Normal and defective pathways in biogenesis and maintenance of the insulin storage pool

Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic beta cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting beta cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of beta cell identity), or beta cell dedifferentiation, or beta cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for beta cell failure in type 1 diabetes.

Automated summary

Both basal and glucose-stimulated insulin release primarily occur through insulin secretory granule exocytosis from pancreatic beta cells, which are essential for maintaining normal blood glucose levels. Loss of insulin-secreting beta cells may result from exhaustion of insulin reserves or beta cell dedifferentiation, affecting glycemic control. Defects in biosynthetic generation and maintenance of the total insulin granule pool can also contribute to diabetes risk.