Postulated Mechanisms of Insulin ResistancePostulated Mechanisms of Insulin Resistance
PTP-1BPTP-1B Mass & Activity Mass & Activity
Impaired Phosphorylation ofImpaired Phosphorylation ofInsulin Receptor, IRS-1Insulin Receptor, IRS-1
PI-3 Kinase ActivityPI-3 Kinase Activity
Attenuated Insulin SignalingAttenuated Insulin Signaling
Reduced Phosphorylation of ApoB or Reduced Phosphorylation of ApoB or an apoB-chaperonean apoB-chaperone
Enhanced Stability and Accelerated Assembly of ApoBEnhanced Stability and Accelerated Assembly of ApoB
Overproduction of VLDLOverproduction of VLDL
ER-60MTP
Intestine
Contribution of the Intestinal LipoproteinsContribution of the Intestinal Lipoproteinsto Metabolic Dyslipidemia in Insulin Resistanceto Metabolic Dyslipidemia in Insulin Resistance
Liver
ApoB48
ApoB100
Intestinal Lipoprotein Metabolism
Dietary Dietary
CholesterolCholesterol
Dietary Dietary
FatFat
LuminalLuminal
TriglycerideTriglyceride
LipasesLipases
Bile AcidsBile Acids
Fatty AcidsFatty Acids
Mocellar CholesterolMocellar Cholesterol
Fatty AcidsFatty Acids
CholrdyrtolCholrdyrtol
ApoB48 + TG + CEApoB48 + TG + CE
TGTG
CMCM
ABCA1ABCA1
ABCG5ABCG5
ABCG8ABCG8
Fatty Acid TransportersFatty Acid Transporters
Intestinal Epithelial CellIntestinal Epithelial Cell
(Intake)(Intake)
(Uptake)(Uptake)
(Chylomicron (Chylomicron
Assembly)Assembly)
(Cholesterol (Cholesterol
Excretion)Excretion)
Intestinal Lipid Absorption
(Trigleride (Trigleride
Synthesis)Synthesis)
Hypothesis III:Fasting and postprandial hyperlipidemia in insulin resistant states may be attributable in part to intestinal oversecretion of apoB-48 containing lipoproteins
Experimental Approach:•Dietary induction of an insulin resistant state in
the hamster by high fructose feeding
• Isolation of adult viable villi from Syrian hamster small intestine.
• -In Vivo Studies to assess production rate of intestinal (apoB48-containing) lipoproteins
• -Ex Vivo Studies to assess intestinal apoB48 lipoprotein synthesis and secretion, mechanisms of chylomicron assembly, role of de novo lipogenesis in intestinal lipoprotein secretion in the fasting and postprandial states
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