Proinsulin entry and transit through the endoplasmic reticulum in pancreatic beta cells

Vitam Horm. 2014;95:35-62. doi: 10.1016/B978-0-12-800174-5.00002-8.

Abstract

Insulin is an essential hormone for maintaining metabolic homeostasis in the body. To make fully bioactive insulin, pancreatic beta cells initiate synthesis of the insulin precursor, preproinsulin, at the cytosolic side of the endoplasmic reticulum (ER), whereupon it undergoes co- and post-translational translocation across the ER membrane. Preproinsulin is cleaved by signal peptidase to form proinsulin that folds on the luminal side of the ER, forming three evolutionarily conserved disulfide bonds. Properly folded proinsulin forms dimers and exits from the ER, trafficking through Golgi complex into immature secretory granules wherein C-peptide is endoproteolytically excised, allowing fully bioactive two-chain insulin to ultimately be stored in mature granules for insulin secretion. Although insulin biosynthesis has been intensely studied in recent decades, the earliest events, including proinsulin entry and exit from the ER, have been relatively understudied. However, over the past 5 years, more than 20 new insulin gene mutations have been reported to cause a new syndrome termed Mutant INS-gene-induced Diabetes of Youth (MIDY). Although these mutants have not been completely characterized, most of them affect proinsulin entry and exit from the ER. Here, we summarize our current knowledge about the early events of insulin biosynthesis and review recent advances in understanding how defects in these events may lead to pancreatic beta cell failure.

Keywords: Diabetes; Endoplasmic reticulum; Pancreatic beta cells; Preproinsulin; Proinsulin; Protein folding; Protein translocation.

Publication types

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

MeSH terms

  • Animals
  • Biological Transport
  • Cytosol / metabolism
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Diabetes Mellitus / physiopathology
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Humans
  • Insulin / biosynthesis
  • Insulin / chemistry
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Models, Biological*
  • Pancreas / cytology
  • Pancreas / pathology
  • Pancreas / physiology
  • Pancreas / physiopathology
  • Proinsulin / biosynthesis
  • Proinsulin / chemistry
  • Proinsulin / metabolism*
  • Protein Folding
  • Protein Precursors / biosynthesis
  • Protein Precursors / chemistry
  • Protein Precursors / metabolism
  • Protein Sorting Signals
  • Proteolysis

Substances

  • Insulin
  • Protein Precursors
  • Protein Sorting Signals
  • preproinsulin
  • Proinsulin