Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Meo, S. Di; Iossa, Susanna; Venditti, Paola

doi:10.1530/joe-16-0598

Cited by 222 publications

(118 citation statements)

References 281 publications

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“…Indeed, NRG1 was shown to attenuate oxidative stress in microglial and cardiac cells 50, 51 . It is also well accepted that increased mitochondrial ROS production is associated with insulin resistance and diabetes 52 . Moreover, excess of ROS production may promote calcium homeostasis impairment leading to contractility defect 53–55 .…”

Section: Discussionmentioning

confidence: 99%

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

Ennequin

Capel

Caillaud

et al. 2017

Sci Rep

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It has been reported that neuregulin1 (NRG1) improves glucose tolerance in healthy and diabetic rodents. In vitro studies also suggest that NRG1 regulates myocyte oxidative capacity. To confirm this observation in vivo, we evaluated the effect on mitochondrial function of an 8-week treatment with NRG1 in db/db diabetic mice and C57BL/6JRJ healthy controls. NRG1 treatment improved complex 2-mediated mitochondrial respiration in the gastrocnemius of both control and diabetic mice and increased mitochondrial complex 2 subunit content by 2-fold. This effect was not associated with an increase in mitochondrial biogenesis markers. Enhanced ERBB4 phosphorylation could mediate NRG1 effects on mitochondrial function through signalling pathways, independently of ERK1/2, AKT or AMPK.

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Section: Discussionmentioning

confidence: 99%

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

Ennequin

Capel

Caillaud

et al. 2017

Sci Rep

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“…However, mitochondria isolated from insulin resistant adipose or muscle tissue generate higher rates of ROS production per unit of substrate (78) suggesting there may be changes within mitochondria that promote ROS production or lower ROS scavenging. Defects in oxidative phosphorylation can increase ROS production yet a number of studies have reported no change in or improved mitochondrial oxidative capacity in insulin resistance (reviewed in (137)(138)(139), (78,83,140)), suggesting that changes in the oxidative phosphorylation pathway are unlikely to be a primary driver of ROS under these conditions. We recently identified a deficiency in coenzyme Q, a cofactor that transfers electrons from Complexes I and II to Complex III of the electron transport chain, in insulin resistant adipose and muscle tissue (83).…”

Section: Why Are Mitochondrial Ros Elevated In Insulin Resistance?mentioning

confidence: 99%

“…The proximal ROS from the electron transport chain is superoxide, but this is rapidly dismutated by SOD2 to hydrogen peroxide and both superoxide and hydrogen peroxide are implicated in causing insulin resistance (132,138). It is not clear whether a specific form of ROS or a specific site of ROS production in mitochondria is responsible for conferring insulin resistance.…”

Section: Why Are Mitochondrial Ros Elevated In Insulin Resistance?mentioning

confidence: 99%

Muscle and adipose tissue insulin resistance: malady without mechanism?

Fazakerley

Krycer

Kearney

et al. 2019

Journal of Lipid Research

118

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Insulin resistance is a major risk factor for numerous diseases including Type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of 'common' insulin resistance. Despite considerable effort, the mechanisms that contribute to 'common' insulin resistance are not resolved. There is universal agreement that extracellular perturbations such as nutrient excess, hyperinsulinemia, glucocorticoids or inflammation trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway, but rather is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states such as fasting, and that in the presence of chronic nutrient excess this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort. Insulin resistance is a pathophysiological state where cells display reduced responsiveness to the glucose-lowering activity of insulin. While there are rare cases where mutations in genes associated with insulin signaling or lipodystrophy cause insulin resistance, for the most part insulin resistance is associated with obesity and thus a state of positive energy balance. This form of insulin resistance is frequently associated with hyperinsulinemia, increased waist circumference or visceral adiposity, metabolic dyslipidemia with high triglycerides and low HDL, and hepatic steatosis, features collectively referred to as the metabolic syndrome. We refer to this as "common insulin resistance". Here, both insulin-dependent glucose disposal and suppression of glucose output are impaired, albeit the relative degree of impairment in each process can vary between individuals (1-3).In this review we focus on the literature surrounding insulin resistance in muscle and adipose tissue, and specifically on insulin-stimulated glucose transport into myocytes and adipocytes within these tissues. Impaired insulin action in other tissues, most notably the liver (4, 5), brain (6, 7) and vasculature (8), also play a key role in whole body insulin resistance, and we direct readers to reviews that explore insulin resistance at these sites in detail. We will examine the evidence that common insulin resistance, in the context of muscle and adipose tissue, results from a defect in 'proximal' insulin signaling, which we define for the purposes of this review as the signaling intermediates that lead to the activation of Akt. We argue that common insulin resistance arises ...

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“…Currently, the causes of insulin resistance remain largely unclear, while multiple internal abnormalities seem to contribute to, including the loss-of-function mutation of IR , transduction impairment by obesity-related inflammation and toxic effects of metabolites by overloaded fatty acid or glucose. All these possible mechanisms could destroy the structure or activity of pathway molecules, hence inducing signaling insensitivity [137]. Patients with insulin resistance often suffer from hyperinsulinemia, hyperglycemia, hyperuricemia and dysfunctional lipid metabolism, which may evolve into metabolic disorders such as type 2 diabetes mellitus (T2DM), polycystic ovary syndrome (PCOS) and atherosclerosis [138, 139].…”

Section: Major Cancer-related Signaling Pathways With Links To Ad mentioning

confidence: 99%

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Guo

Cheng²,

North

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Alzheimer’s disease (AD) is an aging-related neurodegenerative disease and accounts for majority of human dementia. The hyper-phosphorylated tau-mediated intracellular neurofibrillary tangle and amyloid β-mediated extracellular senile plaque are characterized as major pathological lesions of AD. Different from the dysregulated growth control and ample genetic mutations associated with human cancers, AD displays damage and death of brain neurons in the absence of genomic alterations. Although various biological processes predominately governing tumorigenesis such as inflammation, metabolic alteration, oxidative stress and insulin resistance have been associated with AD genesis, the mechanistic connection of these biological processes and signaling pathways including mTOR, MAPK, SIRT, HIF, and the FOXO pathway controlling aging and the pathological lesions of AD are not well recapitulated. Hence, we performed a thorough review by summarizing the physiological roles of these key cancer-related signaling pathways in AD pathogenesis, comprising of the crosstalk of these pathways with neurofibrillary tangle and senile plaque formation to impact AD phenotypes. Importantly, the pharmaceutical investigations of anti-aging and AD relevant medications have also been highlighted. In summary, in this review, we discuss the potential role that cancer-related signaling pathways may play in governing the pathogenesis of AD, as well as their potential as future targeted strategies to delay or prevent aging-related diseases and combating AD.

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Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Cited by 222 publications

References 281 publications

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

Muscle and adipose tissue insulin resistance: malady without mechanism?

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

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