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Slides18

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Slides18

  1. 1. Metabolic Dyslipidemia in Insulin Resistant States Pathobiology & Molecular Mechanisms Khosrow Adeli Ph.D., FCACB, DABCC, NACB Head & Professor, Clinical Biochemistry Laboratory Medicine and Pathobiology Hospital for Sick Children University of Toronto Toronto, CANADA
  2. 2. Summary of PresentationSummary of Presentation Introduction:Introduction: Insulin Resistance/Metabolic DyslipidemiaInsulin Resistance/Metabolic Dyslipidemia Recent ObservationsRecent Observations Animal Model of Insulin ResistanceAnimal Model of Insulin Resistance (Fructose-Fed Syrian Golden Hamster) • Evidence for Hepatic VLDL Overproduction • Evidence for Hepatic Insulin Resistance • Evidence for Intestinal Lipoprotein Overproduction
  3. 3. The diverse biological manifestations of the insulin resistant state arise as a consequence of both a blunted insulin action as well as the compensatory hyperinsulinemia per se. Insulin Resistance Insulin resistant peripheral tissues Insulin Increased insulin action in more sensitive tissues or biochemical pathwaysPancreas
  4. 4. Clinical spectrum of insulin resistant states • Rare (genetic) forms of insulin resistance • Obesity (central, abdominal, visceral, android) • Fasting hyperglycemia/Impaired glucose tolerance • Type 2 diabetes mellitus
  5. 5. Putative Candidate Gene Mutations inPutative Candidate Gene Mutations in Insulin ResistanceInsulin Resistance •• Glut 1Glut 1 •• Glut 4Glut 4 •• HexokinaseHexokinase IIII •• ISPK-1ISPK-1 •• GSK-3(GSK-3(αα,,ββ)) •• PPIC (PPIC (αα,,ββ,,γγ)) •• PPIGPPIG •• GlycogenGlycogen SynthaseSynthase •• GS-inhibitor-2GS-inhibitor-2 •• GlycogeninGlycogenin •• PhosphofructokinasePhosphofructokinase •• Hormone Sensitive LipaseHormone Sensitive Lipase •• Insulin ReceptorInsulin Receptor •• IRS-1/2IRS-1/2 •• ShcShc •• PI3-PI3-kinasekinase •• ProteinProtein KinaseKinase B (B (αα,,ββ)) •• PPARPPARγγ •• LeptinLeptin •• LeptinLeptin ReceptorReceptor •• b2-b2-adrenergicadrenergic receptorreceptor •• UCP-1UCP-1 •• UCP-2UCP-2 •• NPYNPY •• NPY receptorNPY receptor isoformsisoforms Glucose MetabolismGlucose Metabolism Lipid MetabolismLipid Metabolism Insulin Sensitization/Insulin Sensitization/ desensitizationdesensitization Insulin ActionInsulin Action ObesityObesity
  6. 6. Disorders associated with insulin resistance • Dyslipidemia • Hypertension • Polycystic ovarian disease • Hyperuricemia • Thrombogenic/fibrinolytic abnormalities • Atherosclerosis
  7. 7. Features of Metabolic Dyslipidemia •• HypertriglyceridemiaHypertriglyceridemia TG,TG, ApoBApoB VLDL-TG and VLDL-apoB secretionVLDL-TG and VLDL-apoB secretion Small Dense LDLSmall Dense LDL ( LDL particle density)( LDL particle density) •• Reduced HDL-CReduced HDL-C •• Increase FFAIncrease FFA
  8. 8. FFA FA VLDL DNL Adipose tissue Muscle Liver Intestine TG mobilization by tissue lipases TG, CE ApoB Cytosolic TG stores Oxidation Lipases LPL Mechanisms of VLDL overproductionMechanisms of VLDL overproduction in Insulin Resistancein Insulin Resistance Hepatic Insulin Resistance Adeli K. et al. (2000) J. Biol. Chem. 275: 8416-8425. Adeli K. et al. (2002) J. Biol. Chem. 277:793-803.

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