Defects in insulin secretion are central to the pathogenesis of type 2 diabetes (T2D) but the molecular basis and physiological consequences of those defects are poorly understood, impeding efforts to develop novel therapeutic approaches. Key questions remain unanswered, such as the extent to which T2D-associated islet dysfunction reflects endogenous defects in beta-cell mass or function, as opposed to disruption of external factors impinging on the beta-cells, such as incretins.