Abstract
Pancreatic β-cells respond to metabolic stress by upregulating insulin secretion, however underlying mechanisms remain unclear. In β-cells from overweight humans without diabetes, and mice fed high-fat diet (HFD) for as little as 2 days, insulin exocytosis and secretion are enhanced without increased Ca2+ influx. β-cell RNA-seq suggests altered metabolic pathways linked to cytosolic redox following HFD. The increased β-cell exocytosis upon HFD is dependent on a shift towards a reduced intracellular redox state, and increased expression of sentrin-specific protease-1 (Senp1). Mechanistically, allosteric binding of Zn2+ at a site that includes C535 suppresses basal SENP1 activity and unrestrained β-cell exocytosis and increases SENP1 sensitivity to activation by redox signals. Mice with pancreas- or β-cell SENP1 deletion fail to up-regulate exocytosis after 2-day HFD and become rapidly glucose intolerant. This highlights a key role for Zn2+-dependent redox signaling via SENP1 in β-cell functional responses to metabolic stress. (Words: 145)
Teaser Early after high fat feeding in mice, a cytosolic reducing signal acting via SENP1 increases the capacity of β-cells to secrete insulin.
Competing Interest Statement
The authors have declared no competing interest.