Exogenous nitric oxide inhibits IRS-1 expression in rat hepatocytes and skeletal myocytes.
Accumulative evidence has supported the role of nitric oxide (NO) in a variety of normal physiological functions as well as many pathological conditions. In this study, we examined the possible diabetogenicity of NO by measuring the expression of the insulin receptor substrate (IRS)-1 in rat hepatocytes and skeletal myocytes. IRS-1 is important in the insulin-mediated signal transduction pathway in both liver and skeletal muscle. Exogenous NO donated by S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) resulted in significant reduction in levels of IRS-1 in both cells, when compared to the insulin-stimulated control (p<0.001). Reversal to near normal levels was achieved using the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO). SNAP was the more potent drug, and the skeletal myocytes were the more sensitive cells to the inhibitory effects of NO released from the drugs. These results provide further evidence that exogenous NO is a potent modulator of insulin-mediated signal transduction and may play a significant role in the pathogenesis of type 2 diabetes mellitus.
Department of Basic Medical Sciences (Biochemistry section), University of the West Indies, Kingston, Jamaica.
Simone
S
Badal
Paul D
PD
Brown
Dalip
D
Ragoobirsingh
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D001565:Benzoates; D007093:Imidazoles; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D009574:Nitro Compounds; D010750:Phosphoproteins; C110881:S-nitro-N-acetylpenicillamine; C116027:S-nitroglutathione; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D005978:Glutathione; D010396:Penicillamine