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

Diabetes Obes Metab. 2007 Nov;9 Suppl 2:56-66. doi: 10.1111/j.1463-1326.2007.00774.x.

Abstract

Insulin is stored in pancreatic beta-cells in beta-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 beta-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 beta-granules undergo secretion, with most remaining in the storage pool for approximately 5 days. Aged beta-granules are retired by intracellular degradation mechanisms, either via crinophagy and/or autophagy, as another long-term means of maintaining beta-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 beta-granule numbers. However, if this increased autophagy becomes chronic, autophagia-mediated cell death occurs that could then contribute to beta-cell loss in type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics
  • Autophagy / physiology*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism*
  • Proinsulin / biosynthesis*
  • Proprotein Convertase 1 / metabolism
  • Proprotein Convertase 2 / metabolism
  • RNA, Messenger / metabolism

Substances

  • Insulin
  • RNA, Messenger
  • Proinsulin
  • Proprotein Convertase 1
  • Proprotein Convertase 2