Introduction
Nitric oxide (NO) is a short-lived, volatile gas that also serves as a ubiquitous signaling molecule involved in a variety of biological functions, which, if altered, could contribute to the genesis of many pathological conditions (Lundberg et al., 2018[77]). One area of recent interest is the potential role of NO in the regulation of insulin synthesis and secretion; these effects are, however, highly complex as both inhibitory and stimulatory effects of NO on insulin secretion have been reported (Nystrom et al., 2012[95]; Sansbury and Hill, 2014[109]; Bahadoran et al., 2020[10]).
Nitric oxide through increasing intracellular Ca2+ levels or via S-nitrosylation of glucokinase and syntaxin 4, as well as vasodilation of islet vasculature, increases insulin secretion (Laffranchi et al., 1995[67]; Rizzo and Piston, 2003[105]; Wiseman et al., 2011[134]; Nystrom et al., 2012[95]; Kruszelnicka, 2014[65]). Decreased NO bioavailability has been shown in obesity and type 2 diabetes in both animal and human studies (Wu and Meininger, 2009[136]; Jiang et al., 2014[59]; Sansbury and Hill, 2014[109]; Bakhtiarzadeh et al., 2018[12]) and restoration of NO levels has many favorable metabolic effects in type 2 diabetes (Carlstrom et al., 2010[18]; Gheibi et al., 2017[40], 2018[41], 2019[42]). These studies suggest that NO through modulation of insulin secretion and its signaling pathways may be a potential target for the treatment of type 2 diabetes. By contrast, inhibition of islet NO synthase (NOS) activity is accompanied by an increase in glucose-stimulated insulin secretion (GSIS) (Panagiotidis et al., 1995[100]; Akesson et al., 1999[1]; Henningsson et al., 2000[49], 2002[52]; Eckersten and Henningsson, 2012[28]). Moreover, GSIS has been shown to be suppressed by different concentrations of NO donors (Panagiotidis et al., 1995[100]; Antoine et al., 1996[5]; Akesson and Lundquist, 1999[2]), indicating a negative role of NO in insulin secretion.
The controversy of NO's role in insulin secretion may depend on the use of various β-cell lines with different qualitative/quantitative secretory reaction patterns, incubation of islets/β-cells in high or low glucose media, using different NOS inhibitors, or different types of extracellular/intracellular NO donors. Also varying enzymatic activities of the different isoforms of NOS may be of importance. This review focuses on the role of NO in the regulation of insulin secretion as well as the possible factors and reasons which may contribute to discrepancies in the results between different studies.