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 dex-trorphan (DXO) or glibenclamide enhances GSIS, whereas chronic treatment with high concentrations of these drugs reduces 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 NAPDH/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.

Automated summary

Type 2 diabetes is characterized by excessive and then reduced insulin secretion. The insulin secretagogues DXO and glibenclamide can enhance glucose-stimulated insulin secretion acutely, but reduce it chronically while protecting islets from cell death. Long-term stimulation of islets leads to increased expression of serine-linked mitochondrial OCM genes, altered metabolism, and activation of Atf4, which is required for islet protection and reduces insulin secretion.