Ozone exposure triggers insulin resistance through muscle c-Jun N-terminal kinase activation.

A growing body of evidence suggests that exposure to traffic-related air pollution is a risk factor for type 2 diabetes. Ozone, a major photochemical pollutant in urban areas, is negatively associated with fasting glucose and insulin levels, but most aspects of this association remain to be elucidated. Using an environmentally realistic concentration (0.8 parts per million), we demonstrated that exposure of rats to ozone induced whole-body insulin resistance and oxidative stress, with associated endoplasmic reticulum (ER) stress, c-Jun N-terminal kinase (JNK) activation, and disruption of insulin signaling in skeletal muscle. Bronchoalveolar lavage fluids from ozone-treated rats reproduced this effect in C2C12 myotubes, suggesting that toxic lung mediators were responsible for the phenotype. Pretreatment with the chemical chaperone 4-phenylbutyric acid, the JNK inhibitor SP600125, or the antioxidant N-acetylcysteine alleviated insulin resistance, demonstrating that ozone sequentially triggered oxidative stress, ER stress, and JNK activation to impair insulin signaling in muscle. This study is the first to report that ozone plays a causative role in the development of insulin resistance, suggesting that it could boost the development of diabetes. We therefore provide a potential mechanism linking pollutant exposure and the increased incidence of metabolic diseases.

White adipose tissue overproduces the lipid-mobilizing factor zinc α2-glycoprotein in chronic kidney disease.

Chronic kidney disease (CKD) is frequently associated with protein-energy wasting, a recognized strong predictive factor of mortality. Zinc α2-glycoprotein (ZAG) is a new adipokine involved in body weight control through its lipid-mobilizing activity. Here we tested whether the uremic environment in CKD could alter ZAG production by white adipose tissue and contribute to CKD-associated metabolic disturbances. Compared with normal plasma, uremic plasma induced a significant increase in ZAG synthesis (124%), was associated with a significant increase in basal lipolysis (31%), and significantly blunted lipogenesis (-53%) in 3T3-L1 adipocytes in vitro. In 5/6 nephrectomized rats and mice in vivo, there was a significant decrease in white adipose tissue accretion (-44% and -43%, respectively) and a significantly higher white adipose tissue content of ZAG protein than in sham-operated, pair-fed control animals (498% and 106%, respectively). Subcutaneous white adipose tissue biopsies from patients with end-stage renal disease exhibited a higher content of ZAG (573%) than age-matched controls. Thus, the ZAG content is increased in white adipose tissue from patients or animal models with CKD. Overproduction of ZAG in CKD could be a major contributor to metabolic disturbances associated with CKD.

Chronic treatment with myo-inositol reduces white adipose tissue accretion and improves insulin sensitivity in female mice.

Type 2 diabetes is a complex disease characterized by a state of insulin resistance in peripheral tissues such as skeletal muscle, adipose tissue or liver. Some inositol isomers have been reported to possess insulin-mimetic activity and to be efficient in lowering blood glucose level. The aim of the present study was to assess in mice the metabolic effects of a chronic treatment with myo-inositol, the most common stereoisomer of inositol. Mice given myo-inositol treatment (0.9 or 1.2 mg g(-1) day(-1), 15 days, orally or intraperitoneally) exhibited an improved glucose tolerance due to a greater insulin sensitivity. Mice treated with myo-inositol exhibited a decreased white adipose tissue accretion (-33%, P<.005) compared with controls. The decrease in white adipose tissue deposition was due to a decrease in adipose cell volume (-33%, P<.05), while no change was noticed in total adipocyte number. In skeletal muscle, in vivo as well as ex vivo myo-inositol treatment increased protein kinase B/Akt phosphorylation under baseline and insulin-stimulated conditions, suggesting a synergistic action of myo-inositol treatment and insulin on proteins of the insulin signalling pathway. Myo-inositol could therefore constitute a viable nutritional strategy for the prevention and/or treatment of insulin resistance and type 2 diabetes.

The lipid peroxidation by-product 4-hydroxy-2-nonenal (4-HNE) induces insulin resistance in skeletal muscle through both carbonyl and oxidative stress.

Numerous oxidants are produced as by-products of aerobic cell metabolism, and there is growing evidence that they play key roles in the pathogenesis of insulin resistance. Under conditions of oxidative stress, lipid peroxidation of ω6-polyunsaturated fatty acids leads to the production of 4-hydroxy-2-nonenal (4-HNE). Several lines of evidence suggest that 4-HNE could be involved in the pathophysiology of metabolic diseases; therefore, in this study we assessed the direct effects of 4-HNE on skeletal muscle insulin sensitivity. Gastrocnemius muscle and L6 muscle cells were treated with 4-HNE. Insulin signaling was measured by Western blotting and glucose uptake using 2-deoxy-d-[3H]glucose. Carbonyl stress, glutathione content, and oxidative stress were assessed as potential mechanisms leading to insulin resistance. Protection of cells was induced by pretreatment with 3H-1,2-dithiole-3-thione, N-acetyl-cysteine, aminoguanidine, or S-adenosyl-methionine. 4-HNE induced a time- and dose-dependent decrease in insulin signaling and insulin-induced glucose uptake in muscle. It induced a state of carbonyl stress through adduction of proteins as well as a depletion in reduced glutathione and production of radical oxygen species. A pharmacological increase in glutathione pools was achieved by 3H-1,2-dithiole-3-thione and protected the cells against all deleterious effects of 4-HNE; furthermore, N-acetylcysteine, aminoguanidine, and S-adenosylmethionine prevented 4-HNE noxious effects. 4-HNE can impair insulin action in muscle cells through oxidative stress and oxidative damage to proteins, eventually leading to insulin resistance. These deleterious effects can be prevented by pretreatment with antioxidants, scavengers, or an increase in intracellular glutathione pools. Use of such molecules could represent a novel strategy to combat insulin resistance and other oxidative stress-associated pathologies.