Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2

Cell Rep. 2020 May 5;31(5):107609. doi: 10.1016/j.celrep.2020.107609.

Abstract

During early obesity, pancreatic β cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We find evidence that β cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by O-GlcNAc transferase (OGT), is critical for coupling hyperlipidemia to β cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises and falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of β-cell-specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identify the endoplasmic reticulum (ER) Ca2+ ATPase SERCA2 as a β cell O-GlcNAcylated protein in mice and humans that is able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for β cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor.

Publication types

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

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / metabolism
  • Endoplasmic Reticulum / metabolism
  • Insulin / metabolism*
  • Insulin Secretion / physiology*
  • Insulin-Secreting Cells / metabolism
  • Lipids*
  • Mice
  • Obesity / metabolism
  • Protein Processing, Post-Translational
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*

Substances

  • Blood Glucose
  • Insulin
  • Lipids
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Atp2a2 protein, mouse