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bioRxiv · 10.1101/2022.04.05.487203

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

Lin, H.·Suzuki, K.·Smith, N.·Li, X.·Nalbach, L.·Fuentes, S.·Spigelman, A. F.·Dai, X.-Q.·Bautista, A.·Ferdaoussi, M.·Aggarwal, S.·Pepper, A. R.·Roma, L. P.·Ampofo, E.·Li, W.-h.·MacDonald, P. E.
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Abstract

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.

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Lin, H., Suzuki, K., Smith, N., Li, X., Nalbach, L., Fuentes, S., Spigelman, A. F., Dai, X.-Q., Bautista, A., Ferdaoussi, M., Aggarwal, S., Pepper, A. R., Roma, L. P., Ampofo, E., Li, W.-h., MacDonald, P. E.. 2022-04-06. Redox sensing by SENP1 augments insulin secretion early after high-fat feeding in mice. https://doi.org/10.1101/2022.04.05.487203

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