Altogether, our analysis of islet metabolism and transcriptionally defined β cell states builds the working model that SIRT2 deacetylates metabolic enzymes to restrain OxPhos during S961 treatment, and this direct effect of SIRT2 on metabolism is reflected by transcriptional changes indicating differences in the stress response of β cells to hyperglycemia. Here, SIRT2 is linked to Hyperglycemia.