β-Cell Failure in Type 2 Diabetes: A Case of Asking Too Much of Too Few?

The islet in type 2 diabetes (T2DM) is characterized by a deficit in beta-cells, increased beta-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide (IAPP). In the absence of longitudinal studies, it is unknown if the low beta-cell mass in T2DM precedes diabetes onset (is a risk factor for diabetes) or develops as a consequence of the disease process. Although insulin resistance is a risk factor for T2DM, most individuals who are insulin resistant do not develop diabetes. By inference, an increased beta-cell workload results in T2DM in some but not all individuals. We propose that the extent of the beta-cell mass that develops during childhood may underlie subsequent successful or failed adaptation to insulin resistance in later life. We propose that a low innate beta-cell mass in the face of subsequent insulin resistance may expose beta-cells to a burden of insulin and TAPP biosynthetic demand that exceeds the cellular capacity for protein folding and trafficking. If this threshold is crossed, intracellular toxic IAPP membrane permeant oligomers (cylindrins) may form, compromising beta-cell function and inducing beta-cell apoptosis. Diabetes 62:327-335, 2013