Fat Chance: The Bitter Truth about Sugar 6/19/13 Robert...

Fat Chance: The Bitter Truth about Sugar 6/19/13

Robert H. Lustig, MD

BIOGRAPHY: Robert H. Lustig, M.D. is Professor of Pediatrics, in the Division of Endocrinology at University of

California, San Francisco. Dr. Lustig is a neuroendocrinologist who performs research and clinical care

on patients with obesity and diabetes. For the last decade, Dr. Lustig’s clinical research has focused on

the regulation of energy balance by the central nervous system. He is currently investigating the

contribution of biochemical, neural, hormonal, and genetic influences in the expression of the current

obesity epidemic both in children and adults. He is interested in the hypothalamic signal transduction of

the hormones insulin and leptin, how these two systems interact, and how they become dysfunctional in

obesity. He is studying the interplay between the changes in the nutritional environment and defective

hormone signaling; in particular, the role of fructose and lack of fiber in the genesis of the metabolic

syndrome. He is assessing the cardiovascular morbidity associated with insulin excess, and developing

methods to evaluate and prevent this phenomenon in children.

Dr. Lustig graduated from MIT in 1976, and received his M.D. from Cornell University Medical College in

1980. He completed his pediatric residency at St. Louis Children’s Hospital in 1983, and his clinical

fellowship at UCSF in 1984. From there, he spent six years as a research associate in neuroendocrinology

at The Rockefeller University. He is the author of many academic works, and of the popular book “Fat

Chance: beating the odds against sugar, processed food, obesity, and disease”. Dr. Lustig is also

President of the non‐profit Institute for Responsible Nutrition, a think tank devoted to improving our

food supply.

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Hudson Street Press (Penguin USA)Fourth Estate (Harper Collins UK)

• No disclosures

Past

2001

Currently there are 30% more obese than undernourished people worldwide

(World Health Organization)

366 million diabetics in 2011

(5% of the world‘s population)(International Diabetes Federation)

Present

8 March 2013

Diabetes Costs The US $245 Billion A Year Says New Report

Diagnosed diabetes cost the United States

an estimated $245 billion in 2012, according

to new research released by the

American Diabetes Association (ADA) this week.

The new figure represents a 41% rise in five years.

In 2007, when the cost were last estimated,

it came to $174 billion.

Experts predict:

165 million Americans will be obese by 2030(4 part obesity series in Lancet, 8/26/11)

42% of Americans will be obese by 2030 (Finkelstein et al. Am J Prev Med epub 5/7/12)

100 million Americans will have diabetes by 2050(CDC Division of Diabetes Translation, 2011)

Future

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“Exclusive” view of obesity and metabolic dysfunction

Obese (30%)

Normal weight (70%)

240 million adults in U.S.

72 million

168 million

Obese (30%)

Obese and sick(80% of 30%)

Normal weight (70%)


72 million

168 million

Total: 57 million sick

“Exclusive” view of obesity and metabolic dysfunction

Obese (30%)

Normal weight (70%)


72 million

168 million

“Inclusive” view of obesity and metabolic dysfunction

Obese (30%)

Normal weight (70%)


Normal weight,Metabolic dysfunction

(40% of 70%)

Obese and sick(80% of 30%)

57 million 67 million

Total: 124 million sick

72 million

168 million

“Inclusive” view of obesity and metabolic dysfunction

Relation between visceral and subcutaneous obesity:(thin on the outside, fat on the inside)

Thomas et al. Obesity doi: 10.1038/oby.2011.142, 2011

Obesity is not the problem

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Metabolic Syndrome: where all the money goes(75% of all healthcare dollars)


Metabolic Syndrome: where all the money goes(75% of all healthcare dollars)

DiabetesHypertension

Lipid abnormalitiesCardiovascular disease

Non-alcoholic fatty liver diseasePolycystic ovarian disease

CancerDementia

The First Law of Thermodynamics

The total energy inside a closed system remains constant.


The total energy inside a closed system remains constant.

Two interpretations:


CaloriesIn


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CaloriesInCalories

Out


CaloriesInCalories

Out

Weight Gain


CaloriesInCalories

Out

Weight Gain


Obesity is the result of two aberrant behaviors

The dogma

A calorie is a calorie

The dogma

A calorie is a calorie

The corollaries

Free willPersonal responsibility

Gluttony and slothDiet and excercise

Just a caloric bachanalia?

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Just a caloric bachanalia?

+187 kcal/d (men), +335 kcal/d (women), +275 kcal/d (teens)In last 25 years

CDC, 2005

The evolution of fast food

Thickburger1420 calories

Just an activity famine?

Kimm et al. N Engl J Med 347:709, 2002

“Education consists mainly of what we have unlearned.”

--Mark Twain

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Behavior?Personal responsibility?

Behavior?Personal responsibility?

1. No child chooses to obese.

The quality of life of an obese child is equivalent to those on cancer chemotherapy.

(Schwimmer et al. JAMA 289:1813-1819, 2003)

Six reasons to doubt this formulation:

Wadden et al. Int J Obes. 13(suppl 2):39, 1989

Schwartz, Arterioscler Thromb Vasc Biol 17:233, 1997

2. Does diet work?

ADULTS

2. Does exercise work?

Shaw et al. Cochrane Reviews 2006, Issue 4: CD003817. DOI: 10.1002/14651858.CD003817.pub3.

When compared with no treatment, exercise resulted in small weight losses

across studies.

3. This isn’t just about America

Not just the UK, not just Australia

Childhood obesity is on the rise in:

CanadaJapanKoreaIndia

ThailandPhilippinesSouth Africa

Every other developing country

4. The poor are disproportionately affected

They don’t have access to choices for healthy dieting and exercise

If you don’t have a choice, is it personal responsibility?

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5. The prevalence of obesity in children is going up even faster than in adults

6. We even have an epidemic of obese 6-month olds

They don’t exhibit any of these behaviors

(Kim et al, Obesity 15:1107, 2006)

So any hypothesis that attemptsto explain the obesity epidemic,

must be able to explain this as well

• Gestational diabetes has increased in prevalence

• Birthweight has increased by 200 grams

throughout the world

South AfricaIsrael

RussiaU.S.

DEXA scans for body compositionshow greater fat depostion

Behavior

Stedman’s Medical Dictionary

Def. A stereotyped motor response to a physiological stimulus

Behavior



Corollary: Behavior has a biochemical basis

Behavior



Corollary: Behavior has a biochemical basis

What are the biochemical underpinnings of gluttony and sloth?

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The neuroendocrinology of energy balance

If you give a 5 year old kid a cookie:

PARADOX:

PARADOX:

If you give a 5 year old kid a cookie:

Leptin stimulates the SNS

Mark et al. Acta Physiol Scand 177:345, 2003

But if you give a 5 year old obese kid a cookie:

PARADOX:

But if you give a 5 year old obese kid a cookie:

PARADOX:

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The leptin negative feedback loop

Farooqi et al. N Engl J Med 341:913, 1999

Leptin promotes weight loss in a leptin-deficient patient Leptin Tx in LeptinDeficiency

Age 3.5 yearsAge 3.5 years Age 8 yearsAge 8 yearsO’Rahilly et al JCI Oct 2002

Obese subjects are leptin resistantWhat’s blocking leptin from working?

If we could solve that, we could solve obesity

X?

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What does insulin do? Anatomic leptin resistance:Hypothalamic obesity due to a brain tumor

Models/Hypotheses of Hypothalamic Obesity

Damaged VentromedialNucleus

Hyperphagia

Obesity

Insulin Secretion

IGF-I Receptor

Growth

Adapted fromSklar. Pediatr Neurosurg.

1994;21:120-123.

Damaged VentromedialNucleus

Vagal Firing Rate

Insulin Secretion

Glucose Utilization

Hyperphagia

Obesity

Adapted fromBray and Gallagher. Medicine.

1975;54:301-330.

X octreotide

Octreotide x 1 yr

364 lbs. 326 lbs.

Octreotide-LAR x 6 months

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The cause of leptin resistance The cause of leptin resistanceis insulin!

So where did the increased insulin come from?

Addictive and hazardous to your health

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Addictive and hazardous to your health

New York Times, April 17, 2011

Nature 487:27-29, Feb 1, 2012

Hazardous to your health

“A calorie is NOT a calorie”

High Fructose Corn Syrup is 42-55% Fructose;Sucrose is 50% Fructose

Glucose Fructose

Sucrose

Bray, Am J Clin Nutr 86:895, 2007; Vos et al. Medscape Med J 10:160, 2008

Secular trend in U.S. fructose consumption

Natural consumption of fruits and vegetables • 15 gm/day

Prior to WWII (estimated):• 16-24 gm/day

1977-1978 (USDA Nationwide Food Consumption Survey):• 37 gm/day (8% of total caloric intake)

1994 (NHANES III): • 54.7 gm/day (10.2% of total caloric intake)

Adolescents: • 72.8 gm/day (12.1% of total caloric intake)• 25% consumed at least 15% of calories from fructose

Adulteration of our food supply

Addition of fructose

• palatability (esp. with decreased fat)

• browning agent

Removal of fiber

• shelf life

• freezing

Substitution of trans-fats

• hardening agent, shelf life

• now being removed due to CVD risk

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Mozaffarian et al. N Engl J Med 364:2392, 2011

Foods that cause weight gain





Loweringsugar

Raisingsugar

Effects of sugar on obesity (meta-analysis)

Te Morenga et al. BMJ 345:e7492, 2013

The first problem

Common wisdom: “Sugar is just “empty calories”

But:

• Hepatic fructose metabolism is different

• Chronic fructose exposure promotes the Metabolic Syndrome

Elliot et al. Am J Clin Nutr, 2002Bray et al. Am J Clin Nutr, 2004Teff et al. J Clin Endocrinol Metab, 2004Gaby, Alt Med Rev, 2005

Le and Tappy, Curr Opin Clin Nutr Metab Care, 2006Wei et al. J Nutr Biochem, 2006Johnson et al. Am J Clin Nutr 2007Rutledge and Adeli, Nutr Rev, 2007Brown et al. Int. J. Obes, 2008

Hepatocyte

24 kcal

96 kcal

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Ethanol is a carbohydrate


CH3-CH2-OH


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

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60 kcal(+ 12 kcalglucose)

48 kcal

The second problem

The browning reaction or Maillard reaction or non-enzymatic glycation

Instead of roasting 1 hour at 375 degreeswe slow cook at 98.6 degrees for 75 years

Aging and costal cartilage

Courtesy Dr Baynes

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Sucrose is necessary for NAFLD in theMethionine-Choline deficient diet

Pickens et al. J Lipid Res 50:2072, 2009

Association of fructose consumption with severity of steatosis and fibrosis

Grade of Steatosis

p =0.06p < 0.005

Stage of Fibrosis

p < 0.0007

Non NonOccasional OccasionalDaily Daily

Error bar = 95%CI

Abdelmalek et al. Hepatology 51:1961, 2010

10 Most Obese States

> 30% obese

10 Most Obese States 10 Laziest States

> 30% obese < 63% active



10 Most Unhappy States

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10 Most Unhappy States 10 Most Obese States 10 Laziest States



Adult Heart Disease Rate




Adult Heart Disease Rate

Global consumption of sugar/sugarcropsCalories per day, 2007

Data from Food and Agriculture Organization, World Health Organization, 2007

Prevalence of diabetes, 2010102

Correlation is not causationCorrelation is not causation

But we have causation tooBut we have causation too

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An international longitudinal panel analysis of

diet and diabetes

Food and Agriculture Organization (FAO); FAOSTATFood Supply data in kcal/capita/day calculation: Food Supply= ∑Supply Elements - ∑Utilization Elements =

(Production + Import Quantity + Stock Variation – Export Quantity) - (Feed + Seed + Processing + Waste).

Only industrial waste factored in.

Extracted Food Supply data for 2000 and 2007:Total Calories Roots & Tubers, Pulses, Nuts, Vegetables Fruits-Excluding Wine MeatOils CerealsSugar, Sugarcrops & Sweeteners

International Diabetes Federation (IDF)2000 (1st ed) and 2007 (3rd ed)

The World Bank World Development Indicators DatabaseGDP expressed in purchasing power parity in 2005 US dollars for

comparability among countries Basu et al. PLoS One, Feb 27, 2013

Total 204 countries; complete data for 154 countries (50 not different)


diet and diabetes

Basu et al. PLoS One, Feb 27, 2013


Data monitoring and quality

Generalized estimating equations

Conservative fixed effects approach (Hausman test)

Hazard model to control for selection bias (Heckman selection model)

Longitudinal data to determine what preceded diabetes (Granger causality)

Period effects controlled for secular trends that may have occurred as a

result of changes diabetes detection capacity or importation policies.


diet and diabetes



Data monitoring and quality

Generalized estimating equations

Conservative fixed effects approach (Hausman test)

Hazard model to control for selection bias (Heckman selection model)

Longitudinal data to determine what preceded diabetes (Granger causality)

Period effects controlled for secular trends that may have occurred as a

result of changes diabetes detection capacity or importation policies.

Controlled for:

GDP per capita % population living in urban areas

Obesity % of population over age 65

physical inactivity


diet and diabetes



diet and diabetes

Diabetes prevalence rose from 5.5% to 7.0% for 204 countries 2000-2007



diet and diabetes

Diabetes prevalence rose from 5.5% to 7.0% for 204 countries 2000-2007

Sugar

Sugar+controls

Sugar+controls+period

Overall

Model # countries Effect (95% CI)


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diet and diabetes



diet and diabetes

Context

Only changes in sugar availability correlated with changes in diabetes prevalence

Every extra 150 calories increased diabetes prevalence by 0.1%

But if those 150 calories were a can of soda, diabetes prevalence

increased 11-fold, by 1.1%; p <0.001)

Controlled for many confounders; obesity exacerbated, but did not confound the effect

These data estimate that 25% of diabetes worldwide is explained by sugar

These data meet the criteria for Causal Medical Inference:

— dose — directionality

— duration — precedence


Types of Proof

• Anecdotal Data

• Correlation

• Causal Inference

• Scientific Proof

Types of Proof

• Anecdotal Data

• Correlation

• Causal Inference

• Scientific Proof

What level of proof do you need to act?

Addictive

(Reuters) March 28, 2010 - Bingeing on high-calorie foods may be as addictive as cocaine or nicotine, and could cause compulsive eating and obesity, according to a study published on Sunday.

The third problem

Johnson and Kenny, Nat Neurosci Epub 2010 Mar 28.

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Obesity and reward

Volkow et al. Philos Trans R Soc Lond B Biol Sci. 2008 363:3191, 2008

Dopamine binding correlates with glucose metabolism both in drug addiction and obesity

CTL Cocaine

D2receptors

CTL Obesity

Cocaine

Metamphet-amine

Cingulate

OFC

(Luscher, 2004) The Ventral Tegmental Area and the Nucleus Accumbens:Sites of opiate and nicotine effects on reward

Mansvelder et al. Eur J Pharmacol 480:117, 2003

Kelly et al. Physiol Behav 76:365, 2002

The Ventral Tegmental Area and the Nucleus Accumbens:Sites of opiate and nicotine effects on reward The integration of the starvation and addiction pathways

Cota et al. Neuron 51:678, 2006

LepR

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Decreased Dopamine D2 Receptors in Obese Human, Monkey and Rodent

PET [11C]raclopride

High

Low

Bonnet macaquesHuman

Autoradiography

[3H]spiperone

BMI = 42BMI = 50 Weight = 650 g

BMI = 23BMI = 23 Weight = 400 g

Zucker rat2

1Wang et al. J Nucl Med. 49(Suppl 1):208P, 2008; 2Thanos et al. Synapse. 62:50, 2008

Direct effects on the reward system:

Is fast food addictive?

Garber and Lustig, Curr Drug Abuse Rev 4:190, 2011

Caffeine

Salt

• In rodents, dopamine signaling (reward) in response to salt, bingeing, cross-sensitization with amphetamines

• In humans, – Lower threshold physiologically fixed– Higher levels attributed to “preference”, can

retrain– Salt-losing congenital adrenal hyperplasia Caffeine

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Caffeine

Fat

• Rodents binge but no signs of dependence• In humans, binge foods are high fat but

also high carb/sugar (e.g. pizza, ice cream)– Likely synergy, adding sugar increases

preference for fatty foods [Drewnowski et al.]

• Atkins diet does not show dependence• Energy density: stronger association with

obesity, metabolic syndrome

Caffeine Caffeine

Caffeine

• “Model drug” of dependence

• In humans, dependence shown in children, adolescents and adults– 30% who consume it meet DSM criteria for

dependence

– Physiologic addiction established: headache (increased cerebral blood flow). Impaired task performance, fatigue Caffeine

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Caffeine

Direct effects on the reward system:

Is sugar (fructose) addictive?

Garber and Lustig, Curr Drug Abuse Rev 4:190, 2011

Sugar and opioids

Sweet-Ease increases endogenous opioids to reduce pain,Even in neonates

Is there really such a thing as sugar addiction?

Need to look for similarities to drugs of dependence

• nicotine

• morphine

• amphetamine

• cocaine

• ethanol

Criteria for addiction

Cross-sensitizationIncreased

ConsumptionEnhanced locomotion

BINGEING

WITHDRAWAL

Tolerance

CRAVING

Negative emotion

Anticipation

Avena et al. Neurosci Biobehav Rev 32:20, 2008 (Courtesy Dr. B. Hoebel)

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Federal Trade Commission vs. Sugar Information, 1972

The birth of the “Un-Cola”

Recognition at the American Heart Association

Circulation 120:1011, 2009

Recommends reduction in sugar intake from 22 tsp/day to 9 tsp/day (males) and 6 tsp/day (females)

Who’s winning the war?• Despite the economic downturn of 2008,McDonald’s revenues and stock price continues to rise; and Coke and Pepsi still fared better than the S&P 500

Week of Apr 18, 2011: ^GSPC 1330.36 MCD 78.40 KO 67.85 PEP 67.33

© 2011 Yahoo! Inc.

0

-50%

-40%

-30%

-20%

-10%

10%

20%

30%

2007 2008 Apr Jul Oct 2009 Apr Jul Oct 2010 Apr Jul Oct 2011 Apr

1D 5D 1M 3M YTD 6M 1Y 2Y 5Y Max FROM: Oct 8 2007 TO: Apr 18 2011 -14.82%

Volume: 4,115,440,128

2B4B6B8B

Pepsi

McD

Coke

S&P 500

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Stock prices of various food companies comparedto the S&P500 2008-2011

S&P

Who’s winning the war?

Apr 18, 2011: ^GSPC 1305.14 CAG 24.37 ADM 34.45 PG 64.00 GIS 37.18 MON 66.18 KFT 33.22

HRL 28.29

© 2011 Yahoo! Inc.

0

-60%

-40%

-20%

20%

40%

2008 Apr Jul Oct 2009 Apr Jul Oct 2010 Apr Jul Oct 2011 Apr

1D 5D 1M 3M YTD 6M 1Y 2Y 5Y Max FROM: Jan 2 2008 TO: Apr 18 2011 -9.81%

Volume: 4,223,739,904

5B

10B

Archer Daniels MidlandProctor & Gamble

Kraft

Monsanto

General Mills

ConAgraHormel

S&P500Kraft


Weight Gain

Obligate weight gain


CaloriesOut

Weight Gain



CaloriesInCalories

Out

Weight Gain



CaloriesInCalories

Out

Weight Gain



The two aberrant behaviors are a result of our biochemistryOur biochemistry is a result of our environment

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Question 1:

Can our “toxic environment” be changed

without government/societal intervention?

Especially when there are potentially addictive

substances involved?

Question 2:

Can we afford to wait to enact public health measures

when health care will be bankrupt due to

chronic metabolic disease?

Nat Rev Gastroenterol Hepatol 7:251, 2010

J Am Diet Assoc 110:1305, 2010

Further reading

Arterioscler Throm Vasc Biol 25:2451, 2005

Is fast food addictive?

Andrea K. Garber, Robert H. Lustig

Curr Drug Abuse Rev 4:146, 2011

Pediatric Annals 41:23, 2012

Further reading

Arterioscler Throm Vasc Biol 25:2451, 2005

Andrew A. Bremer, M.D., Ph.D.a, Michele Mietus-Snyder, M.D.b, Robert H. Lustig, M.D.c*

Pediatrics 129:557, 2012

Advances in Nutrition 4:1, 2013

Annals NY Academy of Sciences, 1, 2013

Further reading

PLoS One 8:e57873, 2013

Further reading

Current Opinion Gastroenterology, 29:170, 2013

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