Hypoxia causes pancreatic β-cell dysfunction by activating a transcriptional repressor BHLHE40

Hypoxia can occur in pancreatic {beta}-cells in type 2 diabetes. Although hypoxia exerts deleterious effects on {beta}-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 {beta}-cells and suppresses insulin secretion. Conversely, BHLHE40 deficiency in hypoxic MIN6 cells or in the {beta}-cells of ob/ob mice reversed the insulin secretion. Mechanistically, BHLHE40 represses expression of Mafa, which encodes the transcription factor musculoaponeurotic fibrosarcoma oncogene family A (MAFA), by attenuating binding of pancreas/duodenum homeobox protein 1 (PDX1) to its enhancer region. Impaired insulin secretion in hypoxic {beta}-cells was recovered by MAFA expression. Collectively, this work identifies BHLHE40 as a key hypoxia-induced transcriptional repressor in {beta}-cells and its implication in the {beta}-cell dysfunction in type 2 diabetes.