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Page 1: RISK FACTORS FOR ATHEROSCLEROSIS IN OBESE CHILDREN

RISK FACTORS FOR ATHEROSCLEROSIS IN OBESE CHILDREN

DyslipidemiaHigh triglycerides, VLDLLow HDLHigh small, dense LDL

Glucose intolerance, diabetes

Hypertension

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Pathobiological Determinants of Atherosclerosis in Youth Study (PDAY)

Strong, et al. JAMA 281:727-735, 1999

• 3000 autopsies after trauma, age 15-34y, 9 centers• 15-19y: fatty streaks in all aortas, half of coronaries • More fatty streaks and advanced plaque with

» high LDL, VLDL» low HDL» high blood pressure» smoking» obesity» glucose intolerance

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McGill et al Am J Clin Nutr 72:1307S-15S, 2000

PDAY: Low Risk vs. High Risk Lipid Profiles

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Title: Differences in Vascular Compliance in Pediatric Patients at Risk for Cardiovascular Disease as Measured by Endo-PAT Technology

PI: Rubin Cooper, M.D., Dept. of Cardiology

Subjects: age 8-18, 20 per group:1) healthy controls2) overweight (BMI>95%)3) high cholesterol and/or triglycerides4) fatty liver

Study Design: at baseline, 6 and 12 months:1) endo-PAT test2) carotid artery wall thickness by ultrasound3) fasting blood sample

Pediatric Obesity Council Protocol

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Does sugar make us Does sugar make us fatfat, , dyslipidemicdyslipidemic and and diabeticdiabetic??

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Duffey, K. J et al. Am J Clin Nutr 2008;88:1722S-1732S

Major Sources of Calories as High-fructose Corn syrup (HFCS) and Sucrose

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Nutritional Studies of:

1) Chronic effects of the equicaloric substitution of carbohydrate for fat

1) Acute effects of oral challenges with fructose

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Dietary Fructose:- Does not acutely raise glucose or insulin- Raises plasma triglycerides more than glucose- Rapidly increases palmitate synthesis?

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AU

C T

G %

16:0

AU

C T

G %

16:0

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Hypothesis: In overweight subjects, the synthesis of palmitate from dietary fructose will be

1) greater when consumed with glucose2) show a dose-response.

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Study Design:Outpatient, random order, cross-over, single blinded study in 15 overweight subjects

1)Screening visit with 3h OGTT (75 g glucose, mean 0.9g/kg)

2)Sugar in 12 oz water, 15 min:• Fructose, 0.5g/kg• Fructose:Glucose 1g/kg• Fructose:Glucose 2g/kg

3)Blood sampling at 0, 1, 2, 3, 4h

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Lessons Learned:

• The equicaloric substitution of fat with sugar does not increase body fat.

• The equicaloric substitution of fat with sugar, fructose more than glucose, causes dyslipidemia by increasing the production of fat from sugar in the liver.

• The large within-subject variability in response may be partially explained by differences in insulin sensitivity.

• Dyslipidemia associated with obesity is readily corrected by modifications in diet and physical activity.

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Some unanswered questions:

1)Does the lipogenic response to sugar predict susceptibility to diabetes, fatty liver and atherosclerosis?

2)Are there age- and family-specific differences in sugar-induced lipogenesis?

3)What are optimal levels of HFCS/sucrose in the diet?

4)What are the best ways to evaluate extent and progression of insulin resistance and atherosclerosis?

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% De Novo Lipogenesis Pre- and Post-FructoseControls (n=15)

Hours Post-Fructose

-5 0 5 10 15 20 25 30

% D

NL

0

10

20

30

40

50

%%

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