A Role for iNOS in Fasting Hyperglycemia and Impaired Insulin Signaling in the Liver of Obese Diabetic Mice

Abstract

Chronic inflammation has been postulated to play an important role in the pathogenesis of insulin resistance. Inducible nitric oxide synthase (iNOS) has been implicated in many human diseases associated with inflammation. iNOS deficiency was shown to prevent high-fat diet-induced insulin resistance in skeletal muscle but not in the liver. A role for iNOS in fasting hyperglycemia and hepatic insulin resistance, however, remains to be investigated in obesity-related diabetes. To address this issue, we examined the effects of a specific inhibitor for iNOS, L-NIL, in obese diabetic (ob/ob) mice. iNOS expression was increased in the liver of ob/ob mice compared with wild-type mice. Treatment with iNOS inhibitor reversed fasting hyperglycemia with concomitant amelioration of hyperinsulinemia and improved insulin sensitivity in ob/ob mice. iNOS inhibitor also increased the protein expression of insulin receptor substrate (IRS)-1 and -2 1.5-and 2-fold, respectively, and enhanced IRS-1-and IRS-2-mediated insulin signaling in the liver of ob/ob mice. Exposure to NO donor and ectopically expressed iNOS decreased the protein expression of IRS-1 and -2 in cultured hepatocytes. These results suggest that iNOS plays a role in fasting hyperglycemia and contributes to hepatic insulin resistance in ob/ob mice. Diabetes 54:1340 -1348, 2005 C hronic low-grade inflammation has been proposed to be involved in the pathogenesis in obesity-related insulin resistance and type 2 diabetes. The expression of proinflammatory cytokines, including tumor necrosis factor-␣ (1) and interleukin-6 (2), is upregulated in animal models of and patients with type 2 diabetes. However, limited knowledge is thus far available about the molecular mechanisms by which chronic inflammation mediates insulin resistance and type 2 diabetes.The activation of inhibitor 〉 kinase ␤ (IKK␤)-nuclear factor-〉 (NF-〉), a crucial signaling cascade for inflammatory response, has been highlighted as a mediator of insulin resistance. The pharmacological inhibition or gene disruption of IKK␤ reversed obesity-related insulin resistance and fasting hyperglycemia in rodents and humans (3-5). However, little is known about genes that function as downstream effectors of the IKKb-NF-B pathway to mediate insulin resistance.Inducible nitric oxide synthase (iNOS; also termed NOS2), whose expression is regulated by IKK␤-NF-B (6), is assumed to be one of the candidates that mediate inflammation-involved insulin resistance. Accumulating evidence indicates a close link between iNOS and insulin resistance. Although iNOS was originally identified in macrophages, it is now known that it is widely expressed in many tissues, including insulin-sensitive organs such as skeletal muscle, adipose tissue, and liver, in normal rodents and humans. The expression of iNOS is upregulated by most, if not all, inducers of insulin resistance, including proinflammatory cytokines, obesity (7), free fatty acids (8), hyperglycemia (9,10), endotoxins (6,11), and oxidative stress. In fact, elevated expression of i...

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

“…In agreement with our previous studies 26 , iNOS disruption in ob/ob mice caused a reduction in body weight as well as an improvement in glucose and lipid metabolism as compared to ob/ob counterparts. Although a large controversy exists on the role of iNOS on glucose homeostasis, [40][41][42] our results are in agreement with our previous studies 26 . In order to analyze the impact of the absence of iNOS on AT in ob/ob mice, markers of adipogenesis (Pparg, Fasn, and Cidec) and fat browning (Prdm16 and Ucp1) were evaluated.…”

Nitric oxide inhibits insulin-degrading enzyme activity and function through S-nitrosylation

“…This inhibition has implications in conditions such as diabetes, insulin resistance, and Alzheimer's disease. Increased inflammation and the elevated production of NO have been shown to affect insulin clearance and processing, which contributes to overall insulin resistance [29,30]. Enhanced expression of iNOS as a result of inflammation is a factor in insulin resistance, and depletion of iNOS has been shown to enhance insulin sensitivity [7,8,29].…”

“…Increased inflammation and the elevated production of NO have been shown to affect insulin clearance and processing, which contributes to overall insulin resistance [29,30]. Enhanced expression of iNOS as a result of inflammation is a factor in insulin resistance, and depletion of iNOS has been shown to enhance insulin sensitivity [7,8,29]. A large body of literature has shown that inflammation and insulin resistance may be underlying causes in the development of Alzheimer's disease as well [31][32][33].…”

Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion

“…In humans, the infusion of the arginine analogue L-NG-nitroarginine methyl ester (L-NAME) raised blood pressure but had no effect on fasting hepatic glucose production [10]. Other studies showing a direct role of NO in inducing hepatic insulin resistance have used models in which excess NO was generated through liver-specific overexpression of the inducible nitric oxide synthase (NOS) isoform [11]. In liver homogenates, NO has recently been shown to dosedependently inhibit the specific protease insulin-degrading enzyme (IDE), which is largely responsible for whole-body insulin clearance [12].…”