| Titre : | The Bi-Directional Relationship Between Sarcopenia And Type 2 Diabetes |
| Auteurs : | NAAR Ilhem, Auteur ; Nasr-Eddine KEBIR, Directeur de thèse |
| Type de document : | texte imprimé |
| Editeur : | Dr. Moulay Tahar Université Saida, Faculté des Sciences Naturelles et de la Vie, 2024/2025 |
| Format : | 135 p / 29 CM |
| Accompagnement : | CD |
| Langues: | Anglais |
| Langues originales: | Anglais |
| Catégories : | |
| Mots-clés: | Sarcopenia ; Type 2 diabetes mellitus ; Insulin resistance ; Muscle atrophy ; Inflammation ; Mitochondrial dysfunction ; Sarcopenic obesity |
| Résumé : |
Sarcopenia, a progressive loss of skeletal muscle mass, strength, and function, is
increasingly recognized as a significant comorbidity in individuals with type 2 diabetes mellitus (T2DM), with both conditions sharing overlapping pathophysiological mechanisms such as insulin resistance, chronic inflammation, oxidative stress, mitochondrial dysfunction, and hormonal imbalance. This cross-sectional study involving 200 T2DM patients from Saïda, Algeria, investigated the bidirectional relationship between T2DM and sarcopenia, focusing on clinical, functional, and metabolic parameters. Results revealed that 95% of participants were unaware of sarcopenia, and 82% did not understand the importance of muscle strengthening in diabetes management. Alarmingly, 64% reported no physical activity, and 55% had inadequate or uncertain protein intake. Functional impairments were common: 31% struggled with lifting 5 kg objects, and among patients with over 10 years of T2DM, 56.2% reported stair-climbing difficulties. Muscle decline was observed even in patients under 40 years, with 42.1% reporting significant loss. Poor glycemic control (HbA1c >8%) was strongly associated with decreased muscle strength. Comparative analysis showed that diabetic patients exhibited reduced muscle mass indices and higher intramuscular fat accumulation compared to nondiabetic individuals. Sarcopenic obesity further exacerbated metabolic dysfunction. A significant negative correlation between skeletal muscle mass and insulin resistance markers reinforces the central role of muscle in glycemic regulation. These findings confirm a self-reinforcing cycle between sarcopenia and T2DM, underlining the urgent need for integrated strategies—targeting nutrition, physical activity, and metabolic control—to disrupt this cycle and improve patient outcomes. |
| Note de contenu : |
Part I: introduction ................................................................................................................. 1
PART II : LITERATURE REVIEW ........................................................................................... 5 II.1. INTRODUCTION TO SARCOPENIA .................................................................................. 6 II.1.1. BACKGROUND AND HISTORICAL CONTEXT: ................................................................. 6 II.1.2. EVOLUTION OF THE CURRENT DEFINITION AND DIAGNOSTIC CRITERIA ...................... 6 II.1.3. EPIDEMIOLOGY AND PREVALENCE OF SARCOPENIA ..................................................... 8 II.2. PATHOPHYSIOLOGY OF SARCOPENIA ......................................................................... 11 II.2.1. AGE-RELATED CHANGES IN MUSCLE TISSUE: ........................................................... 11 II.2.1.1. Muscle Fiber Atrophy: ........................................................................................... 11 II.2.1.1.1. Skeletal Muscle Structure ................................................................................... 11 II.2.1.1.2. Muscle Fiber Types and Classification ............................................................... 12 II.2.1.1.3. Organelles and Energy Metabolism .................................................................... 13 II.2.1.1.4. Excitation-Contraction Coupling (ECC) ............................................................ 13 II.2.1.1.5. Muscle Atrophy and Sarcopenia ......................................................................... 13 II 2 1 1 6 Mechanisms leading to skeletal muscle atrophy ............................................... 14 II.2.1.2. Changes in Muscle Composition: .......................................................................... 15 II.2.1.2.1. Increased intramuscular fat infiltration (myosteatosis)....................................... 15 II.2.1.2.1.1. Definition of Myosteatosis............................................................................... 15 II.2.1.2.1.2. Types of Fat Infiltration in Skeletal Muscle .................................................... 15 II.2.1.2.1.3. Cellular Origin of Fat Infiltration in Skeletal Muscle ...................................... 16 II 2 1 2 2 Increased connective tissue and fibrosis. ........................................................... 17 II.2.1.2.2.1. Extracellular Matrix (ECM) in Skeletal Muscle .............................................. 17 II.2.1.2.2.1.1Definition and Role of ECM ....................................................................... 17 II.2.1.2.2.1.2Composition of Muscle ECM ..................................................................... 17 xTable of content II.2.1.2.2.2. Structural Features and Fibrosis ...................................................................... 18 II.2.1.2.2.3. Key Molecular Factors Regulating Fibrosis in Aging Muscle ........................ 19 II.2.1.2.2.4. Definition and Development of Muscle Fibrosis ............................................. 20 II.2.1.2.2.5. Fibrosis in Dystrophic Muscle via TGF-β Signaling ....................................... 20 II.2.1.2.2.6. Age-Related Fibrosis and Muscle Function ..................................................... 21 II.2.1.3. Motor Unit Remodeling in Sarcopenia .................................................................. 21 II.2.1.3.1. The structure of the motor unit and the phenomenon of sarcopenia................... 22 II.2.1.3.2. Classification of Motor Units in Aging Muscle.................................................. 23 II.2.1.3.3. Denervation and Reinnervation in Sarcopenia ................................................... 24 II.2.1.3.4. Motor Unit Loss and Muscle Atrophy ................................................................ 24 II.2.1.3.5. Morphological Changes in Sarcopenic Muscle .................................................. 24 II.2.1.3.6. Functional Consequences for Sarcopenia ........................................................... 25 II.2.1.3.7. Neuromuscular Fatigue in Sarcopenia ................................................................ 25 II.2.2. CELLULAR AND MOLECULAR MECHANISMS: ............................................................. 26 .II.2.2.1 Protein Metabolism Imbalance:............................................................................. 26 II.2.2.1.1. Definition of MPS and MPB .............................................................................. 26 II.2.2.1.2. Muscle Protein Turnover .................................................................................... 26 II.2.2.1.3. Key Anabolic Signaling Pathway ....................................................................... 26 II.2.2.1.4. Anabolic Resistance with Aging ......................................................................... 26 II.2.2.1.5. Hormonal Contributions ..................................................................................... 27 II.2.2.1.6. Amino Acids and Protein Intake ......................................................................... 27 II.2.2.1.7. Nutritional and Exercise Interventions ............................................................... 28 II.2.2.2. Inflammation (Inflammaging): .............................................................................. 28 II.2.2.2.1. Inflammaging and Systemic Inflammation ......................................................... 28 II.2.2.2.2. Direct Effects on Skeletal Muscle ...................................................................... 28 II.2.2.2.3. Indirect Effects of Inflammation on Skeletal Muscle ......................................... 29 II.2.2.2.4. Key Inflammatory Mediators in Muscle Repair and Atrophy ............................ 30 II.2.2.2.4.1. Pro-Inflammatory Cytokines ........................................................................... 30 II.2.2.2.4.2. Anti-Inflammatory Cytokines .......................................................................... 30 II.2.2.2.4.3. TGF-β Family .................................................................................................. 31 II.2.2.2.4.4. TWEAK ........................................................................................................... 31 II.2.2.2.5. Inflammatory Response Pathways in Muscle Regeneration ............................... 31 II.2.2.3. Oxidative Stress: .................................................................................................... 31 II.2.2.3.1. Sources and Mechanisms .................................................................................... 31 xiTable of content II.2.2.3.2. Impact on Muscle Function ................................................................................ 32 II.2.2.3.3. Oxidative Stress and Inflammation ..................................................................... 32 II.2.2.4. Hormonal Changes: ............................................................................................... 33 II.2.2.5. Mitochondrial Dysfunction: ................................................................................... 34 II.2.2.5.1. Mitochondrial Homeostasis in Skeletal Muscle ................................................. 34 II.2.2.5.2. Age-Related Mitochondrial Impairments ........................................................... 34 II.2.2.5.3. Mitochondria and Aging ..................................................................................... 35 II.2.2.5.4. Mitochondrial Role in Sarcopenia ...................................................................... 35 II.2.2.5.5. Cellular Senescence and Inflammation ............................................................... 35 II.2.2.5.6. Mitochondrial Autophagy (Mitophagy) .............................................................. 35 II.2.2.6. Satellite Cell Dysfunction ...................................................................................... 36 II.2.2.6.1. Activation and Regenerative Role ...................................................................... 36 II.2.2.6.2. Satellite Cell Dysfunction Mechanisms in Sarcopenia ....................................... 36 II.2.2.6.3. Functional Consequences.................................................................................... 37 II.2.2.7. Neural Factors: ....................................................................................................... 37 II.2.2.7.1. Neuromuscular Junction and Sarcopenia ............................................................ 38 II.2.2.7.2. Age-Related NMJ Instability .............................................................................. 38 II.2.2.7.3. Denervation and Muscle Atrophy ....................................................................... 38 II.2.2.7.4. Sympathetic Nervous System Dysregulation ..................................................... 39 II.2.2.7.5. Functional Impairments in Sarcopenia ............................................................... 39 II.2.2.7.6. Interventions Targeting Neural Factors .............................................................. 39 II.3. RISK FACTORS FOR SARCOPENIA ............................................................................... 40 II.3.1. NON-MODIFIABLE RISK FACTORS: ............................................................................ 40 II.3.1.1. Age: ........................................................................................................................ 40 II.3.1.2. Sex: ........................................................................................................................ 40 II.3.1.3. Genetics: ................................................................................................................ 40 II.3.2. MODIFIABLE RISK FACTORS ...................................................................................... 42 II.3.2.1. Physical Inactivity: ................................................................................................ 42 II.3.2.2. Nutritional Deficiencies: ........................................................................................ 42 II.3.2.3. Chronic Diseases and Sarcopenia .......................................................................... 43 II.3.2.4. Lifestyle Factors Influencing Sarcopenia .............................................................. 43 II.4. CLINICAL MANIFESTATIONS AND CONSEQUENCES OF SARCOPENIA ........................ 43 II.4.1. PHYSICAL SIGNS AND SYMPTOMS: ............................................................................. 43 II.4.2. FUNCTIONAL LIMITATIONS AND DISABILITY: ............................................................ 44 xiiTable of content II.4.3. IMPACT ON METABOLIC HEALTH: .............................................................................. 45 II.4.4. INCREASED MORBIDITY AND MORTALITY ................................................................. 46 II.4.5. QUALITY OF LIFE IMPLICATIONS: ............................................................................... 47 II.5. DIAGNOSIS AND ASSESSMENT OF SARCOPENIA.......................................................... 48 II.5.1. SCREENING TOOLS FOR SARCOPENIA ......................................................................... 48 II.5.2. MEASUREMENT OF MUSCLE MASS: ........................................................................... 49 II.5.3. MEASUREMENT OF MUSCLE STRENGTH ..................................................................... 52 II.5.4. ASSESSMENT OF PHYSICAL CAPACITY ........................................................................ 52 PART II. CHAPTER 2 ........................................................................................................... 55 II.1. INTRODUCTION TO TYPE 2 DIABETES MELLITUS (T2DM) ....................................... 56 II.1.1. HISTORICAL PERSPECTIVE ......................................................................................... 56 II.1.2. CURRENT DEFINITION AND DIAGNOSTIC CRITERIA:................................................... 58 II.1.3. EPIDEMIOLOGY AND GLOBAL BURDEN ...................................................................... 59 II.2. PATHOPHYSIOLOGY OF TYPE 2 DIABETES MELLITUS............................................... 62 II.2.1. INSULIN RESISTANCE: ................................................................................................ 62 II.2.1.1. Definition of Insulin............................................................................................... 62 II.2.1.2. Biochemical Composition...................................................................................... 62 II.2.1.3. Synthesis in Pancreatic β-Cells .............................................................................. 62 II.2.1.4. Metabolic and Physiological Functions ................................................................. 62 II.2.1.5. Mechanisms of Insulin Action: .............................................................................. 62 II.2.1.6. Insulin resistance .................................................................................................... 65 II.2.1.7. Mechanisms and Pathophysiology of Insulin Resistance: ..................................... 65 II.2.1.8. Target Tissue Dysfunction : ................................................................................... 68 II.2.2. PANCREATIC BETA-CELL DYSFUNCTION : ................................................................. 68 II.2.2.1. Β-Cell Physiology .................................................................................................. 68 II.2.2.2. Mechanisms of β-Cell Dysfunction ....................................................................... 69 II.2.3. ROLE OF OTHER HORMONES AND FACTORS: .............................................................. 70 II.2.3.1. Incretins (GLP-1 and GIP) ..................................................................................... 70 II.2.3.1.1. Definition ............................................................................................................ 70 II.2.3.1.2. Function .............................................................................................................. 70 II.2.3.1.3. Pathophysiology of Incretins (GLP-1 and GIP) in Type 2 Diabetes Mellitus .... 71 II.2.3.2. Glucagon ................................................................................................................ 72 II.2.3.3. Gut Microbiota: ...................................................................................................... 73 II.3. RISK FACTORS FOR TYPE 2 DIABETES MELLITUS ..................................................... 75 xiiiTable of content II.3.1. NON-MODIFIABLE RISK FACTORS: ............................................................................ 75 II.3.1.1. Age : ....................................................................................................................... 75 II.3.1.2. Family History and Genetics: ................................................................................ 75 .II.3.1.3 Ethnicity ................................................................................................................ 76 II.3.1.4. History of Gestational Diabetes. ............................................................................ 76 II.3.1.5. Polycystic ovary syndrome (PCOS) ...................................................................... 77 II.3.2. MODIFIABLE RISK FACTORS: ..................................................................................... 77 II.3.2.1. Obesity and Overweight: ....................................................................................... 77 II.3.2.2. Physical Inactivity.................................................................................................. 78 II.3.2.3. Unhealthy Diet: ...................................................................................................... 78 II.3.2.4. Hypertension: ......................................................................................................... 78 II.3.2.5. Dyslipidemia: ......................................................................................................... 79 II.3.2.6. Smoking: ................................................................................................................ 79 II.3.2.7. Sleep Deprivation and Poor Sleep Quality: ........................................................... 80 II.4. CLINICAL MANIFESTATIONS AND COMPLICATIONS OF TYPE 2 DIABETES MELLITUS ............................................................................................................................................. 80 II.4.1. CLASSIC SYMPTOMS (OFTEN SUBTLE IN EARLY STAGES): ......................................... 80 II.4.2. ACUTE COMPLICATIONS (LESS COMMON IN T2DM AT ONSET): ................................ 81 II.4.3. CHRONIC MICROVASCULAR COMPLICATIONS : .......................................................... 82 II.4.4. CHRONIC MACROVASCULAR COMPLICATIONS:.......................................................... 82 II.5. MANAGEMENT OF TYPE 2 DIABETES MELLITUS ....................................................... 83 II.5.1. LIFESTYLE MODIFICATIONS ....................................................................................... 83 II.5.2. PHARMACOLOGICAL INTERVENTIONS ........................................................................ 84 II.5.3. GOALS OF DIABETES MANAGEMENT .......................................................................... 85 PART II: CHAPTER 03 ......................................................................................................... 87 II.1. THE IMPACT OF TYPE 2 DIABETES ON SARCOPENIA (DIABETIC SARCOPENIA) ....... 88 II.1.1. ACCELERATED MUSCLE LOSS IN INDIVIDUALS WITH T2DM: .................................... 88 II.1.1.1. Epidemiology and Prevalence ............................................................................... 88 II.1.1.2. Sex Differences in Muscle Loss ............................................................................ 88 II.1.1.3. Pathological Changes in Muscle Fibers ................................................................. 88 II.1.1.4. Impact on Endocrine and Metabolic Regulation ................................................... 89 II.1.2. UNDERLYING MECHANISMS CONTRIBUTING TO DIABETIC SARCOPENIA: .................. 89 II.1.2.1. Insulin Resistance and Impaired Muscle Protein Metabolism:.............................. 89 II.1.2.1.1. Dysregulated Protein Synthesis and Degradation Pathways .............................. 89 xivTable of content II.1.2.1.2. Role of Hyperglycemia and Glycemic Control .................................................. 90 II.1.2.2. Chronic Low-Grade Inflammation and Advanced Glycation End Products (AGEs):................................................................................................................................ 90 II.1.2.2.1. Pro-Inflammatory Cytokines .............................................................................. 90 II.1.2.2.2. Anti-Inflammatory Cytokines ............................................................................. 90 II.1.2.2.3. Protein Degradation ............................................................................................ 91 II.1.2.2.4. mTORC1 Dysregulation ..................................................................................... 91 II.1.2.2.5. Muscle Mass and Strength Impact ...................................................................... 91 II.1.2.2.6. Advanced Glycation End-Products (AGEs) ....................................................... 91 II.1.2.3. Oxidative Stress in Diabetic Muscle: ..................................................................... 91 II.1.2.3.1. Hyperglycemia-Induced ROS and Protein Degradation ..................................... 92 II.1.2.3.2. Mitochondrial Dysfunction ................................................................................. 92 II.1.2.3.3. Impaired Muscle Repair and Signaling Pathways .............................................. 92 II.1.2.4. Microvascular Complications and Impaired Muscle Perfusion: ............................ 93 II.1.2.4.1. Diabetic Nephropathy ......................................................................................... 93 II.1.2.4.2. Diabetic Neuropathy ........................................................................................... 94 II.1.2.4.3. Diabetic Retinopathy .......................................................................................... 94 II.1.2.4.4. Pathophysiological Mechanisms ......................................................................... 94 II.2. THE IMPACT OF SARCOPENIA ON TYPE 2 DIABETES (SARCOPENIA AS A RISK FACTOR AND CONTRIBUTING FACTOR) ............................................................................. 95 II.2.1. SARCOPENIA AS A RISK FACTOR FOR DEVELOPING T2DM: ....................................... 95 II.2.2. MECHANISMS BY WHICH SARCOPENIA CONTRIBUTES TO INSULIN RESISTANCE AND METABOLIC DYSFUNCTION: ................................................................................................. 95 II.2.2.1. Reduced Glucose Disposal: ................................................................................... 95 II.2.2.2. Altered Adipokine Profile: ..................................................................................... 96 II.2.2.3. Lipid Infiltration and Lipotoxicity in Skeletal Muscle .......................................... 96 II.2.2.4. Reduced Proportion of Type I Muscle Fibers ........................................................ 97 PART III : MATERIALS AND METHODS .................................................................. 99 III.3. RESEARCH METHODOLOGY .................................................................................... 100 III.3.1. STUDY DOMAIN ...................................................................................................... 100 III.3.1.1. Temporal Domain ............................................................................................... 100 III.3.1.2. Spatial Domain ................................................................................................... 100 xvTable of content III.3.2. OBJECTIVE OF THE STUDY ...................................................................................... 101 III.3.3. MATERIALS AND METHODS .................................................................................... 101 III.3.3.1. Study Design ...................................................................................................... 101 III.3.3.2. Study Population and Sampling ......................................................................... 101 III.3.3.3. Data Collection Tool .......................................................................................... 102 III.3.4. DATA ANALYSIS ..................................................................................................... 102 PART IV : RESULTS AND DISCUSSION .................................................................. 103 III.1. SARCOPENIA IN TYPE 2 DIABETES MELLITUS: THE INTERPLAY OF AGE, GENDER, COMORBIDITIES, LIFESTYLE BEHAVIORS, AND DIETARY FACTORS .............................. 104 CONCLUSION AND PERSPECTIVES ....................................................................... 118 PART V. BIBLIOGRAPHICAL REFERENCES ........................................................ 121 ANNEXES ........................................................................................................................ 132 III.1. SURVEY ON SARCOPENIA AND T2D ......................................................................... 133 III.2. ONLINE QUESTIONNAIRE:........................................................................................ 135 |
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