the trouble with fructose robert h. lustig, m.d. division of endocrinology department of pediatrics...
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The trouble with fructoseThe trouble with fructose
Robert H. Lustig, M.D.Robert H. Lustig, M.D.Division of EndocrinologyDivision of EndocrinologyDepartment of PediatricsDepartment of Pediatrics
University of California, San FranciscoUniversity of California, San Francisco
ASTPHND, Madison, WI, June 8, 2008
Hill et al. Science 299:853, 2003
Prediction of BMI distribution in adults, 2008Prediction of BMI distribution in adults, 2008
The entire curve has shifted
The First Law of ThermodynamicsThe First Law of Thermodynamics
CaloriesInCalories
Out
Weight Gain
Children 2-17 yrs, CSFII (USDA) 1989-91 vs. 1994-95http://www.usda.gov/cnpp/FENR%20V11N3/fenrv11n3p44.PDF
Total Caloric IntakeTotal Caloric Intake
275 kcal in teen boys
Fat Intake: GramsFat Intake: Grams
5 g (45 cal) in teen boys
Children 2-17 yrs, CSFII (USDA) 1989-91 vs. 1994-95
Carbohydrate Intake: GramsCarbohydrate Intake: Grams
57 g (228 cal) in teen boys
Children 2-17 yrs, CSFII (USDA) 1989-91 vs. 1994-95
0
10
20
30
40
50
60
1960 1970 1980 1990 2000
Obesity prevalence
Calories from fat
Year
Per
cen
tPrevalence of Obesity Compared to PercentPrevalence of Obesity Compared to Percent
Calories from Fat Among US AdultsCalories from Fat Among US Adults
Beverage IntakeBeverage Intake
41% soft drinks
Children 2-17 yrs, CSFII (USDA) 1989-91 vs. 1994-95
35% fruit drinks
Beverage IntakeBeverage Intake
41% soft drinks
Children 2-17 yrs, CSFII (USDA) 1989-91 vs. 1994-95
35% fruit drinks
One can of soda/day = 150 cal x 365 d/yr ÷ 3500 cal/lb = 15.6 lbs/yr!One can of soda/day = 150 cal x 365 d/yr ÷ 3500 cal/lb = 15.6 lbs/yr!
“There is no association between sugar
consumption and obesity.”Richard Adamson
Scientist for National Soft Drink Association
BMJ 326, March, 2003
• Each additional sugar-sweetened drink increase over a 19 month follow-up
– BMI 0.24 kg/m2 (95% CI: 0.1-0.39)
– OR for obesity 1.6 (95% CI: 1.14-2.24)Ludwig et al. Lancet 2001
Are soft drinks the cause of obesity?Are soft drinks the cause of obesity?
Meta-Analysis of Soft Drinks and ObesityMeta-Analysis of Soft Drinks and Obesity
88 cross-sectional and longitudinal studies regressing
soft drink consumption with —
• energy intake r = 0.16 (P < 0.001)
• body weight r = 0.08 (P < 0.001)
• milk and calcium intake r = -0.12 (P < 0.001)
• adequate nutrition r = -0.10 (P < 0.001)
Those studies funded by the beverage industry demonstrated smaller effects than independent studies
Vartanian et al. Am J Public Health epub March 2007; 10.2105/AJPH.2005.083782
Obesi
ty P
revale
nce
(%
)
James et al. BMJ 328:1237, 2004
Curtailing soft drinks limits childhood obesityCurtailing soft drinks limits childhood obesity
High Fructose Corn Syrup
Current US annual consumption of HFCS
• 63 pounds per person
High Fructose Corn SyrupHigh Fructose Corn Syrup
SucroseSucrose
FructoseFructose 173173
invert sugar* 120
HFCS (42-55% fructose)HFCS (42-55% fructose) 120120
Sucrose 100
Xylitol 100
Tagatose 92
Glucose 74
high-DE corn syrup 70
Sorbitol 55
Mannitol 50
Trehalose 45
regular corn syrup 40
Galactose 32
Maltose 32
Lactose 15
Relative sweetness of various carbohydratesRelative sweetness of various carbohydrates
From the Corn Refiners AssociationFrom the Corn Refiners AssociationDecember, 2006December, 2006
Unlikely Duo Opposes San Francisco Soft Drink Tax PlanCorn Refiners and CSPI Agree High-Fructose Corn Syrup No Worse Than Sugar
WASHINGTON—The nonprofit Center for Science in the Public Interest has long supported small taxes on soft drinks to help pay for bike paths, nutrition education, and other obesity-prevention programs. But CSPI opposes a measure proposed by San Francisco Mayor Gavin Newsom because it would tax only drinks made with high-fructose corn syrup and not drinks made with other forms of sugar. Less surprisingly, the Corn Refiners Association also opposes the measure, but the two groups cosigned an unusual joint letter to Mayor Newsom urging him to reconsider his plan.
“We respectfully urge that the proposal be revised as soon as possible to reflect the scientific evidence that demonstrates no material differences in the health effects of high-fructose corn syrup and sugar,” wrote CSPI executive director Michael F. Jacobson and Corn Refiners Association president Audrae Erickson. “The real issue is that excessive consumption of any sugars may lead to health problems.”
The letter goes on to explain that high-fructose corn syrup and sucrose, or table sugar, are similar in composition and that several studies have shown that the two types of sugars are similarly metabolized by the body.
Press Release, February 6, 2008
High Fructose Corn Syrup is 42-55% Fructose;High Fructose Corn Syrup is 42-55% Fructose;Sucrose is 50% FructoseSucrose is 50% Fructose
GlucoseGlucose FructoseFructose
SucroseSucrose
Faith MS et al. Pediatrics 118:2066, 2006
Juice is sucrose:Juice is sucrose:Change in BMI z-score in lower socioeconomic status Change in BMI z-score in lower socioeconomic status children versus number of fruit juice servings per daychildren versus number of fruit juice servings per day
High Fructose Corn SyrupHigh Fructose Corn Syrup
SucroseSucrose
JUICEJUICE
MOST FRUCTOSE ITEMS
Fructose is not glucoseFructose is not glucose
• Fructose is 7 times more likely than glucose to form Advanced Glycation End-Products (AGE’s)
• Fructose does not suppress ghrelin
• Acute fructose does not stimulate insulin (or leptin)
• Hepatic fructose metabolism is different
• Chronic fructose exposure promotes the Metabolic Syndrome
Elliot et al. Am J Clin Nutr, 2002Elliot et al. Am J Clin Nutr, 2002Bray et al. Am J Clin Nutr, 2004Bray et al. Am J Clin Nutr, 2004Teff et al. J Clin Endocrinol Metab, 2004Teff et al. J Clin Endocrinol Metab, 2004
Gaby, Alt Med Rev, 2005Gaby, Alt Med Rev, 2005Le and Tappy, Curr Opin Clin Nutr Metab Care, 2006Le and Tappy, Curr Opin Clin Nutr Metab Care, 2006Wei et al. J Nutr Biochem, 2006Wei et al. J Nutr Biochem, 2006
Hepatocyte
24 kcal
96 kcal
Ethanol is a carbohydrate
CH3-CH2-OH
But ethanol is also a toxin
Acute ethanol exposure
• CNS depression
• Vasodilatation, decreased BP
• Hypothermia
• Tachycardia
• Myocardial depression
• Variable pupillary responses
• Respiratory depression
• Diuresis
• Hypoglycemia
• Loss of fine motor control
Acute fructose exposure
60 kcal(+ 12 kcalglucose)
48 kcal
Isganaitis and Lustig, Arterio Thromb Vasc Biol 25:2451, 2006
Why is exercise important in obesity?Why is exercise important in obesity?
Because it burns calories?
Because it improves skeletal muscle insulin sensitivity
Because it reduces stress, and resultant cortisol release
Because it makes the TCA cycle run faster, and detoxifies fructose, improving hepatic insulin sensitivity
Chronic ethanol exposure
• Hematologic disorders
• Electrolyte abnormalities
• Hypertension
• Cardiac dilatation
• Cardiomyopathy
• Dyslipidemia
• Pancreatitis
• Malnutrition
• Obesity
• Hepatic dysfunction (ASH)
• Fetal alcohol syndrome
• Addiction
Chronic fructose exposure
• Hypertension
• Myocardial infarction
• Dyslipidemia
• Pancreatitis (2o dyslipidemia)
• Obesity
• Hepatic dysfunction (NASH)
• Fetal insulin resistance
• Habituation, if not addiction
UCSF Weight Assessment for Teen and Child Health (WATCH) Clinic
294 patients 2003-2006
• Race/Ethnicity Median Min Max Normal BMI 33.2 20.0 92.4 <25 BMI z-score 2.5 1.3 4.4 0 FBG 87 58 119 <100 Insulin 20.7 2 117.5 5-20 HOMA-IR 4.3 0.34 28.1 <4 Maternal BMI 28.9 17.7 58.6 <25 Paternal BMI 28.9 16.7 48.8 <25
• Biochemistry
Mietus-Snyder et al. (submitted)
UCSF WATCH ClinicUCSF WATCH ClinicAssociations with the Metabolic SyndromeAssociations with the Metabolic Syndrome
Baseline Characteristic (mean ± SD)
HOMA-IR >5* N=124
HOMA-IR<5 N=147
P-value**
BMI z-score 2.6, 2.3-2.8 2.5, 2.2-2.7 0.06
BP syst 125 ± 13 113 ± 15 <0.001
BP diast 68 ± 9 64 ± 8 <0.001
Triglyceride (mU/dl)
102, 69-138 83, 57-110 0.005
HDL-c (mU/dl)
41 ± 10 43 ± 10 0.04
Fasting Glc (mg/dl)
92 + 9
85 + 9
<0.001
Fasting Insulin (mU/ml)
33.7,28.6-47.1
15.2,11.2-19.8
<0.001
Creatinine (mg/dl)
0.64 + 0.14
0.58 + 0.15
0.003
ALT (U/L) 35, 23-50 23, 18-31 <0.001
MetS+ 52% 29% <0.001
Sugared Beverage Intake (kcal/d)
269, 100-423
129, 21-288
0.002
Breakfast (days/wk)
4, 0-7 7, 5-7 <0.001
Mietus-Snyder et al. (submitted)
UCSF WATCH ClinicUCSF WATCH ClinicLifestyle InterventionLifestyle Intervention
• Get rid of all sugared liquids—only water and milk
• Eat your carbohydrate with fiber
• Wait 20 minutes for second portions
• Buy your screen time minute-for-minute with
physical activity
Pts are followed every 3 months
UCSF WATCH Clinic Lifestyle Intervention:UCSF WATCH Clinic Lifestyle Intervention:Median Change in BMI z-score from BaselineMedian Change in BMI z-score from Baseline
0 10 20 30Median Time (mos) from initial visit
Madsen et al. (submitted)
UCSF WATCH Clinic Predictors of Lifestyle Intervention
• Forward selection model, 4 variables
Source | SS df MS Number of obs = 130-------------+------------------------------ F( 4, 125) = 6.49 Model | .169200646 4 .042300161 Prob > F = 0.0001 Residual | .81467663 125 .006517413 R-squared = 0.1720-------------+------------------------------ Adj R-squared = 0.1455 Total | .983877276 129 .007626956 Root MSE = .08073
------------------------------------------------------------------------------ Delta z/yr | Coef. Std. Err. t P>|t| Beta-------------+---------------------------------------------------------------- sugared bev| .012786 .0048643 2.63 0.010 .2268616 HOMA| .0034239 .0018131 1.89 0.061 .1707474Baseline BMIZ| .0311507 .0199972 1.56 0.122 .1430862Baseline Age | .0027542 .0022543 1.22 0.224 .1055135 _cons | -.1475346 .0573037 -2.57 0.011 .------------------------------------------------------------------------------
Madsen et al. (submitted)
The “fructosification” of AmericaThe “fructosification” of America
(and the world)(and the world)
Can you name the seven foodstuffs atCan you name the seven foodstuffs at
McDonald’s that don’t have HFCS or sucrose?McDonald’s that don’t have HFCS or sucrose?
1. French Fries (salt, starch, and fat)
2. Hash Browns (salt, starch, and fat)
3. Chicken McNuggets (salt, starch, and fat)
4. Sausage
5. Diet Coke
6. Coffee
7. Iced Tea
Who’s really drinking this?Who’s really drinking this?
The SFUSD School Milk Program
Courtesy ofM. Lustig
J. Nutr. 136:1086, 2006
What about WIC?What about WIC?
Could this be the reason for obesity with Could this be the reason for obesity with formula feeding?formula feeding?
INGREDIENTS (Powder)((U) Pareve*)
43.2% Corn syrup solids, 14.6% soy protein isolate, 11.5% high oleic safflower oil, 10.3% sugar (sucrose), 8.4% soy oil, 8.1% coconut oil
Courtesy of M. Walker
Calories 150 150Percent CHO 10.5% (sucrose) 3.6% (alcohol)Calories from
fructose 75 (4.1 kcal/gm)other carbs 75 (glucose) 60 (maltose)alcohol 90 (7 kcal/gm)
1st pass GI metabolism 0% 10%Calories reaching liver 90 92
What’s the difference?What’s the difference?
Fructose is a carbohydrate
Fructose is metabolized like fat
Fructose is also a toxin
(corollary: a low fat diet isn’t really low fat, because the fructose/sucrose doubles as fat)
DESIGN, MANUFACTURING AND MARKETING OF DESIGN, MANUFACTURING AND MARKETING OF TOBACCO PRODUCTS: TOWARDS A SENSIBLE TOBACCO PRODUCTS: TOWARDS A SENSIBLE
REGULATORY FRAMEWORKREGULATORY FRAMEWORKBates Number: 2065346777/6799, Page 3Bates Number: 2065346777/6799, Page 3
… Under the regulations governing food additives, it’s required that
additives be “safe”, defined as a reasonable certainty by
competent scientists that no harm will result from the intended
use of the additive. 21 C.F.R. Sec. 170(3)(I)(1998). Using this
standard, numerous additives generally thought of as “fat”,
including fatty acids, cocoa butter substitute, epoxidized
soybean oil and the like are permitted to be used in ordinary
course.
Philip Morris (Altria) Company: From the UCSF Legacy Tobacco Documents Library
HFCS has FDA GRAS status (Generally Regarded as Safe)
… Although there is no existing regulatory framework permitting FDA to restrict a consumer’s choice to consume high fat foods, such products are, like all food products, subject to general FDA requirements regarding adulteration and misbranding. See e.g. 21 U.S.C. Sec 402(a) “A food shall be deemed to be adulterated if it bears of contains any poisonous or deleterious substance which may render it injurious to health”….Thus, under existing law the agency is charged with the responsibility of ensuring that consumption of high fat (and all other) food products does not result in acute injuries such as poisoning, and with preventing consumers from being misled, but not with the prevention of chronic diseases even though its own regulations explicitly postulate the connection between such products and such diseases.
DESIGN, MANUFACTURING AND MARKETING OF DESIGN, MANUFACTURING AND MARKETING OF TOBACCO PRODUCTS: TOWARDS A SENSIBLE TOBACCO PRODUCTS: TOWARDS A SENSIBLE
REGULATORY FRAMEWORKREGULATORY FRAMEWORKBates Number: 2065346777/6799, Page 3Bates Number: 2065346777/6799, Page 3
Philip Morris (Altria) Company: From the UCSF Legacy Tobacco Documents Library
SummarySummary• Fructose (sucrose vs. HFCS) consumption has increased in the past 30 years, coinciding with the obesity epidemic
• Fructose is everywhere
• A calorie is not a calorie, and fructose is not glucose
• Hepatic fructose metabolism leads to all the manifestations of the Metabolic Syndrome:
hypertensionde novo lipogenesis, dyslipidemia, and hepatic steatosisinflammationhepatic insulin resistance obesityCNS leptin resistance, promoting continuous consumption
• Fructose ingestion interferes with obesity intervention
• Fructose is a chronic hepatotoxin (it’s “alcohol without the buzz”) but FDA can’t and won’t regulate it
UCSF Dept. of PediatricsChaluntorn Preeyasombat, M.D.Elvira Isganaitis, M.D.Michele Mietus-Snyder, M.D.Andrea Garber, Ph.D., R.D.Joan Valente, Ph.D.Cam-Tu Tran, M.D.Kristine Madsen, M.D., M.P.H.Stephanie Nguyen, M.D.Carolyn Jasik, M.D., M.P.H.
UCSF Dept. of Epidemiology and BiostatisticsAnn Lazar, Ph.D.Peter Bacchetti, Ph.D.Saunak Sen, Ph.D.
UC Berkeley Dept. of Nutritional SciencesJean-Marc Schwarz, Ph.D.Sharon Fleming, Ph.D.Lorene Ritchie, Ph.D.
CollaboratorsCollaborators
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