Invited Review: Exercise training-induced changes in insulin signaling in skeletal muscle

2002 ◽  
Vol 93 (2) ◽  
pp. 773-781 ◽  
Author(s):  
Juleen R. Zierath
Keyword(s):  
Skeletal Muscle ◽  
Signal Transduction ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Exercise Training ◽  
Molecular Mechanism ◽  
Insulin Signaling ◽  
Insulin Signal Transduction ◽  
Insulin Signal ◽  
Insulin Resistant

This review will provide insight on the current understanding of the intracellular signaling mechanisms by which exercise training increases glucose metabolism and gene expression in skeletal muscle. Participation in regular exercise programs can have important clinical implications, leading to improved health in insulin-resistant persons. Evidence is emerging that insulin signal transduction at the level of insulin receptor substrates 1 and 2, as well as phosphatidylinositol 3-kinase, is enhanced in skeletal muscle after exercise training. This is clinically relevant because insulin signaling is impaired in skeletal muscle from insulin-resistant Type 2 diabetic and obese humans. The molecular mechanism for enhanced insulin-stimulated glucose uptake after exercise training may be partly related to increased expression and activity of key proteins known to regulate glucose metabolism in skeletal muscle. Exercise also leads to an insulin-independent increase in glucose transport, mediated in part by AMP-activated protein kinase. Changes in protein expression may be related to increased signal transduction through the mitogen-activated protein kinase signaling cascades, a pathway known to regulate transcriptional activity. Understanding the molecular mechanism for the activation of insulin signal transduction pathways after exercise training may provide novel entry points for new strategies to enhance glucose metabolism and for improved health in the general population.

scholarly journals Low-Grade Hypothalamic Inflammation Leads to Defective Thermogenesis, Insulin Resistance, and Impaired Insulin Secretion

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1314-1326 ◽  
Author(s):  
Ana Paula Arruda ◽  
Marciane Milanski ◽  
Andressa Coope ◽  
Adriana S. Torsoni ◽  
Eduardo Ropelle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signal Transduction ◽  
Wistar Rats ◽  
Low Grade ◽  
O2 Consumption ◽  
Tnf Receptor ◽  
Insulin Signal Transduction ◽  
Insulin Signal ◽  
Impaired Insulin ◽  
Hypothalamic Inflammation

Abstract Hypothalamic inflammation is present in animal models of obesity, and the intracerebroventricular injection of TNFα can reproduce a number of features of the hypothalamus of obese animals. Because obesity is a risk factor for type 2 diabetes (DM2) we hypothesized that, by inducing hypothalamic inflammation, we could reproduce some clinical features of DM2. Lean Wistar rats and TNF receptor 1-knockout mice were employed to determine the effects of hypothalamic actions of TNFα on thermogenesis and metabolic parameters. Signal transduction and protein expression were evaluated by immunoblot and real-time PCR. Thermogenesis was evaluated in living rats, and respirometry was determined in isolated muscle fiber. In Wistar rats, hypothalamic TNFα blunts the anorexigenic effect of leptin, which is accompanied by reduced leptin signaling and increased expression of suppressor of cytokine signaling 3. In addition, hypothalamic TNFα reduces O2 consumption and the expression of thermogenic proteins in brown adipose tissue and skeletal muscle. Furthermore, hypothalamic inflammation increases base-line plasma insulin and insulin secretion by isolated pancreatic islets, which is accompanied by an impaired insulin signal transduction in liver and skeletal muscle. Hypothalamic inflammation induced by stearic acid also reduces O2 consumption and blunts peripheral insulin signal transduction. The use of intracerebroventricular infliximab restores O2 consumption in obese rats, whereas TNF receptor 1-knockout mice are protected from diet-induced reduced thermogenesis and defective insulin signal transduction. Thus, low-grade inflammation of the hypothalamus is sufficient to induce changes in a number of parameters commonly impaired in obesity and DM2, and TNFα is an important mediator of this process.

Compensatory alterations for insulin signal transduction and glucose transport in insulin-resistant diabetes

1995 ◽  
Vol 269 (4) ◽  
pp. E759-E765 ◽  
Author(s):  
J. A. Bonini ◽  
J. R. Colca ◽  
C. Dailey ◽  
M. White ◽  
C. Hofmann
Keyword(s):  
Signal Transduction ◽  
Growth Factor Receptor ◽  
Insulin Binding ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Signal Transduction ◽  
Insulin Signal ◽  
Insulin Resistant ◽  
Protein Levels ◽  
Kkay Mice ◽  
Altered Glucose

Insulin binding activates the receptor tyrosine kinase toward the insulin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 then interacts with the p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K), Nck, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branching insulin's signal for both mitogenic and metabolic responses. To determine whether the expression of these proteins is altered in insulin resistance, the levels of these proteins were compared in adipose and liver tissues of nondiabetic mice and obese insulin-resistant diabetic KKAy mice. IR and PI3K p85 alpha protein levels were significantly lower in KKAy mice than in control nondiabetic mice, whereas IRS-1 protein levels were not altered. In contrast, the protein levels of GRB2, Nck, Syp, and GLUT-1 were dramatically elevated in KKAy fat, with less striking changes in liver. Treatment of diabetic animals with pioglitazone, an insulin-sensitizing antihyperglycemic agent, partially corrected the expression of some of these proteins. Taken together, these findings suggest that the insulin-resistant diabetic condition is characterized by changes in expression of insulin signal transduction components that may be associated with altered glucose metabolism.

Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle

2005 ◽  
Vol 288 (2) ◽  
pp. R473-R481 ◽  
Author(s):  
Marianne S. Anderson ◽  
M. Thamotharan ◽  
Doris Kao ◽  
Sherin U. Devaskar ◽  
Liping Qiao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signal Transduction ◽  
Insulin Receptor ◽  
Mrna Translation ◽  
Insulin Concentration ◽  
Fetal Sheep ◽  
Insulin Signal Transduction ◽  
Insulin Signal ◽  
Signal Transduction Proteins ◽  
Ovine Fetal

To test the effects of acute fetal hyperinsulinemia on the pattern and time course of insulin signaling in ovine fetal skeletal muscle, we measured selected signal transduction proteins in the mitogenic, protein synthetic, and metabolic pathways in the skeletal muscle of normally growing fetal sheep in utero. In experiment 1, 4-h hyperinsulinemic-euglycemic clamps were conducted in anesthetized twin fetuses to produce selective fetal hyperinsulinemia-euglycemia in one twin and euinsulinemia-euglycemia in the other. Serial skeletal muscle biopsies were taken from each fetus during the clamp and assayed by Western blot for selected insulin signal transduction proteins. Tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1, and the p85 subunit of phosphatidylinositol 3-kinase doubled at 30 min and gradually returned to control values by 240 min. Phosphorylation of extracellular signal-regulated kinase 1,2 was increased fivefold through 120 min of insulin infusion and decreased to control concentration by 240 min. Protein kinase B phosphorylation doubled at 30 min and remained elevated throughout the study. Phosphorylation of p70 S6K increased fourfold at 30, 60, and 120 min. In the second experiment, a separate group of nonanesthetized singleton fetuses was clamped to intermediate and high hyperinsulinemic-euglycemic conditions for 1 h. GLUT4 increased fourfold in the plasma membrane at 1 h, and hindlimb glucose uptake increased significantly at the higher insulin concentration. These data demonstrate that an acute increase in fetal plasma insulin concentration stimulates a unique pattern of insulin signal transduction proteins in intact skeletal muscle, thereby increasing pathways for mRNA translation, glucose transport, and cell growth.

scholarly journals Direct Cross-talk of Interleukin-6 and Insulin Signal Transduction via Insulin Receptor Substrate-1 in Skeletal Muscle Cells

2006 ◽  
Vol 281 (11) ◽  
pp. 7060-7067 ◽  
Author(s):  
Cora Weigert ◽  
Anita M. Hennige ◽  
Rainer Lehmann ◽  
Katrin Brodbeck ◽  
Frank Baumgartner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signal Transduction ◽  
Insulin Receptor ◽  
Cross Talk ◽  
Interleukin 6 ◽  
Muscle Cells ◽  
Insulin Receptor Substrate ◽  
Insulin Signal Transduction ◽  
Insulin Signal ◽  
Direct Cross
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