ATP6V1H deficiency impairs glucose tolerance by augmenting endoplasmic reticulum stress in high fat diet fed mice

Vacuolar H⁺-ATPase (V-ATPase) is a ubiquitous proton pump that mediates the proton transmembrane transportation in various cells. Previously, H subunit of V-ATPase (ATP6V1H) was found to be related with insulin secretion and diabetes. However, the mechanism by which ATP6V1H regulates insulin secretion and glucose metabolism remains unclear. Herein, we established a high-fat-diet (HFD) fed model with Atp6v1h^+/- mice and detected the expression and secretion of insulin and some biochemical indices of glucose metabolism, in order to explore the related mechanisms in β-cells. Transcriptome sequencing, qPCR and western blot analysis showed that ATP6V1H deficiency worsened fatty acid-induced glucose tolerance impairment by augmenting endoplasmic reticulum stress in β-cells, and alternative splicing of ATP6V1H might be involved in this process. These results indicated that ATP6V1H deficiency increased the susceptibility to T2DM.