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

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 in the β-cells ofob/obmice reversed the insulin secretion. Mechanistically, BHLHE40 represses expression ofMafa, 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 β-cells was recovered by MAFA expression. Collectively, this work identifies BHLHE40 as a key hypoxia-induced transcriptional repressor in β-cells and its implication in the β-cell dysfunction in type 2 diabetes.