Translational regulation of proinsulin biosynthesis and proinsulin conversion in the pancreatic beta-cell

Abstract

Insulin secretion from the pancreatic beta -cell can be initiated in minutes, vary as much as 50-100-fold, and be sustained for several hours without need for changes in insulin gene transcription. Remarkably, the cellular content of the hormone and its molecular composition do not vary appreciably in the face of changes of insulin granule exocytosis. Minimal morphological changes are apparent, further indicating that the movement of lipids and membrane proteins between the granule storage pool, the plasma membrane, and Golgi are likewise tightly controlled. Such homeostasis is achieved by an interplay of signaling pathways originating from the metabolism of glucose with downstream targets at the level of translation of dense-core granule proteins, granule biogenesis, and membrane trafficking. Our scant knowledge in this area is confined mostly to a descriptive account of the fate of the major secreted components, principally insulin and the enzymes PC1, PC2, and CPH involved in the proteolytic conversion of proinsulin to insulin. A common theme seems to be the role of intracellular energy homeostasis in integrating the stimulus-secretion and stimulus-biosynthetic responses of this cell.