Regulation of the production and secretion of insulin

Normal glucose homeostasis depends on the coordinated regulation of insulin production and secretion. Insulin is stored in the pancreatic β-cell until an appropriate stimulus triggers its release. Consequently, a parallel stimulation of proinsulin biosynthesis is necessary to replenish the intracellular insulin stores. Among the diverse insulin secretagogues, glucose is the most physiologically relevant stimulus for insulin secretion and proinsulin biosynthesis. Under normal physiologic circumstances, glucose stimulates proinsulin biosynthesis mainly at the translational level. The regulation of glucosestimulated proinsulin translation seems to rest in the 5’and 3’untranslated regions (UTRs) of the preproinsulin mRNA molecule. Recently, it has been demonstrated that the translation of preproinsulin mRNA variants, which lack the 5’-UTR, the 3’-UTR or both, is dramatically inhibited. It seems that there is cooperativity between the 5’and 3’-UTRs, likely by their interaction with trans-acting factors. Nevertheless, the stimulus-coupling mechanism for glucose-stimulated proinsulin biosynthesis is unfortunately very poorly understood. Glucose metabolism is necessary for proinsulin biosynthesis stimulation. In the β-cell, glucose undergoes glycolysis in the cytosol and then oxidative phosphorylation in the mitochondria. Stimulus-coupling secondary signals originated in the mitochondria are necessary for the regulation of proinsulin biosynthesis. ATP is required for general protein translation, but it is not a specific signal for glucose-induced proinsulin biosynthesis. Currently, succinate and/or succinylCoA are the most promising candidates as the mitochondria originated stimulus-coupling signal specific for glucose-stimulated proinsulin biosynthesis. Whether succinate, succinyl-CoA or other downstream signals are the trans-acting factors necessary for the stimulation of preproinsulin mRNA translation remains to be demonstrated.