SHAPE Society

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. 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. 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. 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. 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. Disorders associated with insulin resistance
• Dyslipidemia
• Hypertension
• Polycystic ovarian disease
• Hyperuricemia
• Thrombogenic/fibrinolytic abnormalities
• Atherosclerosis

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. 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.