Dissertation > Excellent graduate degree dissertation topics show

Long-term Aerobic Exercise Sensitizes Myocardial Response to Insulin: Role of Akt-dependent eNOS Activation

Author: ZhangQuanJiang
Tutor: GaoFeng
School: Fourth Military Medical University
Course: Physiology
Keywords: aerobic exercise myocardium insulin sensitivity protein kinase B endothelial nitric oxide synthase nitric oxide
CLC: R587.1
Type: PhD thesis
Year: 2007
Downloads: 224
Quote: 1
Read: Download Dissertation


BackgroundAdequate myocardial insulin sensitivity is essential to the maintenance of cardiovascular function. Physical activity is known to improve glucose homeostasis and insulin sensitivity in peripheral insulin-targeted organs such as skeletal muscle, liver and adipose tissue in both humans and experimental animals. However, whether physical activity improves myocardial insulin sensitivity remains unanswered. Recently, Huisamen et al. reported that short-term swimming exercise training significantly increased insulin-stimulated protein kinase B (Akt) phosphorylation and glucose uptake transporter 4 (GLUT4) expressions in hearts from the Zucker diabetic fatty rat, suggesting that Akt may be crucial for myocardial insulin sensitization by exercise. However, signaling mechanism downstream of Akt in response to exercise has not been elucidated. Our previous studies revealed that insulin exerts cardioprotective effects against ischemic/reperfused myocardial injury through an Akt-endotheial nitric oxide synthase (eNOS)-nitric oxide (NO)-dependent mechanism, suggesting that eNOS-NO system may serve as a downstream player for Akt in the exercise-associated myocardial insulin sensitization. ON plays an important role in the protection against the onset and progression of cardiovascular diseases. In a recent study, we demonstrated that upregulation of eNOS via adenoviral gene transfer directly promotes cardiomyocyte contractile function. NO has also been implicated to exert a critical role in insulin-induced glucose uptake in skeletal muscle, liver and adipose tissues. This seems to be consistent with the notion of NO synthase (NOS)-NO dysregulation in the etiology of type 2 diabetes. The study demonstrated that eNOS knockout animals exhibit overt insulin resistance in liver and other peripheral tissues. These data suggested that endogenous eNOS-NO signaling system may play a key role in insulin responsiveness, the abnormality of which contributes to the pathogenesis of systemic insulin resistance. However, to what extent the endogenous eNOS-NO system participates in exercise-associated myocardial insulin sensitization remains poorly defined.AimThe aims of our present study were two-fold: (1) to determine whether exercise improves myocardial responsiveness to insulin, and if so, (2) to examine if the endogenous eNOS-NO system underscores exercise-induced myocardial sensitization to insulin.Methods(1) A total of 120 adult male Sprague-Dawley (SD) rats (180-200 g) at 3 months of age were subjected to a ten-week free-loading swim training (3 h/d, 5 d/wk) or assigned as sedentary control.(2) Oral glucose tolerance test (OGTT) and insulin sensitivity test (IST) were performed following an 8-9 h fasting to assess whole insulin sensitiveity in rats following swim training.(3) The extraction of the heart plasma membrane (PM) fraction was performed using Ultracentrifugation. GLUT4 translocation by insulin was measured through Western blot analysis.(4) Glucose uptake by insulin was measured as the rate of cleavage of D-[2-3H]-glucose from KH solution.(5) The expressions of insulin signaling proteins and the phosphorylations of Akt and eNOS were measured using Western blot.(6) Calcium-tolerant cardiomyocytes were isolated from control and exercise rat hearts by the standard enzymatic technique. Contraction and Ca2+ transient of cardiomyocytes were assessed by a video-based motion edge-detection system.(7) Whole heart contractile function was assessed using Langendorff system.Results(1) Swim training significantly delayed the growth of body weight and the decrease of food intake, and reduced the ratio of fat to body weight. The ratios of heart and left ventricle to body weight were significantly increased following swim training (n=10, p<0.01 vs. the sedentary control).(2) Swim training significantly improved systemic insulin sensitivity as evidenced by OGTT and IST. Moreover, swim traning significantly improves myocardial insulin sensitivity as evidenced by the enhanced insulin-induced GLUT4 translocation (n=6, p<0.01 vs. the sedentary rat hearts treated with insulin) and the faciliated insulin-stimulated glucose uptake (n=6, p<0.05 vs. the sedentary rat hearts treated with insulin). However, swim training failed to enhance GLUT4 expression (n=5, p>0.05 vs. sedentary). These data indicate that exercise significantly improves myocardial insulin sensitivity.(3) Swim training significantly upregulated the expressions of IRS2 (insulin receptor substrate 2), PI3-kinase, Akt and eNOS in ventricle tissue (n=5, p<0.01 vs. sedentary).(4) Treatment with insulin resulted in a 3.6- and 2.2-fold increase of eNOS phosphorylation (n=5, p<0.01), as well as a 3.0- and 1.9-fold increase of Akt phosphorylation in ventricle tissue in exercise and sedentary groups, respectively (n=5, p<0.01).(5) Pre-treatment with either LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor or L-NAME, a NOS inhibitor, abolished the exercise-improved glucose uptake by insulin (n=6, p<0.01 vs. the exercised rat hearts treated with insulin) and the exercise-facilitated GLUT4 translocation by insulin (n=6, p<0.01 vs. the exercised rat hearts treated with insulin).(6) Improved myocardial insulin sensitivity significantly enhanced insulin’s positive inotropic effects as evidenced by the facilitated contractile responses of cardiomyocyte and perfused heart to insulin stimulation. Pre-treatment with either LY294002 or L-NAME abolished both the exercise-improved myocardial insulin sensitivity, and insulin’s positive inotropic effects enhanced by exercise.Conclusions(1) These results demonstrate that swim training is capable of sensitizing myocardial insulin sensitivity via upregulation of Akt- and eNOS signaling cascades.(2) Improved myocardial insulin sensitivity enhances insulin’s positive inotropic effects via upregulation of Akt- and eNOS signaling cascades.

Related Dissertations

  1. Preliminary Study of Phosphorylation Effect on UGT1A3 Metabolism Activity Towards Drugs,R346
  2. Studies on the Effects of Exogenous Nitric Oxide on Rice under Cadmium Stress,S511
  3. Study on the Transgenic Tobacco Expressing Protein Kinase Like Gene TA50-10 of Wheat and Analysis of Disease Resistance,S572
  4. Study on Heat Resistance of Chrysanthemum Floral Organ and Effects of Exogenously Nitric Oxide on Heat Resistance of Chrysanthemum,S682.11
  5. The Effect and Mechanism of p38MAPK Inhibitor CBS3830 on Intimal Hyperplasia in Autogenous Vein Grafts of Diabetic Rats,R587.1
  6. Tissue-engineered Construction and Preliminary Implantation Study of Diamond-like Carbon Films for Artificial Mechanical Valve Applications,R654.2
  7. Kinase Activities Analysis and Localization of ZmCCaMK Induced by Abscisic Acid in Leaves of Maize Plants,S513
  8. The Effects of Aerobic Exercise Training on Oxidative Stress and Ultrastructure of Pancreatic Organization in Diabetic Rats,R587.1
  9. Effects of Cold-adaptation Swimming on Hemorheology and Quantity of NO and NOS in Aorta of SD Rats in Acute Cold Water Stress,R87
  10. Effect of Nrf2-ARE Pathway on Isolated Rat Hearts Using Ischemia or Pinacidil Postconditioning,R96
  11. Changes and Roles of Plasma Hydrogen Sulfide in Elderly Patients with Ischemic Heart Failure,R541.6
  12. The Relationship between Exhale Nitric Oxide and Serum Eosinophil Cationic Protein, IL-13, IL-8 in Acute Asthma Exacerbation,R562.25
  13. The Mechanism and Role of Cavelion-1 in Oxidative Stress Induced by Intermittent High Glucose in Endothelial Cells,R587.1
  14. The Injury Induced by High Glucose and with the Correlation of SelS and PKC Signal Transduction Pathway,R587.1
  15. The Relationship of Serum Adiponectin、Nitric Oxide Synthase and Carotid Atherosclerosis in Patients with Acute Cerebral Infarction,R743.33
  16. Protection of Retional photoreceptors y Activation of AMPK with Metformin,R779.1
  17. p38MAPK on allergic rhinitis peripheral blood mononuclear cells IL-4, IL-5 effects,R765.21
  18. Hyperaccumulators Solanum nigrum (Solanum nigrum L.) tolerance and accumulation of Cd physiological and molecular mechanism of,X173
  19. Soft tissue crush injury in rats induced reactivity of isolated thoracic aorta changes,R686
  20. O Single- amino- phenyl-substituted porphyrin derivatives and research,O626
  21. MWCNTs and ZnO / SnO 2 Composites and NO gas research,TB33

CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetes
© 2012 www.DissertationTopic.Net  Mobile