Role of Reduced β-Cell Mass Versus Impaired β-Cell Function in the Pathogenesis of Type 2 Diabetes

Although it has long been assumed that insulin resistance is the leading factor in the pathogenesis of type 2 diabetes (1), evidence for the importance of the pancreatic β-cells has accumulated over the past decades. In fact, the vast majority of genes associated with type 2 diabetes have been linked to the β-cell, and impairments in β-cell mass and in insulin secretion have been reported in numerous studies in patients with type 2 diabetes. One misconception that has prevented the appreciation of the β-cell defects for a long time is the idea of a “hyperinsulinemia” in patients with type 2 diabetes. This concept has arisen from the observation that patients with type 2 diabetes often present with higher fasting insulin concentrations than nondiabetic individuals. However, if insulin concentrations are interpreted in the context of the concurrently elevated glucose levels in patients with type 2 diabetes, a relative insulin deficit rather than hyperinsulinemia becomes apparent. Furthermore, when insulin secretion is evaluated under stimulated conditions (e.g., after intravenous glucose administration), the typical defects, especially in early-phase insulin release, can be unmasked (2,3). It has also been suggested that obesity causes type 2 diabetes through impaired insulin action. Undoubtedly, the risk of developing type 2 diabetes increases markedly with BMI. However, if obesity were really the cause of type 2 diabetes, one would expect the vast majority of obese individuals to develop hyperglycemia, whereas in reality ∼80% of obese individuals remain free of diabetes (4). These findings suggest that obesity and insulin resistance are indeed important cofactors that increase the individual risk of diabetes but that the actual cause of the disease seems to be clearly linked to the β-cells. If one accepts this notion, the next question is whether β-cell defects are primarily functional in nature or whether a …