Proinsulin misfolding is an early event in the progression to type 2 diabetes

Elife. 2019 Jun 11;8:e44532. doi: 10.7554/eLife.44532.

Abstract

Biosynthesis of insulin - critical to metabolic homeostasis - begins with folding of the proinsulin precursor, including formation of three evolutionarily conserved intramolecular disulfide bonds. Remarkably, normal pancreatic islets contain a subset of proinsulin molecules bearing at least one free cysteine thiol. In human (or rodent) islets with a perturbed endoplasmic reticulum folding environment, non-native proinsulin enters intermolecular disulfide-linked complexes. In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks with the onset of islet insulin deficiency and diabetes. Proinsulin-Cys(B19) and Cys(A20) are necessary and sufficient for the formation of proinsulin disulfide-linked complexes; indeed, proinsulin Cys(B19)-Cys(B19) covalent homodimers resist reductive dissociation, highlighting a structural basis for aberrant proinsulin complex formation. We conclude that increased proinsulin misfolding via disulfide-linked complexes is an early event associated with prediabetes that worsens with ß-cell dysfunction in type two diabetes.

Keywords: GRP78; cell biology; disulfide bonds; endoplasmic reticulum; mouse; prediabetes; protein trafficking.

Publication types

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

MeSH terms

  • Animals
  • Cysteine / chemistry
  • Cysteine / genetics
  • Cysteine / metabolism
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Progression
  • Disulfides / chemistry
  • Disulfides / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Proinsulin / chemistry*
  • Proinsulin / genetics
  • Proinsulin / metabolism
  • Protein Folding*
  • Receptors, Leptin / deficiency
  • Receptors, Leptin / genetics

Substances

  • Disulfides
  • Receptors, Leptin
  • Proinsulin
  • Cysteine