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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.