Cell Reports (May 2020)

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

  • Amber Lockridge,
  • Seokwon Jo,
  • Eric Gustafson,
  • Niklas Damberg,
  • Ramkumar Mohan,
  • Miranda Olson,
  • Juan E. Abrahante,
  • Emilyn U. Alejandro

Journal volume & issue
Vol. 31, no. 5

Abstract

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Summary: 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.