IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function

Nat Commun. 2019 Jun 18;10(1):2679. doi: 10.1038/s41467-019-10444-1.

Abstract

The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by β-cells. In common with amyloidogenic proteins implicated in neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers implicated in misfolded protein stress. Here, we establish that hIAPP misfolded protein stress activates HIF1α/PFKFB3 signaling, this increases glycolysis disengaged from oxidative phosphorylation with mitochondrial fragmentation and perinuclear clustering, considered a protective posture against increased cytosolic Ca2+ characteristic of toxic oligomer stress. In contrast to tissues with the capacity to regenerate, β-cells in adult humans are minimally replicative, and therefore fail to execute the second pro-regenerative phase of the HIF1α/PFKFB3 injury pathway. Instead, β-cells in T2D remain trapped in the pro-survival first phase of the HIF1α injury repair response with metabolism and the mitochondrial network adapted to slow the rate of cell attrition at the expense of β-cell function.

Publication types

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

MeSH terms

  • Adult
  • Animals
  • Animals, Genetically Modified
  • Apoptosis
  • Cell Line, Tumor
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology*
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / physiology*
  • Glycolysis / physiology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin-Secreting Cells / pathology*
  • Islet Amyloid Polypeptide / genetics
  • Islet Amyloid Polypeptide / metabolism*
  • Male
  • Middle Aged
  • Mitophagy / physiology
  • Oxidative Phosphorylation
  • Phosphofructokinase-2 / metabolism
  • Protein Aggregates / physiology
  • Rats
  • Unfolded Protein Response / physiology*

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Islet Amyloid Polypeptide
  • Protein Aggregates
  • PFKFB3 protein, human
  • Phosphofructokinase-2