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

Y. Uchizono, C. Alarcón, B. L. Wicksteed, B. J. Marsh, Christopher J. Rhodes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)56-66
Number of pages11
JournalDiabetes, Obesity and Metabolism
Volume9
Issue numberSUPPL. 2
DOIs
StatePublished - Nov 2007

Keywords

  • Autophagy
  • Insulin secretion
  • Pancreatic islets
  • Proinsulin synthesis
  • Type 2 diabetes
  • β-cells

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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