| First Author | Deguchi-Horiuchi H | Year | 2023 |
| Journal | Sci Rep | Volume | 13 |
| Issue | 1 | Pages | 7291 |
| PubMed ID | 37147373 | Mgi Jnum | J:353808 |
| Mgi Id | MGI:7481784 | Doi | 10.1038/s41598-023-34336-z |
| Citation | Deguchi-Horiuchi H, et al. (2023) Pancreatic beta-cell glutaminase 2 maintains glucose homeostasis under the condition of hyperglycaemia. Sci Rep 13(1):7291 |
| abstractText | Glutaminase 2 (GLS2), a master regulator of glutaminolysis that is induced by p53 and converts glutamine to glutamate, is abundant in the liver but also exists in pancreatic beta-cells. However, the roles of GLS2 in islets associated with glucose metabolism are unknown, presenting a critical issue. To investigate the roles of GLS2 in pancreatic beta-cells in vivo, we generated beta-cell-specific Gls2 conditional knockout mice (Gls2 CKO), examined their glucose homeostasis, and validated the findings using a human islet single-cell analysis database. GLS2 expression markedly increased along with p53 in beta-cells from control (RIP-Cre) mice fed a high-fat diet. Furthermore, Gls2 CKO exhibited significant diabetes mellitus with gluconeogenesis and insulin resistance when fed a high-fat diet. Despite marked hyperglycaemia, impaired insulin secretion and paradoxical glucagon elevation were observed in high-fat diet-fed Gls2 CKO mice. GLS2 silencing in the pancreatic beta-cell line MIN6 revealed downregulation of insulin secretion and intracellular ATP levels, which were closely related to glucose-stimulated insulin secretion. Additionally, analysis of single-cell RNA-sequencing data from human pancreatic islet cells also revealed that GLS2 expression was elevated in beta-cells from diabetic donors compared to nondiabetic donors. Consistent with the results of Gls2 CKO, downregulated GLS2 expression in human pancreatic beta-cells from diabetic donors was associated with significantly lower insulin gene expression as well as lower expression of members of the insulin secretion pathway, including ATPase and several molecules that signal to insulin secretory granules, in beta-cells but higher glucagon gene expression in alpha-cells. Although the exact mechanism by which beta-cell-specific GLS2 regulates insulin and glucagon requires further study, our data indicate that GLS2 in pancreatic beta-cells maintains glucose homeostasis under the condition of hyperglycaemia. |
