S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance.
Evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance in muscle. Here, we investigated whether this insulin resistance could be mediated by S-nitrosation of proteins involved in early steps of the insulin signal transduction pathway. Exogenous NO donated by S-nitrosoglutathione (GSNO) induced in vitro and in vivo S-nitrosation of the insulin receptor beta subunit (IRbeta) and protein kinase B/Akt (Akt) and reduced their kinase activity in muscle. Insulin receptor substrate (IRS)-1 was also rapidly S-nitrosated, and its expression was reduced after chronic GSNO treatment. In two distinct models of insulin resistance associated with enhanced iNOS expression-diet-induced obesity and the ob/ob diabetic mice-we observed enhanced S-nitrosation of IRbeta/IRS-1 and Akt in muscle. Reversal of S-nitrosation of these proteins by reducing iNOS expression yielded an improvement in insulin action in both animal models. Thus, S-nitrosation of proteins involved in insulin signal transduction is a novel molecular mechanism of iNOS-induced insulin resistance.
Carvalho-Filho
Marco A
MA
Department of Internal Medicine, State University of Campinas, UNICAMP, Campinas, Brazil.
Ueno
Mirian
M
Hirabara
Sandro M
SM
Seabra
Amedea B
AB
Carvalheira
José B C
JB
de Oliveira
Marcelo G
MG
Velloso
Lício A
LA
Curi
Rui
R
Saad
Mario J A
MJ
D000818:Animals; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018482:Muscle, Skeletal / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D009574:Nitro Compounds / Q000494:pharmacology; D015538:Nitrosation; D009765:Obesity / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D009574:Nitro Compounds; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C116027:S-nitroglutathione; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009569:Nitric Oxide; D011972:Receptor, Insulin; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione