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The Effect of Actin Reorganization in Insulin Mediated Glucose Transport on L6 Rat Skeletal Muscle Cells

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The Effect of Actin Reorganization in Insulin Mediated Glucose Transport on L6 Rat Skeletal Muscle Cells THE EFFECT OF ACTIN REORGANIZATION IN INSULIN MEDIATED GLUCOSE TRANSPORT ON L6 RAT SKELETAL MUSCLE CELLS CHAN Chung Sing Degree of Master of Philosophy in Medical Science • The Chinese University of Hong Kong June 2002 The Chinese University of Hong Kong holds the copyright of this thesis. Any person(s) intending to use a part or whole of the materials in the thesis in a proposed publication must seek copyright release from the Dean of the Graduate School. 」 ffo 2厕• I ！^ p! UNIVERSITY Wi^sLIBRARY SYSTEM ^^^^ ACKNOWLEDGEMENT I would like to express my sincere gratitude to my supervisor Dr. P. Tong for his supportive guidance, constructive criticisms and valuable advice throughout the study. Moreover, I would like to thank Dr. F. L. Chan in the Department of Anatomy for his valuable advice and technical support in TEM project. In addition, special thanks go to Mr. Stanley Ho in the Department of Medicine and Therapeutics for his valuable advice and technical support. Also, thanks go to Ms Gene L. S. Kung and Ms H. L. Choi in the Department of Anatomy for their skillful assistance in TEM project. Heart!ul thanks go to Ms Minnie Ng, Ms P. K. Ma and the rest of colleagues for their encouragement and spiritual support, especially during the time when I was admitted to the hospital and when I became unreasonable. Finally, dedicated with love to Ms Anne Lee. i TABLE OF CONTENT Acknowledgement i Abstract ix List of Abbreviations xvii CHATPER ONE INTRODUCTION 1.1 Glucose Homeostasis 1 1.1.1 Function 1 1.1.2 Origins and regulation of glucose 2 1.1.3 Glucoregulatory factors 4 1.1.4 Insulin 6 1.1.4.1 Function of Insulin 7 1.1.4.2 Discovery and Production of Insulin 7 1.1.4.3 Insulin Signaling Pathway 8 1.1.4.3.1 Insulin Receptor 8 1.1.4.3.2 MAPK Pathway 9 1.1.4.3.3 Phosphatidylinositol 3-kinase (PI3-K) Pathway 10 1.1.5 Glucose Transporters 11 1.1.6 Role of skeletal muscle in glucose homeostasis 13 1.1.7 Insulin Resistance 14 1.1.8 Glucose abnormality and its complications 16 1.2 Actin 19 1.2.1 Function of Actin 20 1.2.2 Actin Accessory Protein 22 1.2.3 Actin Polymerization 23 1.3 Interaction between Insulin, GLUT4 and Actin in Glucose Homeostasis 24 1.3.1 Insulin-Induced Actin Remodeling 25 1.3.2 Actin Remodeling and Insulin-Induced GLUT4 Translocation 26 1.3.3 Involvement of Insulin Signaling Molecules in Actin Remodeling 27 1.3.4 Actin Remodeling and Insulin Resistance 30 1 • • 11 ij 1.4 Hypothesis and Objective 30 1.4.1 Rationale 30 1.4.2 Hypothesis 31 1.4.3 Objective 31 CHAPTER TWO MATERIALS AND METHODS 2.1 Materials 33 2.2 Cell Culture 36 2.2.1 Cell Culture 36 2.2.2 Reagents Preparation and Incubation 39 2.3 2-Deoxyglucose Uptake 39 2.4 Immunofluorescence Microscopy 41 2.4.1 Permeabilized cell staining 41 2.4.2 Membrane-intact cell staining 43 2.4.3 The analysis of actin remodeling reduction 44 2.5 Live Image Microscopy 44 2.6 Transmission Electron Microscope Study 44 2.7 Statistical Analysis 46 CHAPTER THREE RESULTS 3.1 Cell Growth 48 3.2 Acute Effect of Insulin on L6 myotubes 48 3.2.1 Immunofluorescence Microscopy 49 3.2.1.1 The time profile of insulin on actin cytoskeleton in permeabilized L6 myotubes 49 3.2.1.2 The concentration effect of insulin on actin cytoskeleton in permeabilized L6 myotubes 50 3.2.1.3 Relationship between actin cytoskeleton and GLUT4myc in permeabilized L6 myotubes 51 iii 3.2.1.4 Translocation of GLUT4myc in membrane-intact L6 myotubes 51 3.2.1.5 Effect of methyl-P-cyclodextrins, MeOH or EtOH in permeabilized and membrane-intact L6 myotubes 52 3.2.2 2-Deoxyglucose Uptake 52 3.2.2.1 Effects of insulin, methyl-P-cyclodextrins, MeOH and EtOH in L6 myotubes 52 3.2.3 TEM Study 53 3.2.3.1 Effects of insulin on actin cytoskeleton and GLUT4myc in L6 myotubes 53 3.3 Effect of high glucose and high insulin incubation in L6 myotubes 54 3.3.1 Immunofluorescence Microscopy 54 3.3.1.1 High insulin and high glucose preincubation in permeabilized L6 myotubes 55 3.3.1.2 Effect of high insulin and high glucose incubation in membrane-intact L6 myotubes 55 3.3.2 2-Deoxyglucose Uptake 56 3.3.2.1 Effect of high insulin and high glucose incubation in L6 myotubes 56 3.3.3 TEM Study 57 3.3.3.1 Effect of high insulin and high glucose incubation in L6 myotubes 57 3.4 Effect of FFA incubation in L6 myotubes 58 3.4.1 Immunofluorescence Microscopy 58 3.4.1.1 FFA preincubation in permeabilized L6 myotubes 58 3.4.1.2 FFA incubation in membrane-intact L6 myotubes 59 3.4.2 2-Deoxyglucose Uptake 59 3.4.2.1 FFA incubation in L6 myotubes (24 hours) 60 3.4.3 TEM Study 62 3.4.3.1 FFA incubation in L6 myotubes 62 3.5 Effect of CHO incubation in L6 myotubes 62 3.5.1 Immunofluorescence Microscopy 62 3.5.1.1 CHO preincubation in permeabilized L6 myotubes 63 3.5.1.2 CHO incubation in membrane-intact L6 myotubes 63 3.5.2 2-Deoxyglucose Uptake 64 iv 3.5.2.1 CHO incubation in L6 myotubes (24 hours) 64 3.5.3 TEM Study 65 3.5.3.1 CHO incubation in L6 myotubes 65 3.6 Overall changes in glucose uptake after preincubation experiment 65 CHAPTER FOUR DISCUSSION 4.1 Effect of insulin on L6 myotubes 69 4.2 Effect of methyl-P-cyclodextrins, MeOH and EtOH on L6 myotube 75 4.3 Effect of pretreatment of cells in conditions of insulin resistance 76 4.3.1 Effect of high glucose and high insulin preincubation on L6 myotubes 76 4.3.2 Effect of FFA preincubation on L6 myotubes 78 4.3.3 Effect of CHO preincubation on L6 myotubes 82 4.3.4 Effect of cell preincubation in conditions of insulin resistance on L6 myotubes (TEM) 83 4.4 Summary of the effects of cell preincubation in conditions of insulin resistance 84 4.5 Possible mechanisms involved in insulin resistance induction 86 4.5.1 Possible changes in GLUT expression and activities 87 4.5.2 Possible changes in insulin signaling propagation 88 4.5.3 Altered functioning of various actin accessory proteins 89 4.6 Limitation of the study 90 4.7 Conclusion 90 4.8 Future study 91 REFERENCES 93 TABLES vii 1. Ratio of LR White and EtOH used in TEM study. 45a 2. Effects of preincubations on actin remodeling. 52d 52e 3. Effects of insulin, methyl -/5- cyclodextrins, MeOH and EtOH preincubations on glucose uptake. 53a 4. Effect of Glucose and Insulin preincubation on glucose uptake. 56c 5. Effect of OA preincubation on glucose uptake. 60a 6. Effect of LA preincubation on glucose uptake. 60b 7. Effect of PA preincubation on glucose uptake. 61a 8. Effect of CHO preincubation on glucose uptake. 64a 9. Percentage of increase on glucose uptakes compared with carrier-control cells before and after insulin treatment. 66a FIGURES 1. Metabolic and mitogenic signaling pathway in insulin action 8a 2. Differentiation of L6 muscle cells from myoblasts to myotubes. 48a 3. Effects of insulin on actin cytoskeleton in permeabilized L6 myotubes (time). 49a 3. Effects of insulin on actin cytoskeleton in permeabilized L6 myotubes (concentration). 50a 4. Relationship between actin cytoskeleton and GLUT4myc in permeabilized L6 myotubes. 51a i！^I •jII i 5. Translocation of GLUT4myc in membrane-intact L6 myotubes. 52a Ij I i vi 6. Effect of methyl-P-cyclodextrin, MeOH or EtOH in permeabilized L6 myotubes. 52b 6. Effects of methyl-p-cyclodextrin，MeOH or EtOH in membrane-intact L6 myotubes. 52c 7. Distribution of actin cytoskeleton and GLUT4myc at basal state in L6 myotubes (TEM). 54a 7. Effects of insulin on actin cytoskeleton and GLUT4myc in L6 myotubes (TEM). 54b 8. High insulin and high glucose preincubation on actin cytoskeleton in permeabilized L6 myotubes. 55a 9. High glucose and high insulin and CHO preincubations on GLUT4myc translocation in membrane-intact L6 myotubes. 56a 9. FFA preincubation on GLUT4myc translocation in membrane-intact L6 myotubes. 56b 10. High glucose and high insulin preincubation on actin cytoskeleton and GLUT4 translocation in insulin-stimualted L6 myotubes (TEM). 57a 10. CHO and FFA preincubation on actin cytoskeleton and GLUT4 translocation in insulin-stimualted L6 myotubes. 57b 10. FFA preincubation on actin cytoskeleton and GLUT4 translocation in insulin-stimualted L6 myotubes. 57c 11. OA preincubation on actin cytoskeleton in permeabilized L6 myotubes. 58a 12. LA preincubation on actin cytoskeleton in permeabilized L6 myotubes. 58b 13. PA preincubation on actin cytoskeleton in permeabilized L6 myotubes. 58c 14. CHO preincubation on actin cytoskeleton in permeabilized L6 myotubes. 63a vii i I 1i GRAPH 1. Example of protein standard curve. 41a viii Ii I The Effect of Actin Reorganization in Insulin Mediated Glucose Transport on L6 Rat Skeletal Muscle Cells Abstract Maintaining of glucose homeostasis is vital to human life. The human brain, which serves as the central processing unit of the body, utilizes glucose as the primary metabolic fuel. Since the brain cannot store or synthesize glucose, glucose is derived from the circulation continuously. Thus, the prevention or rapid correction of hypoglycemia is critical to our survival. However, sustained hyperglycemia can cause severe tissue damage and lead to diabetic complications such as blindness, renal failure, cardiac and peripheral vascular diseases, neuropathy and sexual dysfunction.
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