The role of the BHLHE40 gene
The researchers first carried out an experiment to understand the impact of hypoxia on global gene expression of human and mice β-cells in order to search for genes whose expression varied in response to the created hypoxic conditions. They discovered that the expression of a gene called BHLHE40 is elevated under hypoxic conditions. This gene codes for the protein BHLHE40 that acts as a ‘transcriptional repressor’, a molecule that reduces the expression of other genes.
The researchers then investigated the role of BHLHE40 in pancreatic β-cells. They found that when it was overexpressed, BHLHE40 impaired insulin secretion by reducing the expression of genes involved in β-cell function, a prominent one among them being musculoaponeurotic fibrosarcoma oncogene
family A (MAFA).
Further, in order to confirm their findings in vivo, the researchers removed BHLHE40 gene from a diabetic mouse model. They noted that deletion of BHLHE40 not only restored the expression of MAFA, but also increased insulin secretion and improved the mice’s ability to metabolize glucose.
Elucidating the mechanism through which BHLHE40 affects the progression of T2D, the researchers concluded that hyperglycaemia-induced glycotoxicity in pancreatic β-cells led to low-oxygen conditions that resulted in increased expression of BHLHE40, followed by the inhibition of MAFA, and the subsequent disruption of insulin secretion. Restoration of insulin secretion in mice deficient in BHLHE40 confirmed that targeting this gene can reverse β-cell dysfunction and may prove to be a promising candidate for newer therapies against T2D.
Discussing their study, Dr Tsuyama emphasized: “These findings provide valuable insights into the molecular mechanisms underlying hypoxia-induced β-cell dysfunction. By targeting the gene BHLHE40, we may be able to develop new therapies aimed at preserving β-cell function and ultimately slow down the progression of T2D.”
The findings of their study are published in the June 21, 2023 issue of EMBO Reports: https://doi.org/10.15252/embr.202256227