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

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 to activate serine-linked mitochondrial OCM genes in islets, with gain- and loss-of-function experiments showing that Atf4 reduces GSIS and is required, but not sufficient, for full DXO-mediated islet protection. In sum, we identify a reversible metabolic pathway that provides islet protection at the expense of secretory function. [Display omitted] •Chronic insulin secretagogues increase islet viability but decrease secretory function•Insulin secretagogues can enhance serine-linked mitochondrial one-carbon metabolism•High-dose KATP-dependent insulin secretagogue DXO can deviate glucose flux to serine•Phgdh, Mthfd2, and Shmt2 limit insulin secretion but promote islet cell viability Pelligra et al. find that chronic exposure to high doses of KATP-dependent insulin secretagogues protects islets from cell death at the expense of secretory function. Dysfunctional islets upregulate serine-linked OCM genes and glucose flux to serine. Simultaneous knockdown of serine-linked mitochondrial OCM genes enhances insulin secretion but decreases islet viability.