β-cells can adapt the rate of insulin secretion to the plasma concentration of glucose and other nutrients by a unique coupling system between nutrient metabolism and insulin production. The coupling system involves accelerating glycolysis, and mitochondrial metabolism with rapid changes in the oxidation state of several redox couples, e.g., NADH/NAD
+ and NADPH/NADP
+ and is also directly linked to ROS production as mentioned above. Upon higher substrate load, the demand for oxygen supply to the cells grows as well. At such a high metabolic activity, the oxygen demand exceeds oxygen supply, resulting in the establishment of intracellular transient hypoxia [
105]. Such features have been described, for example, in neurosecretory cells, which require high mitochondrial activity and ATP production to restore resting membrane potential and to maintain intracellular Ca
2+ levels [
106] and also in working skeletal muscle cells, in which increased ATP demand is reflected by mitochondrial biogenesis and elevated oxygen consumption resulting in expression of hypoxia-inducible genes [
107]. Hypoxia could serve as another coupling factor via enhanced ROS production for insulin secretion in β-cells. Moreover, the beneficial effect of hypoxia in healthy β-cells could be attributed to the biogenesis of the mitochondrial respiratory chain proteins [
107] and effective calcium signaling [
106], which are inevitable for the maintenance of mature β-cells. It was also suggested that the basal activity of hypoxia-induced pathways is necessary for normal β-cell function [
108]. An interesting study by Olsson and Carlsson [
109] has shown that oxygenation may differ widely between individual islets within the pancreas at a given time point. These differences may reflect a mechanism to recruit only a fraction of the available islets into an active (normoxic) β-cell mass. The remaining less well-oxygenated (hypoxic) islets may represent a dormant subpopulation, constituting a functional reserve of endocrine cells. According to this model, the reserve islet pool may be available for recruitment upon reduction of the total islet mass [
109]. In any case, the importance of redox signaling in GSIS machinery was also documented by our research group, which showed recently that insulin secretion is inhibited upon deletion of constitutively active NOX4 enzyme in rodent β-cells in vivo. Our results demonstrated that the sole increase in ATP/ADP ratio is not sufficient to stimulate insulin secretion in vitro and in vivo. We thus confirmed that the presence of ROS, namely H
2O
2 as a metabolic coupling factor, is essential for insulin secretion [
2]. Many targets of redox signaling in the insulin secretory pathway were suggested (); however, a more detailed/complex view is still missing. K
ATP channel with its essential function in GSIS [
110] mediating depolarization of plasma membrane was shown to be inhibited by H
2O
2 in smooth muscle cells [
111], but no such regulation has been observed in β-cells. Also, another depolarizing transient receptor potential (TRP) channel subfamily M member (TRPM2) was reported to be directly redox activated [
112]. The subsequent repolarizing events on the plasma membrane seem to be potentially redox-regulated as H
2O
2 could directly or indirectly inhibit repolarizing K
+-channels, such as K
V [
113,
114,
115]. Besides redox targets of signaling pathways mentioned above, downstream aims in the secretory pathway were found to be, for example, redox-sensitive proteins of calcium signaling, e.g., ryanodine receptor 2 (RyR2), sarcoplasmic Ca
2+ ATPase (SERCA) and inositol triphosphate receptor (IP3R) [
11,
102]. The glucose-induced changes in the redox environment affect these proteins, leading to increased exocytosis of insulin secretory vesicles. Further, proteins of the secretory machinery were also implicated to be redox-regulated. For example, redox-regulated posttranslational modification of exocytosis-regulating
t-SNARE proteins has been proposed to result in an increased rate of maturation, or priming, of secretory vesicles in yeasts (for an overview, see [
116]). mRNA/protein expression studies and electrophysiological analysis of exocytosis suggested that both the expression level of
Grx1 and
Trx1 in the β-cell as well as the NADPH/NADP
+ redox status are important factors for the regulation of exocytosis [
117]. Redox-dependent regulation was suggested for the NADPH–GSH–GRX1 signaling axis in rodent β-cells [
118], and GRX1-GSH was shown to mediate deSUMOylation of sentrin/SUMO-specific protease 1 (SENP1) in humans [
119] via modulation of its key thiol groups [
120]. SUMOylation/deSUMOylation processes were previously reported to be redox-regulated and were implicated to be involved in response to oxidative stress [
121]. Moreover, SUMOylation of insulin secretory pathway proteins had an inhibitory effect on insulin granule exocytosis, and several proteins involved in insulin granule exocytosis were shown to be modified by SUMOylation [
121]. However, it is tempting to speculate that the redox signal mediated by the thiol exchange is transformed at the exocytotic site to signal mediated via SUMO posttranslational modification.