Overstimulation and beta-cell function

Previous and present evidence ascribes an important role to overstimulation of beta -cells for the secretory abnormalities associated with type 2 diab etes. The abnormality most clearly linked to overstimulation is the elevate d ratio of circulating proinsulin to insulin. Evidence obtained in human pa ncreatic islets suggests that aberrations in insulin oscillations that occu r in type 2 diabetes could at least in part be linked to abnormalities in c ytoplasmic Ca2+ oscillations induced by overstimulation. Furthermore, in a transplantation model, we have obtained evidence for long-lasting, perhaps irreversible, effects of overstimulation, implying that this is a causative factor for the well-recognized deterioration of insulin secretion with inc reasing duration of type 2 diabetes. The mechanisms behind the effects of o verstimulation are only partly clarified, but it is clear that reduced insu lin secretion after overstimulation is only partly explained by decreased i nsulin stores. In cultured human pancreatic islets, overstimulation by high glucose leads to a rise in cytoplasmic Ca2+ levels, which persists after n ormalization of the glucose levels. Persistent elevation of cytoplasmic Ca2 + may trigger apoptosis, thus participating in long-term irreversible deter ioration of beta -cell function. These data provide sufficient rationale fo r clinical studies to test the beneficial effects of relative beta -cell re st in type 2 diabetic patients.