The balance between proinsulin biosynthesis and insulin secretion: Where can imbalance lead?

Insulin is stored in pancreatic β-cells in β-granules. Whenever insulin is secreted in response to a nutrient secretagogue, there is a complementary increase in proinsulin biosynthesis to replenish intracellular insulin stores. This specific nutrient regulation of proinsulin biosynthesis is predominately regulated at the translational level. Recently, a highly conserved cis-element in the 5′-untranslated region (UTR) of preproinsulin mRNA, named ppIGE, has been identified that is required for specific translational regulation of proinsulin biosynthesis. This ppIGE is also found in the 5′-UTR of certain other translationally regulated β-granule protein mRNAs, including the proinsulin processing endopeptidases, PC1/3 and PC2. This provides a mechanism whereby proinsulin processing is adaptable to changes in proinsulin biosynthesis. However, relatively few β-granules undergo secretion, with most remaining in the storage pool for ∼5 days. Aged β-granules are retired by intracellular degradation mechanisms, either via crinophagy and/or autophagy, as another long-term means of maintaining β-granule stores at optimal levels. When a disconnection between insulin production and secretion arises, as may occur in type 2 diabetes, autophagy further increases to maintain β-granule numbers. However, if this increased autophagy becomes chronic, autophagia-mediated cell death occurs that could then contribute to β-cell loss in type 2 diabetes.