Pancreatic islet protection at the expense of secretory function associates with serine-linked one-carbon metabolism

Type 2 diabetes (T2D) is the most common metabolic disease worldwide and is characterized by insulin hypersecretion, followed by reduced glucose-stimulated insulin secretion (GSIS). Even though much has been discovered about insulin producing beta cell physiology, the molecular mechanisms behind beta cell decay in T2D are still unknown and no anti-diabetic drug is available to fully halt or reverse this process. Here, we show that short-term in vitro stimulation of mouse pancreatic islets with insulin secretagogue dextrorphan (DXO) enhances GSIS, but does not protect islets from cell death. In contrast, long-term insulin hypersecretion induced by DXO reduces GSIS, but protects islets from cell death. Bulk RNA sequencing of islets reveals increased expression of genes encoding enzymes of the serine-linked mitochondrial one-carbon metabolism (OCM) after long-term, but not short-term stimulation. In long-term stimulated islets, more glucose was metabolized to serine than citrate, and mitochondrial concentrations of ATP decreased, despite unaltered oxygen consumption, while NAPDH increased. Activating transcription factor-4 (Atf4) is shown to be required and sufficient to activate serine-linked mitochondrial OCM genes in islets, and gain- and loss-of-function experiments revealed that Atf4 reduces GSIS and is necessary, but not solely sufficient for full DXO-mediated islet cell protection. Furthermore, we show that de novo serine synthesis enzyme phosphoglycerate dehydrogenase (Phgdh) and enzymes of the mitochondrial OCM, such as serine hydroxymethyltransferase 2 (Shmt2) and methylenetetrahydrofolate dehydrogenase 2 (Mthfd2), reduce GSIS and regulate islet cell death. In summation, we identified a reversible metabolic pathway associated with islet cell protection at expense of secretory function.