Nitrosative Stress and Pathogenesis of Insulin Resistance

Abstract

Insulin resistance is a major causative factor for type 2 diabetes and is associated with increased risk of cardiovascular disease. Despite intense investigation for a number of years, molecular mechanisms underlying insulin resistance remain to be determined. Recently, chronic inflammation has been highlighted as a culprit for obesity-induced insulin resistance. Nonetheless, upstream regulators and downstream effectors of chronic inflammation in insulin resistance remain unclarified. Inducible nitric oxide synthase (iNOS), a mediator of inflammation, has emerged as an important player in insulin resistance. Obesity is associated with increased iNOS expression in insulin-sensitive tissues in rodents and humans. Inhibition of iNOS ameliorates obesity-induced insulin resistance. However, molecular mechanisms by which iNOS mediates insulin resistance remain largely unknown. Protein S-nitrosylation, a covalent attachment of NO moiety to thiol sulfhydryls, has emerged as a major mediator of a broad array of NO actions. S-nitrosylation is elevated in patients with type 2 diabetes, and increased S-nitrosylation of insulin signaling molecules, including insulin receptor, insulin receptor substrate-1, and Akt/PKB, has been shown in skeletal muscle of obese, diabetic mice. Akt/PKB is reversibly inactivated by S-nitrosylation. Based on these findings, S-nitrosylation has recently been proposed to play an important role in the pathogenesis of insulin resistance.

Cannabinoid Receptor Type 1 Antagonist, AM251, Attenuates Mechanical Allodynia and Thermal Hyperalgesia after Burn Injury

“…Pharmacological examples of reversal of deleterious effects of activated signaling proteins without altering their expression has been described previously following burn injury and other pathologic states. 39–42 For example, inhibitors of glycogen synthase kinase-3β and inducible nitric oxide synthase reversed the deleterious actions of these signaling proteins without altering their expression. 39–42 In other words, the deleterious effects of activated proteins can be modulated without altering their expression but by altering their downstream signaling effects.…”

Reactive oxygen and nitrogen species regulate inducible nitric oxide synthase function shifting the balance of nitric oxide and superoxide production

“…iNOS is of critical importance in immune function and is induced in a variety of diseases with inflammation and oxidative stress [8,53,54]. In contrast to the other NOS isoforms iNOS is not regulated by Ca 2+ /Calmodulin [55].…”

S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction

“…Obesity is characterized by chronic metabolic inflammation, termed metaflammation (11–14), and numerous inflammatory signaling cascades exhibiting aberrant activity in obesity share a common feature: a marked increase in inducible nitric oxide synthase (iNOS) expression (15). Indeed, induction of iNOS and nitric oxide (NO) production is observed in many inflammatory diseases (16, 17).…”