Impaired insulin action despite upregulation of proximal insulin signaling: Novel insights into skeletal muscle insulin resistance in liver cirrhosis

Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague–Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin-stimulated IRS-1 Ser307 and decreased Akt Ser473 and AS160 Thr642 phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin–angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels.

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Mouse models of insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00561.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. E977-E981 ◽

Cited By ~ 40

Author(s):

Marta Letizia Hribal ◽

Francesco Oriente ◽

Domenico Accili

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Insulin Action ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Impaired Insulin

The hallmarks of type 2 diabetes are impaired insulin action in peripheral tissues and decreased pancreatic β-cell function. Classically, the two defects have been viewed as separate entities, with insulin resistance arising primarily from impaired insulin-dependent glucose uptake in skeletal muscle, and β-cell dysfunction arising from impaired coupling of glucose sensing to insulin secretion. Targeted mutagenesis and transgenesis involving components of the insulin action pathway have changed our understanding of these phenomena. It appears that the role of insulin signaling in the pathogenesis of type 2 diabetes has been overestimated in classic insulin target tissues, such as skeletal muscle, whereas it has been overlooked in liver, pancreatic β-cells, and brain, which had been thought not to be primary insulin targets. We review recent progress and try to reconcile areas of apparent controversy surrounding insulin signaling in skeletal muscle and pancreatic β-cells.

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Kinome Profiling Reveals Abnormal Activity of Kinases in Skeletal Muscle From Adults With Obesity and Insulin Resistance

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz115 ◽

2019 ◽

Vol 105 (3) ◽

pp. 644-659

Author(s):

Yue Qi ◽

Xiangmin Zhang ◽

Berhane Seyoum ◽

Zaher Msallaty ◽

Abdullah Mallisho ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Kinases ◽

Insulin Signaling ◽

Human Skeletal Muscle ◽

Molecular Mechanisms ◽

Kinase Activity ◽

Metabolic Diseases ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance

Abstract Context Obesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global kinase activities remain incompletely understood. Objective To investigate abnormal kinase activity associated with OIR in human skeletal muscle. Design Utilization of stable isotopic labeling-based quantitative proteomics combined with affinity-based active enzyme probes to profile in vivo kinase activity in skeletal muscle from lean control (Lean) and OIR participants. Participants A total of 16 nondiabetic adults, 8 Lean and 8 with OIR, underwent hyperinsulinemic-euglycemic clamp with muscle biopsy. Results We identified the first active kinome, comprising 54 active protein kinases, in human skeletal muscle. The activities of 23 kinases were different in OIR muscle compared with Lean muscle (11 hyper- and 12 hypo-active), while their protein abundance was the same between the 2 groups. The activities of multiple kinases involved in adenosine monophosphate–activated protein kinase (AMPK) and p38 signaling were lower in OIR compared with Lean. On the contrary, multiple kinases in the c-Jun N-terminal kinase (JNK) signaling pathway exhibited higher activity in OIR vs Lean. The kinase-substrate–prediction based on experimental data further confirmed a potential downregulation of insulin signaling (eg, inhibited phosphorylation of insulin receptor substrate-1 and AKT1/2). Conclusions These findings provide a global view of the kinome activity in OIR and Lean muscle, pinpoint novel specific impairment in kinase activities in signaling pathways important for skeletal muscle insulin resistance, and may provide potential drug targets (ie, abnormal kinase activities) to prevent and/or reverse skeletal muscle insulin resistance in humans.

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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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