201 metabolic dyslipidemia
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Transcript of 201 metabolic dyslipidemia
Metabolic Dyslipidemia in Insulin Resistant States
Pathobiology & Molecular Mechanisms
Khosrow Adeli Ph.D., FCACB, DABCC, NACBHead & Professor, Clinical Biochemistry
Laboratory Medicine and PathobiologyHospital for Sick Children
University of TorontoToronto, CANADA
Summary of PresentationSummary of PresentationIntroduction: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
The diverse biological manifestations of the insulinresistant state arise as a consequence of botha blunted insulin action as well as the compensatoryhyperinsulinemia per se.
Insulin Resistance
Insulin resistantperipheral tissues
Insulin
Increased insulin action in more sensitive tissues or biochemical pathwaysPancreas
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
Putative Candidate Gene Mutations inPutative Candidate Gene Mutations in Insulin Resistance Insulin Resistance
•• Glut 1Glut 1•• Glut 4Glut 4•• HexokinaseHexokinase II II•• ISPK-1ISPK-1•• GSK-3(GSK-3(,,))•• PPIC (PPIC (,,,,))•• PPIGPPIG•• GlycogenGlycogen Synthase Synthase•• 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 Kinase Kinase B ( B (,,))
•• PPARPPAR
•• LeptinLeptin•• LeptinLeptin Receptor Receptor•• b2-b2-adrenergicadrenergic receptor receptor•• UCP-1UCP-1•• UCP-2UCP-2•• NPYNPY•• NPY receptorNPY receptor isoforms isoforms
Glucose MetabolismGlucose MetabolismLipid MetabolismLipid Metabolism
Insulin Sensitization/Insulin Sensitization/desensitizationdesensitization
Insulin ActionInsulin Action ObesityObesity
Disorders associated with insulin resistance
• Dyslipidemia• Hypertension• Polycystic ovarian disease• Hyperuricemia• Thrombogenic/fibrinolytic abnormalities• Atherosclerosis
Features of Metabolic Dyslipidemia
•• HypertriglyceridemiaHypertriglyceridemiaTG,TG, ApoB ApoBVLDL-TG and VLDL-apoB secretionVLDL-TG and VLDL-apoB secretionSmall Dense LDLSmall Dense LDL( LDL particle density)( LDL particle density)
• • Reduced HDL-CReduced HDL-C
• • Increase FFAIncrease FFA
FFA
FA
VLDL
DNL
Adipose tissue
Muscle
Liver
Intestine
TG mobilizationby tissue lipases
TG, CEApoB
Cytosolic TGstores
Oxidation
Lipases
LPL
Mechanisms of VLDL overproduction Mechanisms 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.