Stimulatory effect of NO on insulin secretion
The initial evidence that NO played a role in the regulation of insulin secretion came from Laychock and colleagues in 1991 (Laychock et al., 1991[70]). They found that sodium nitroprusside by increasing the cGMP level in rat islets, stimulated insulin secretion, while inhibition of NOS decreased glucose- and arginine-induced cGMP release (Laychock et al., 1991[70]). This was further supported by the finding that L-arginine-derived NO increases basal and GSIS in isolated mouse islets (Henningsson and Lundquist, 1998[51]; Henningsson et al., 1999[48]) and the glucose-responsive clonal pancreatic β-cell line HIT-T15 (Schmidt et al., 1992[110]). A concomitant release of insulin and NO is induced by L-arginine in the presence of D-glucose, with the median effective arginine concentrations (EC50) for insulin and NO release equal to 150 µM and 50 µM, respectively, both of which are within the physiological range of circulating L-arginine levels. Interestingly, L-arginine also decreases the EC50 for D-glucose's stimulation of both NO and insulin release (from 15 mM to 5 mM) (Schmidt et al., 1992[110]).
Endogenously produced NO also plays an important role in insulin secretion. Indeed, scavenging of NO with cPTIO (carboxy-2-phenyl-4, 4, 5, 5-tetramethylimidazoline-1-oxyl 3-oxide) in highly glucose-responsive INS-1 cells, is able to significantly reduce the stimulation provided by 15 mM glucose (by ~40 %) (Smukler et al., 2002[116]), highlighting the involvement of endogenously produced NO in secretagogue-induced insulin secretion under physiological conditions. It also seems that the early phase of insulin secretion is NO-dependent as scavenging of endogenous NO or inhibition of NOS with L-NMMA (NG-Monomethyl-L-arginine, monoacetate) in rat pancreatic islets blunts the early insulin peak by 60-65 % and 46 %, respectively (Spinas et al., 1998[119]). This finding may also explain why some studies looking into accumulated insulin release in pancreatic islets argue against a stimulatory effect of NO on insulin release. The mechanism by which NO stimulates insulin secretion is shown in Figure 1(Fig. 1) and also discussed below.