A newly identified mutation in the TMEM167A gene has been shown to disrupt β cell insulin secretion and increase vulnerability to endoplasmic reticulum (ER) stress, offering new insight into the genetic mechanisms underlying neonatal diabetes. These findings were presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting.

The study demonstrated that while the overall differentiation of beta cells was not affected, the mutant cells displayed significant functional impairments. Single-cell RNA sequencing revealed downregulation of CREB3L2, key transcription factors RFX6 and PAX6, and genes involved in insulin processing and secretion. Functional testing showed halved insulin content and reduced secretion in response to glucose and GLP-1 stimulation. Mutant beta cells also underwent more apoptosis when exposed to ER stressors.

In vivo experiments further confirmed the defect: human C-peptide levels were nearly absent in mice transplanted with TMEM167A mutant beta cells, compared to robust secretion from healthy cells.

These findings highlight the critical role of ER-to-Golgi trafficking and the ER stress response in beta-cell function, offering new avenues for understanding and potentially treating neonatal diabetes caused by TMEM167A mutations.