ERK-c-Myc pathway as a novel pathway linking mitochondrial dysfunction and skeletal muscle insulin resistance

Obesity-linked insulin resistance is mainly due to fatty acid overload in non-adipose tissues, particularly skeletal muscle and liver, where it results in high production of reactive oxygen species and mitochondrial dysfunction. Accumulating evidence indicates that resistance and endurance training alone and in combination can counteract the harmful effects of obesity increasing insulin sensitivity, thus preventing diabetes. This review focuses the mechanisms underlying the exercise role in opposing skeletal muscle insulin resistance-linked metabolic dysfunction. It is apparent that exercise acts through two mechanisms: (1) it stimulates glucose transport by activating an insulin-independent pathway and (2) it protects against mitochondrial dysfunction-induced insulin resistance by increasing muscle antioxidant defenses and mitochondrial biogenesis. However, antioxidant supplementation combined with endurance training increases glucose transport in insulin-resistant skeletal muscle in an additive fashion only when antioxidants that are able to increase the expression of antioxidant enzymes and/or the activity of components of the insulin signaling pathway are used.

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NF-κB-Inducing Kinase (NIK) Mediates Skeletal Muscle Insulin Resistance: Blockade by Adiponectin

Endocrinology ◽

10.1210/en.2011-1343 ◽

2011 ◽

Vol 152 (10) ◽

pp. 3622-3627 ◽

Cited By ~ 26

Author(s):

Sanjeev Choudhary ◽

Sandeep Sinha ◽

Yanhua Zhao ◽

Srijita Banerjee ◽

Padma Sathyanarayana ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Kinase Activity ◽

Pi3 Kinase ◽

Dominant Negative ◽

Muscle Insulin Resistance ◽

Akt Phosphorylation ◽

Skeletal Muscle Insulin Resistance ◽

Obese Subjects

Enhanced levels of nuclear factor (NF)-κB-inducing kinase (NIK), an upstream kinase in the NF-κB pathway, have been implicated in the pathogenesis of chronic inflammation in diabetes. We investigated whether increased levels of NIK could induce skeletal muscle insulin resistance. Six obese subjects with metabolic syndrome underwent skeletal muscle biopsies before and six months after gastric bypass surgery to quantitate NIK protein levels. L6 skeletal myotubes, transfected with NIK wild-type or NIK kinase-dead dominant negative plasmids, were treated with insulin alone or with adiponectin and insulin. Effects of NIK overexpression on insulin-stimulated glucose uptake were estimated using tritiated 2-deoxyglucose uptake. NF-κB activation (EMSA), phosphatidylinositol 3 (PI3) kinase activity, and phosphorylation of inhibitor κB kinase β and serine-threonine kinase (Akt) were measured. After weight loss, skeletal muscle NIK protein was significantly reduced in association with increased plasma adiponectin and enhanced AMP kinase phosphorylation and insulin sensitivity in obese subjects. Enhanced NIK expression in cultured L6 myotubes induced a dose-dependent decrease in insulin-stimulated glucose uptake. The decrease in insulin-stimulated glucose uptake was associated with a significant decrease in PI3 kinase activity and protein kinase B/Akt phosphorylation. Overexpression of NIK kinase-dead dominant negative did not affect insulin-stimulated glucose uptake. Adiponectin treatment inhibited NIK-induced NF-κB activation and restored insulin sensitivity by restoring PI3 kinase activation and subsequent Akt phosphorylation. These results indicate that NIK induces insulin resistance and further indicate that adiponectin exerts its insulin-sensitizing effect by suppressing NIK-induced skeletal muscle inflammation. These observations suggest that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes.

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Lowered extracellular pH is involved in the pathogenesis of skeletal muscle insulin resistance

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2014.01.162 ◽

2014 ◽

Vol 445 (1) ◽

pp. 170-174 ◽

Cited By ~ 23

Author(s):

Hiroki Hayata ◽

Hiroaki Miyazaki ◽

Naomi Niisato ◽

Noriko Yokoyama ◽

Yoshinori Marunaka

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Extracellular Ph ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance

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Heat Treatment Improves Glucose Tolerance and Prevents Skeletal Muscle Insulin Resistance in Rats Fed a High-Fat Diet

Diabetes ◽

10.2337/db08-1070 ◽

2008 ◽

Vol 58 (3) ◽

pp. 567-578 ◽

Cited By ~ 129

Author(s):

A. A. Gupte ◽

G. L. Bomhoff ◽

R. H. Swerdlow ◽

P. C. Geiger

Keyword(s):

Heat Treatment ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Tolerance ◽

High Fat Diet ◽

High Fat ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance

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Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e915 ◽

1997 ◽

Vol 273 (5) ◽

pp. E915-E921 ◽

Cited By ~ 12

Author(s):

Carsten Schmitz-Peiffer ◽

Nicholas D. Oakes ◽

Carol L. Browne ◽

Edward W. Kraegen ◽

Trevor J. Biden

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Kinase C ◽

Protein Kinase ◽

Muscle Protein ◽

Skeletal Muscle Protein ◽

Insulin Sensitizer ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance ◽

Kinase C

We have recently shown that the reduction in insulin sensitivity of rats fed a high-fat diet is associated with the translocation of the novel protein kinase Cε(nPKCε) from cytosolic to particulate fractions in red skeletal muscle and also the downregulation of cytosolic nPKCθ. Here we have further investigated the link between insulin resistance and PKC by assessing the effects of the thiazolidinedione insulin-sensitizer BRL-49653 on PKC isoenzymes in muscle. BRL-49653 increased the recovery of nPKC isoenzymes in cytosolic fractions of red muscle from fat-fed rats, reducing their apparent activation and/or downregulation, whereas PKC in control rats was unaffected. Because BRL-49653 also improves insulin-stimulated glucose uptake in fat-fed rats and reduces muscle lipid storage, especially diglyceride content, these results strengthen the association between lipid availability, nPKC activation, and skeletal muscle insulin resistance and support the hypothesis that chronic activation of nPKC isoenzymes is involved in the generation of muscle insulin resistance in fat-fed rats.

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Prevention of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.281.1.e62 ◽

2001 ◽

Vol 281 (1) ◽

pp. E62-E71 ◽

Cited By ~ 96

Author(s):

Charles Lavigne ◽

Frédéric Tremblay ◽

Geneviève Asselin ◽

Hélène Jacques ◽

André Marette

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Amino Acids ◽

Glucose Uptake ◽

Soy Protein ◽

Whole Body ◽

Glucose Disposal ◽

High Fat ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance

In the present study, we tested the hypothesis that fish protein may represent a key constituent of fish with glucoregulatory activity. Three groups of rats were fed a high-fat diet in which the protein source was casein, fish (cod) protein, or soy protein; these groups were compared with a group of chow-fed controls. High-fat feeding led to severe whole body and skeletal muscle insulin resistance in casein- or soy protein-fed rats, as assessed by the euglycemic clamp technique coupled with measurements of 2-deoxy-d-[3H]glucose uptake rates by individual tissues. However, feeding cod protein fully prevented the development of insulin resistance in high fat-fed rats. These animals exhibited higher rates of insulin-mediated muscle glucose disposal that were comparable to those of chow-fed rats. The beneficial effects of cod protein occurred without any reductions in body weight gain, adipose tissue accretion, or expression of tumor necrosis factor-α in fat and muscle. Moreover, L6 myocytes exposed to cod protein-derived amino acids showed greater rates of insulin-stimulated glucose uptake compared with cells incubated with casein- or soy protein-derived amino acids. These data demonstrate that feeding cod protein prevents obesity-induced muscle insulin resistance in high fat-fed obese rats at least in part through a direct action of amino acids on insulin-stimulated glucose uptake in skeletal muscle cells.

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