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