Pancreatic islet protection at the expense of secretory function involves serine-linked mitochondrial one-carbon metabolism.

ABSTRACT: Type 2 diabetes is characterized by insulin hypersecretion followed by reduced glucose-stimulated insulin secretion (GSIS). Here we show that acute stimulation of pancreatic islets with the insulin secretagogue dextrorphan (DXO) or glibenclamide enhances GSIS, whereas chronic treatment with high concentrations of these drugs reduce GSIS but protect islets from cell death. Bulk RNA sequencing of islets shows increased expression of genes for serine-linked mitochondrial one-carbon metabolism (OCM) after chronic, but not acute, stimulation. In chronically stimulated islets, more glucose is metabolized to serine than to citrate, and the mitochondrial ATP/ADP ratio decreases, whereas the NADPH/NADP⁺ ratio increases. Activating transcription factor-4 (Atf4) is required and sufficient

SUBMITTER: Pelligra A 

PROVIDER: S-EPMC10592470 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature