Hypoxia leads to insufficient insulin secretion and worsens diabetes mellitus — Mechanism revealed by Kumamoto University

Chronic hyperglycemia (diabetes mellitus), which impairs pancreatic β-cell survival and insulin secretion function, worsens diabetes mellitus. However, the mechanism of this phenomenon is mostly unknown. A research group led by Assistant Professor Tomonori Tsuyama and Professor Kazuya Yamagata of the Faculty of Life Sciences at Kumamoto University revealed the mechanism by which chronic hyperglycemia impairs insulin secretion from pancreatic β-cells. These findings are expected to lead to the development of novel preventive and therapeutic approaches for diabetes mellitus. These study results were published in EMBO Reports.

The study group performed a comprehensive analysis of pancreatic β-cell genes whose expression levels change when exposed to a hypoxic stimulus. The expression of the gene BHLHE40 in pancreatic β-cells is significantly increased under hypoxic conditions. The increased expression of the BHLHE40 gene in pancreatic β-cells was also identified in diabetic mice. Under stress conditions other than hypoxia, increased expression of the BHLHE40 gene was not observed. These findings suggest that, under a diabetic condition in pancreatic β-cells, the BHLHE40 gene responds specifically to a hypoxic stimulus by increasing its expression.

Next, the research group examined the function of the BHLHE40 gene in pancreatic β-cells and revealed that it inhibits insulin secretion by pancreatic β-cells under a hypoxic stimulus. The group further examined the mechanism of this phenomenon and found that the BHLHE40 gene inhibits insulin secretion by suppressing MAFA gene expression, which is essential for insulin secretion.

To explore whether this mechanism significantly influences the pathology of diabetes mellitus, the research group generated a BHLHE40 knock-out diabetic mouse model. The diabetic mice with BHLHE40 knock-out exhibited recovered MAFA expression and increased insulin secretion. In response, improved systemic glucose metabolism was observed.

This study revealed that hypoxic stress is one cause of glucotoxicity−induced impaired insulin secretion in pancreatic β-cells. Based on these findings of the hypoxia response mechanism in pancreatic β-cells, the development of novel preventive and therapeutic approaches for diabetes mellitus is expected. The research group will further examine the hypoxia response in pancreatic β-cells and develop approaches to control the mechanism.

Journal Information
Publication: EMBO reports
Title: Hypoxia causes pancreatic β-cell dysfunction and impairs insulin secretion by activating the transcriptional repressor BHLHE40
DOI: 10.15252/embr.202256227