PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity

Elife. 2019 Jun 11;8:e44528. doi: 10.7554/eLife.44528.

Abstract

Regulated proinsulin biosynthesis, disulfide bond formation and ER redox homeostasis are essential to prevent Type two diabetes. In ß cells, protein disulfide isomerase A1 (PDIA1/P4HB), the most abundant ER oxidoreductase of over 17 members, can interact with proinsulin to influence disulfide maturation. Here we find Pdia1 is required for optimal insulin production under metabolic stress in vivo. ß cell-specific Pdia1 deletion in young high-fat diet fed mice or aged mice exacerbated glucose intolerance with inadequate insulinemia and increased the proinsulin/insulin ratio in both serum and islets compared to wildtype mice. Ultrastructural abnormalities in Pdia1-null ß cells include diminished insulin granule content, ER vesiculation and distention, mitochondrial swelling and nuclear condensation. Furthermore, Pdia1 deletion increased accumulation of disulfide-linked high molecular weight proinsulin complexes and islet vulnerability to oxidative stress. These findings demonstrate that PDIA1 contributes to oxidative maturation of proinsulin in the ER to support insulin production and ß cell health.

Keywords: PDIA1; beta cell function; cell biology; disulfide bond formation; glucose homeostasis; mouse; proinsulin maturation; type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet, High-Fat / adverse effects
  • Disulfides / metabolism
  • Endoplasmic Reticulum / metabolism
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondrial Swelling
  • Obesity / etiology
  • Obesity / genetics
  • Obesity / metabolism*
  • Oxidative Stress
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism*
  • Proinsulin / metabolism*
  • Protein Disulfide-Isomerases / genetics
  • Protein Disulfide-Isomerases / metabolism*

Substances

  • Disulfides
  • Insulin
  • Proinsulin
  • Procollagen-Proline Dioxygenase
  • P4hb protein, mouse
  • Protein Disulfide-Isomerases