ß-cell responses to high fat feeding in mice: A role and mechanism for redox sensing by SENP1

Pancreatic ß-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. In ß-cells from overweight humans without diabetes, and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca2+ influx. ß-cell RNA-seq suggests altered metabolic pathways early following HFD, where we find increased basal oxygen consumption, proton leak, but a more reduced cytosolic redox state. Increased ß-cell exocytosis after 2-day HFD is dependent on this reduced intracellular redox, and requires the sentrin-specific SUMO-protease-1 (SENP1). Mice with either pancreas- or ß-cell-specific SENP1 deletion fail to up-regulate exocytosis and become rapidly glucose intolerant after 2-day HFD. Mechanistically, redox-sensing by SENP1 requires a thiol group at C535 which together with Zn+-binding suppresses basal protease activity and unrestrained ß-cell exocytosis, and increases SENP1 sensitivity to regulation by redox signals. Overall design: Mice were fed chow diet (n=4) or high fat diet (n=3) for 2 days. Pancreatic islet ß-cells were sorted by FACS and then used for RNA-sequenicng.