Ferdaoussi, M. | bioRxiv Science

bioRxiv2022

Redox sensing by SENP1 augments insulin secretion early after high-fat feeding in mice

Pancreatic {beta}-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. In {beta}-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. {beta}-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 {beta}-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 {beta}-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 {beta}-cell exocytosis and increases SENP1 sensitivity to regulation by redox signals.

cell biology↗

bioRxiv2020

β-cell SENP1 facilitates responsiveness to incretins and limits oral glucose intolerance in high fat fed mice

SUMOylation reduces oxidative stress and preserves islet mass; but this happens at the expense of robust insulin secretion. To investigate a role for the deSUMOylating enzyme sentrin-specific protease 1 (SENP1) in glycemia following metabolic stress, we put pancreas/gut-specific SENP1 knockout mice (pSENP1-KO) on an 8-10-week high fat diet (HFD). Male pSENP1-KO mice were more glucose intolerant following HFD than littermate controls, but this was only obvious in response to oral glucose, and a similar but milder phenotype was observed in females. Plasma incretin responses were identical, and glucose-dependent insulinotropic polypeptide (GIP) was equally upregulated after HFD, in pSENP1-KO and - WT littermates. Islet mass was not different, but insulin secretion and {beta}-cell exocytotic responses to Exendin4 (Ex4) and GIP were impaired in islets lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, consistent with the expected SENP1 knockout in all islet cells, so we generated {beta}-cell-specific SENP1 knockout mice ({beta}SENP1-KO). These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired {beta}-cell exocytosis and insulin secretion to Ex4 and GIP. Thus, {beta}-cell SENP1 limits glucose intolerance following HFD by ensuring a robust facilitation of insulin secretion by incretins such as GIP.

physiology↗