Hypoxia causes pancreatic β-cell dysfunction and impairs insulin secretion by activating the transcriptional repressor BHLHE40

EMBO Rep. 2023 Aug 3;24(8):e56227. doi: 10.15252/embr.202256227. Epub 2023 Jun 21.

Abstract

Hypoxia can occur in pancreatic β-cells in type 2 diabetes. Although hypoxia exerts deleterious effects on β-cell function, the associated mechanisms are largely unknown. Here, we show that the transcriptional repressor basic helix-loop-helix family member e40 (BHLHE40) is highly induced in hypoxic mouse and human β-cells and suppresses insulin secretion. Conversely, BHLHE40 deficiency in hypoxic MIN6 cells or β-cells of ob/ob mice reverses defects in insulin secretion. Mechanistically, BHLHE40 represses the expression of Mafa, encoding the transcription factor musculoaponeurotic fibrosarcoma oncogene family A (MAFA), by attenuating the binding of pancreas/duodenum homeobox protein 1 (PDX1) to its enhancer region. Impaired insulin secretion in hypoxic β-cells was recovered by MAFA re-expression. Collectively, our work identifies BHLHE40 as a key hypoxia-induced transcriptional repressor in β-cells that inhibit insulin secretion by suppressing MAFA expression.

Keywords: BHLHE40; hypoxia; insulin secretion; pancreatic β-cells; transcriptional repressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells* / metabolism
  • Mice
  • Mice, Inbred Strains
  • Pancreas / metabolism

Substances

  • Insulin
  • Homeodomain Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • BHLHE40 protein, human

Associated data

  • GEO/GSE202603