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.