Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ et al.. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci USA 106, 17787-17792

Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2009; 106(42):17787-92. DOI: 10.1073/pnas.0902380106
Source: PubMed


We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/- mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess.

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    • "In this line, antioxidant therapy has been evaluated in vitro (Houstis et al., 2006) and using obese diabetic mice (Kaneto et al., 2006), resulting in an improvement in blood glucose levels, b-cell mass and the concentration of insulin and insulin mRNA. Indeed, antioxidant treatment reversed the effects of TNF-a or dexamethasone-induced IR (Hoehn et al., 2009). In addition, antioxidant treatment of cow hepatocytes cultured with high concentration of either NEFA or BHBA also resulted in the inhibition of the NF-jB pathway and reduced the expression of pro-inflammatory factors (Shi et al., 2014, 2015). "
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    ABSTRACT: Post-parturient insulin resistance (IR) is a common feature in all mammalian animals. However, in dairy cows, it can be exacerbated because of high milk yield, leading to excessive negative energy balance, which is related with increased disease incidence, reduced milk production and worsened reproductive performance. IR has been extensively investigated in humans suffering from diabetes mellitus. In these subjects, it is known that oxidative stress (OS) plays a causative role in the onset of IR. Although OS occurs in transitional dairy cattle, there are yet no studies that investigated the association between IR and OS in dairy cattle. Therefore, the aim of this study was to investigate whether there is a relationship between OS and IR in dairy cattle. Serum samples were taken repeatedly from 22 dairy cows from 2 months prior to the expected calving date to 2 months after calving and were analysed for markers of metabolic and redox balance. Surrogate indices of insulin sensitivity were also calculated. Generalised linear mixed models revealed an effect of the oxidative status on peripheral insulin concentration and on indices of insulin sensitivity. Hence, field trials should investigate the effectiveness of antioxidant therapy on insulin sensitivity in peripheral tissues during the transition period of dairy cattle. Journal of Animal Physiology and Animal Nutrition © 2015 Blackwell Verlag GmbH.
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    • "In this case, elevated flux via í µí»½-oxidation in the absence of added demand is viewed as an underlying cause of the disease. Therefore, mitochondrial-derived oxidative stress is fairly well established as an underlying mechanism responsible for the pathological complications associated with diabetes [40], but it also has a role as a primary factor in the development of insulin resistance (and subsequent overt diabetes), since strong experimental evidence from various animal models utilizing mitochondrial targeted approaches has established a link between mitochondrial-derived ROS and insulin resistance in vivo [41] [42]. "
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    • "Thus deficiencies of essential minerals particularly those which involve the metabolism of carbohydrates for example chromium, manganese, zinc, potassium and magnesium are found in diabetics. Chromium helps to lower cholesterol and triglyceride levels and increases insulin sensitivity (Hoehn et al., 2009).The excess iron can cause oxidative stress and damage the pancreas and thus affect insulin secretion, Manganese is involved in energy metabolism, high levels of zinc may increase glycosylation (Mertz et al., 1994). "

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