The secretion of insulin by pancreatic islet β-cells plays a pivotal role in glucose homeostasis and diabetes. Recent work suggests an important role for SUMOylation in the control of insulin secretion from β-cells. In this paper we discuss mechanisms whereby (de)SUMOylation may control insulin release by modulating β-cell function at one or more key points; and particularly through the acute and reversible regulation of the exocytotic machinery. Furthermore, we postulate that the SUMO-specific protease SENP1 is an important mediator of insulin exocytosis in response to NADPH, a metabolic secretory signal and major determinant of β-cell redox state. Dialysis of mouse β-cells with NADPH efficiently amplifies β-cell exocytosis even when extracellular glucose is low; an effect that is lost upon knockdown of SENP1. Conversely, over-expression of SENP1 itself augments β-cell exocytosis in a redox-dependent manner. Taken together, we suggest that (de)SUMOylation represents an important mechanism that acutely regulates insulin secretion and that SENP1 can act as an amplifier of insulin exocytosis.