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Insulin Signaling Pathways That Regulate Glucose Metabolism in Muscle Cells and Adipocytes

Insulin Signaling Pathways That Regulate Glucose Metabolism in Muscle Cells and Adipocytes. INSULIN RESISTANCE SYNDROME. Mechanisms. Role of Muscles Expression of Cytokines in Insulin Resistance Syndrome. Saghizadeh, JCI 1996. Role of Muscles Expression of Cytokines

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Insulin Signaling Pathways That Regulate Glucose Metabolism in Muscle Cells and Adipocytes

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  1. Insulin Signaling Pathways That Regulate Glucose Metabolism in Muscle Cells and Adipocytes

  2. INSULIN RESISTANCE SYNDROME Mechanisms

  3. Role of Muscles Expression of Cytokines in Insulin Resistance Syndrome Saghizadeh, JCI 1996

  4. Role of Muscles Expression of Cytokines in Insulin Resistance Syndrome Saghizadeh, JCI 1996 (triangles) Insulin sensitive (circles) Insulin resistant (squares) Diabetic

  5. Tumor Necrosis Factor-–Induced Insulin Resistance in Adipocytes Qi, Exp Biol Med 2000

  6. LPS Regulates Proinflammatory Cytokine Expression in Skeletal MuscleFrost,A J P Regul Integr Comp Physiol, 2002

  7. Marked Reduction of GLUT4 in Muscle or Adipose Tissue Causes Insulin Resistance Minokoshi, JBC, 2003

  8. INSULIN RESISTANCE SYNDROME Clinical significance

  9. Hyperglycemia and Outcome in the Acutely IllUmpierrez, JCEM 2002

  10. Hyperglycemia and Outcome in the Acutely van den Berghe, CCM 2003 <110 110-150 >150

  11. Glucose Control and Mortality in Critically Ill Patients Finney et al JAMA 2003

  12. Effects of Intensive Insulin Therapy on Survival in Surgical ICU patients. Van den Berghe, NEJM 2002

  13. Effects of Intensive Insulin Therapy on Morbidity in Surgical ICU patients. Van den Berghe, NEJM 2002 * * *

  14. THE ACTORS? • HYPOTHALAMIC PITUITARY ADRENAL AXIS • NORADRENERGIC SYSTEM • GLUCOSE / INSULINE DUO • VASOPRESSIN

  15. VASOPRESSIN SYNTHESIS Magnocellular nucleus Parvocellular nucleus Hypothalamus Anterior hypophysis PRL ADH GH TSH Neurohypophysis ACTH LH FSH MSH

  16. OSMOTIC ADAPTATION PLASMA URINE VASSOPRESIN (pg/ml) OSMOLALITY (mOsm/kg)

  17. HEMODYNAMIC ADAPTATION VASOPRESSIN (pg/ml) VARIATIONS (%)

  18. VASOPRESSIN INSUFFICIENCY Mechanisms

  19. AVP KINETICS IN SEPTIC SHOCKANIMAL MODELS ENDOTOXIN CONTROLS

  20. VASOPRESSIN IN LATE SEPTIC SHOCK SBP = 92±2 Sodium = 140±2 22.7±2.2 SBP = 101±3 Sodium = 139±1 3.1±0.4 SEPTIC SHOCK CARDIOGENIC SHOCK Landry 1997

  21. 20 15 PATIENTS 10 CONTROLS 5 0 350 250 270 290 310 330 AVP IN LATE SEPTIC SHOCK: OSMOTIC ADAPTATION 25 VASOPRESSIN (pg/ml) PLASMA OSMOLALITY mOsmol/L

  22. AVP IN LATE SEPTIC SHOCK: HEMODYNAMIC ADAPTATION Hypotensive Normotensive 20 15 VASOPRESSIN (pg/ml) 10 5 0 20 40 60 80 100 120 140 160 180 200 Systolic Blood Pressure (mm Hg)

  23. AVP AS A FUNCTION OF TIME IN HUMAN SEPTIC SHOCK

  24. Vasopressin Deficiency Contributes to the Vasodilation of Septic Shock . Donald W. Landry, et al Circulation 1997

  25. VASOPRESSIN IN LATE SEPTIC SHOCK Before AVP infusion 0.01 UI of AVP infusion Landry 1997

  26. IMPAIRED BAROREFLEX MEDIATED SYNTHESIS 20 15 VASOPRESSIN (pg/ml) 10 5 0 20 40 60 80 100 120 140 160 180 200 Systolic Blood Pressure (mm Hg) Impaired Baroreflex Normal Baroreflex

  27. NEUROHYPOPHYSIS IN SEPTIC SHOCK NORMAL SUBJECT ACUTE PHASE RECOVERY

  28. Astrocytic and Microglial Reactions • Nucleus Supra-Opticus

  29. VASOPRESSIN INSUFFICIENCY Clinical significance

  30. Arginine Vasopressin in Advanced Vasodilatory Shock A Prospective, Randomized, Controlled Study Dünser, Circulation 2003 * * * * PAM mmHg * * * Dose NE, µg/kg/min

  31. Arginine Vasopressin in Advanced Vasodilatory Shock A Prospective, Randomized, Controlled Study Dünser, Circulation 2003 * * * CI L/min/m2 SVRI dyne ·cm-5 · xm-2

  32. TAKE HOME MESSAGE • HORMONES ARE ESSENTIAL TO SURVIVE TO A STRESS • ANIMAL MODELS CONSISTENTLY SHOWED THAT SEPSIS IS ASSOCIATED WITH FAILURE OF THE VARIOUS HORMONAL SYSTEMS • OVERALL CLINICAL STUDIES IN SEVERE SEPSIS CONFIRMED BAD OUTCOMES ASSOCIATED WITH FAILING HORMONAL SYSTEMS • HORMONE REPLACEMENT THERAPY MAY BE THE FUTURE OF SEVERE SEPSIS MANAGEMENT

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