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This document discusses metabolic dyslipidemia in insulin resistant states. It provides an overview of insulin resistance and its biological manifestations. It also summarizes recent observations from a animal model showing evidence of hepatic VLDL overproduction, hepatic insulin resistance, and intestinal lipoprotein overproduction in insulin resistant states. Putative candidate genes involved in insulin resistance and its effects on glucose and lipid metabolism are listed. Features of metabolic dyslipidemia such as hypertriglyceridemia, reduced HDL, and small dense LDL particles are described. Mechanisms of increased VLDL production in the liver under insulin resistant conditions are also summarized.
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- 1. Metabolic Dyslipidemia in InsulinResistant 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. Summary of PresentationSummaryof 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. The diverse biologicalmanifestations 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. Clinical spectrum of insulinresistant states • Rare (genetic) forms of insulin resistance • Obesity (central, abdominal, visceral, android) • Fasting hyperglycemia/Impaired glucose tolerance • Type 2 diabetes mellitus
- 5. Putative Candidate GeneMutations 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. Disorders associated withinsulin resistance • Dyslipidemia • Hypertension • Polycystic ovarian disease • Hyperuricemia • Thrombogenic/fibrinolytic abnormalities • Atherosclerosis
- 7. Features of MetabolicDyslipidemia •• 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. FFA FA VLDL DNL Adipose tissue Muscle Liver Intestine TG mobilization bytissue 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.