Nitric oxide (NO) is an important bioactive signaling molecule that mediates a variety of normal physiological functions, which, if altered, could contribute to the genesis of many pathological conditions, including diabetes. In this study, we examined the possible diabetogenicity of NO by noting differences in the cellular binding of insulin in dogs treated with the NO donor, S-nitrosoglutathione (GSNO) compared to captopril-treated controls. GSNO administration resulted in an abnormality in glucose metabolism which was attributed to decreased binding of insulin to its receptor on the cell membrane of mononuclear leucocytes, 11.60 ± 0.60% in GSNO-treated dogs compared with 18.10 ± 1.90% in captopril-treated control (p < 0.05).="" the="" decreased="" insulin="" binding="" was="" attributed="" to="" decreased="" insulin="" receptor="" sites="" per="" cell,="" 21.43="" ±="" 2.51="" ×="">⁴ in GSNO-treated dogs compared with 26.60 ± 1.57 × 10⁴ in captopril-treated controls (p < 0.05).="" average="" affinity="" analysis="" of="" the="" binding="" data="" demonstrated="" that="" this="" decrease="" in="" insulin="" binding="" was="" also="" due="" to="" a="" decrease="" in="" average="" affinity="" of="" the="" receptor="" on="" mononuclear="" leucocytes="" for="" insulin.="" this="" was="" evident="" by="" a="" decrease="" in="" empty="" and="" filled="" site="" affinities="" in="" gsno-treated="" dogs="" compared="" with="" that="" of="" captopril-treated="" dogs="">p < 0.05).="" it="" appears="" that="" gsno="" is="" exerting="" its="" effect="" by="" decreasing="" the="" number="" of="" insulin="" receptor="" sites="" and/or="" decreasing="" the="" average="" receptor="" affinity.="" these="" results="" provide="" evidence="" for="" a="" novel="" role="" of="" no="" as="" a="" modulator="" of="" insulin="" binding="" and="" the="" involvement="" of="" no="" in="" the="" aetiology="" of="" diabetes="" mellitus.="" (mol="" cell="" biochem="">263: 29–34, 2004)