No disclosures. Past. Present. Currently there are 30% more obese than undernourished people worldwide

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Darwin, diet, disease, and dollars No disclosures Robert H. Lu

Division of Endocrinology Department of Pediatrics University of California, San Francisco November 7, 2013 Past Present 2001 Currently there are

(International Diabetes Federation) Future Experts predict 165 million Americans (42%) will be obese by 2030 (4 part obesity series in Lancet,

1 Darwin, diet, disease, and dollars No disclosures Robert H. Lustig, M.D., M.S.L. Division of Endocrinology Department of Pediatrics University of California, San Francisco November 7, 2013 Past Present 2001 Currently there are 30% more obese than undernourished people worldwide (World Health Organization) 371 million diabetics in 2012 (6% of the world s population) (International Diabetes Federation) Future Experts predict 165 million Americans (42%) will be obese by 2030 (4 part obesity series in Lancet, August 26, 2011) 100 million Americans will have diabetes by 2050 (CDC Division of Diabetes Translation, 2011) Venus von Willendorf, Vienna Museum of Natural History Dated to 22,000 BCE, unearthed in 1908 Obesity has been part of the human condition since there were humans But something s happened How did the world get so obese? And how so fast? Medicare will be broke by

2 The explanation? Obesity continues to worsen, both in prevalence and severity Obesity is increasing in all developed (and developing) countries Darwin Obesity is increasing in all age groups, and especially in children Recidivism is high Obesity continues to worsen, both in prevalence and severity Obesity is increasing in all developed (and developing) countries Obesity is increasing in all age groups, and especially in children Recidivism is high The obvious explanation: Gluttony and sloth The explanation? Obesity continues to worsen, both in prevalence and severity Obesity is increasing in all developed (and developing) countries Obesity is increasing in all age groups, and especially in children Recidivism is high The obvious explanation: Gluttony and sloth The explanation? The evolutionary explanation: A mismatch between our environment and our biochemistry What s the selective advantage to obesity? What s the selective advantage to obesity? Energy storage for a rainy day (month, year, decade) Energy storage for a rainy day (month, year, decade) How is this selective advantage achieved? Leptin resistance Insulin resistance 2

3 The neuroendocrinology of energy balance PARADOX: If you give a 5 year old kid a cookie: PARADOX: Leptin stimulates the SNS If you give a 5 year old kid a cookie: Mark et al. Acta Physiol Scand 177:345, 2003" PARADOX: PARADOX: But if you give a 5 year old obese kid a cookie: But if you give a 5 year old obese kid a cookie: 3

4 The leptin negative feedback loop Leptin promotes weight loss in a leptin-deficient patient! Leptin Tx in Leptin Deficiency Farooqi et al. N Engl J Med 341:913, 1999" Age 3.5 years Age 8 years O Rahilly et al, JCI Oct Obese subjects are leptin resistant! What s blocking leptin from working? If we could solve that, we could solve obesity X? 4

What does insulin do? Anatomic leptin resistance:! Hypothalamic Obesity!

Ventromedial Nucleus Damaged Ventromedial Nucleus Damaged Ventromedial Nucleus Damaged Ventromedial

X Insulin Secretion octreotide Insulin Secretion Glucose Utilization Insulin Secretion Glucose

Adapted from Sklar. Pediatr Neurosurg. 1994;21:120-123. Adapted from Bray and Gallagher. Medicine.

5 What does insulin do? Anatomic leptin resistance:! Hypothalamic Obesity! Models/Hypotheses of Hypothalamic Obesity Models/Hypotheses of Hypothalamic Obesity Damaged Ventromedial Nucleus Damaged Ventromedial Nucleus Damaged Ventromedial Nucleus Damaged Ventromedial Nucleus Hyperphagia Obesity Vagal Firing Rate Insulin Secretion Hyperphagia Obesity Vagal Firing Rate X Insulin Secretion octreotide Insulin Secretion Glucose Utilization Insulin Secretion Glucose Utilization IGF-I Receptor Hyperphagia IGF-I Receptor Hyperphagia Growth Obesity Growth Obesity Adapted from Sklar. Pediatr Neurosurg. 1994;21: Adapted from Bray and Gallagher. Medicine. 1975;54: Adapted from Sklar. Pediatr Neurosurg. 1994;21: Adapted from Bray and Gallagher. Medicine. 1975;54: lbs. 172 lbs. 5

6 Octreotide x 1 yr! 364 lbs. 326 lbs. Postulated scheme of hypothalamic obesity Octreotide-LAR x 6 months VAGUS OCTREOTIDE FOOD GLUCOSE INSULIN YOU YOUR FAT The cause of leptin resistance The cause of leptin resistance is insulin! 6

7 Insulin is an endogenous leptin antagonist (?) Insulin is an endogenous leptin antagonist (?) Does this make Darwinian sense? Insulin gives the human the ability to modulate weight gain acutely, by allowing hyperinsulinemia to induce leptin resistance: 1. Puberty 2. Pregnancy Insulin is an endogenous leptin antagonist (?) Does this make Darwinian sense? Insulin gives the human the ability to modulate weight gain acutely, by allowing hyperinsulinemia to induce leptin resistance: Where did the hyperinsulinemia come from?! 1. Puberty 2. Pregnancy Doesn t it make sense that the same hormone that promotes the energy storage also inhibits leptin, so that energy can be stored? Diet 7

come from, including Coca-Cola and everything else with calories!! -The Coca Cola Company, Coming Together, 2013! The Science!

fructose consumption Glucose Fructose Natural consumption of fruits and vegetables 15 gm/day Prior to WWII (estimated): 16-24

8 The Fiction! Beating obesity will take action by all of us, based on one simple common sense fact: All calories count, no matter where they come from, including Coca-Cola and everything else with calories!! -The Coca Cola Company, Coming Together, 2013! The Science! Nature 487:27-29, Feb 1, 2012 Some Calories Cause Disease More than Others!! Different Calories are Metabolized Differently! A Calorie is Not A Calorie!!!! New York Times, April 17, 2011 High Fructose Corn Syrup is 42-55% Fructose; Sucrose is 50% Fructose Secular trend in fructose consumption Glucose Fructose Natural consumption of fruits and vegetables 15 gm/day Prior to WWII (estimated): gm/day (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% consume at least 100 gm/day, 20% of calories from fructose Sucrose Bray, Am J Clin Nutr 86:895, 2007; Vos et al. Medscape Med J 10:160,

Worldwide per capita sugar supply, 2007 Of the 600,000 items in the American food supply, 80% have added sugar (sucrose, HFCS) Ng et al.

End-Products (AGE s) Fructose does not suppress ghrelin Acute fructose does not stimulate insulin (or leptin) Hepatic fructose metabolism is

9 Worldwide per capita sugar supply, 2007 Of the 600,000 items in the American food supply, 80% have added sugar (sucrose, HFCS) Ng et al. J Acad Nutr Diet 2012 FAOStat, 2007 Fructose 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 Prevalence of diabetes, 2010 Elliot et al. Am J Clin Nutr, 2002 Bray et al. Am J Clin Nutr, 2004 Teff et al. J Clin Endocrinol Metab, 2004 Gaby, Alt Med Rev, 2005 Le and Tappy, Curr Opin Clin Nutr Metab Care, 2006 Wei et al. J Nutr Biochem, 2006 Johnson et al. Am J Clin Nutr 2007 Rutledge and Adeli, Nutr Rev, 2007 Brown et al. Int. J. Obes, kcal Hepatocyte 96 kcal 9

10 Ethanol is a carbohydrate Ethanol is a carbohydrate CH 3 -CH 2 -OH Ethanol is a carbohydrate CH 3 -CH 2 -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 10

60 kcal (+ 12 kcal glucose) 48 kcal What s the difference? What s the difference? Calories 150 150 Percent CHO 10.5% (sucrose) 3.6% (alcohol) Calories from fructose 75 (4.

11 60 kcal (+ 12 kcal glucose) 48 kcal What s the difference? What s the difference? Calories Percent 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 Calories Percent 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 What s the difference? Fructose induces insulin resistance, which induces leptin resistance Calories Percent 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

Fructose induces insulin resistance, which induces leptin resistance Does this

Seasonal insulin resistance: Fructose was available at harvest, 1-2 months per

the time, you couldn t store energy Selective advantage by inducing seasonal

resistance by gorging on fruit, while it was available But fructose is now

fiber (read: orange juice) Seasonal fruit binges in orangutans Availability

Ketones Diet Knott, Int J Primatol 19: 1061, 1998 Taste buds Taste buds Sugar

(sweet-and-sour pork) bitter (milk chocolate) Sugar (sweet-and-sour pork) bitter

12 Fructose induces insulin resistance, which induces leptin resistance Does this make Darwinian sense? Seasonal insulin resistance: Fructose was available at harvest, 1-2 months per year Followed by 4-5 months of winter, with no food available If leptin worked all the time, you couldn t store energy Selective advantage by inducing seasonal insulin resistance by gorging on fruit, while it was available Fructose induces insulin resistance, which induces leptin resistance Does this make Darwinian sense? Seasonal insulin resistance: Fructose was available at harvest, 1-2 months per year Followed by 4-5 months of winter, with no food available If leptin worked all the time, you couldn t store energy Selective advantage by inducing seasonal insulin resistance by gorging on fruit, while it was available But fructose is now available globally 24/7/365, and consumed in unlimited amounts And unopposed by fiber (read: orange juice) Seasonal fruit binges in orangutans Availability Calories Is sugar addictive? The lay public seems to know. Ketones Diet Knott, Int J Primatol 19: 1061, 1998 Taste buds Taste buds Sugar hides: salty (Chex mix, honey roasted peanuts) sour (German wines, lemonade) umami (sweet-and-sour pork) bitter (milk chocolate) Sugar hides: salty (Chex mix, honey roasted peanuts) sour (German wines, lemonade) umami (sweet-and-sour pork) bitter (milk chocolate) Does this make Darwinian sense? There are no foodstuffs in nature that are both sweet and acutely poisonous 12

Our sugar craving is also Darwinian Disease Sweet-Ease increases endogenous opioids to reduce pain, Even in neonates Exclusive view of obesity and metabolic dysfunction Exclusive view of obesity and

72 million Normal weight (70%) 168 million 240 million adults in U.S.

13 Our sugar craving is also Darwinian Disease Sweet-Ease increases endogenous opioids to reduce pain, Even in neonates Exclusive view of obesity and metabolic dysfunction Exclusive view of obesity and metabolic dysfunction 240 million adults in U.S. 72 million Normal weight (70%) 168 million 240 million adults in U.S. 72 million Normal weight (70%) 168 million Obese (30%) Obese (30%) Obese and sick (80% of 30%) Total: 57 million sick Inclusive view of obesity and metabolic dysfunction Inclusive view of obesity and metabolic dysfunction 240 million adults in U.S. 72 million Normal weight (70%) 168 million 240 million adults in U.S. 72 million Normal weight (70%) 168 million Obese (30%) Obese (30%) Obese and sick (80% of 30%) Normal weight, Metabolic dysfunchon (40% of 70%) 57 million 67 million Total: 124 million sick 13

Relation between visceral and subcutaneous obesity TOFI (thin on the outside, fat on the

(anyone can get it!) of which obesity is a result, not a cause Thomas et al. Obesity doi: 10.

142, 2011 80 10 Most Obese States 10 Most Obese States 10 Laziest States > 30% obese > 30%

14 Relation between visceral and subcutaneous obesity TOFI (thin on the outside, fat on the inside) The key to the kingdom: It s not about obesity It s about metabolic dysfunction (anyone can get it!) of which obesity is a result, not a cause Thomas et al. Obesity doi: /oby , Most Obese States 10 Most Obese States 10 Laziest States > 30% obese > 30% obese < 63% active 10 Most Obese States 10 Laziest States 10 Most Unhappy States 10 Most Obese States 10 Laziest States 10 Most Unhappy States > 30% obese < 63% active > 30% obese < 63% active 14

10 Most Obese States 10 Laziest States 10 Most Unhappy States 10 Most Obese States 10 Laziest States 10 Most Unhappy States > 30% obese < 63% active > 30% obese < 63% active Adult Heart Disease Rate

An international longitudinal panel analysis of diet and diabetes Food and Agriculture Organization (FAO); FAOSTAT Food Supply data in kcal/capita/day calculation: Food Supply= Supply Elements -

15 10 Most Obese States 10 Laziest States 10 Most Unhappy States 10 Most Obese States 10 Laziest States 10 Most Unhappy States > 30% obese < 63% active > 30% obese < 63% active Adult Heart Disease Rate Adult Heart Disease Rate Correlation is not causation! But we have causation too! Prevalence of diabetes, What about the world s food supply predicts diabetes prevalence over the decade? An international longitudinal panel analysis of diet and diabetes Food and Agriculture Organization (FAO); FAOSTAT Food 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 through 2010: Total Calories Roots & Tubers, Pulses, Nuts, Vegetables Fruits, Excluding Wine Meat Oils Cereals Sugar, Sugarcrops & Sweeteners International Diabetes Federation (IDF) 2000 through 2010 The World Bank World Development Indicators Database GDP expressed in purchasing power parity in 2005 US dollars for comparability among countries Basu et al. PLoS One 8:57873, Feb

Overall Model + + period + controls REM POLS FEM Countries 154 175 0.94 (0.87, 1.01) 0.51 (0.21, 0.80) Size (95% CI) 0.58 (0.30, 0.87) Effect 0.95 (0.74, 1.16) 1.02 (0.92, 1.13) 1.17 (0.99, 1.35) 0.

0% for 204 countries 2000-2007 An international longitudinal panel analysis of diet and diabetes Diabetes prevalence rose from 5.5% to 7.

16 Overall Model + + period + controls REM POLS FEM Countries (0.87, 1.01) 0.51 (0.21, 0.80) Size (95% CI) 0.58 (0.30, 0.87) Effect 0.95 (0.74, 1.16) 1.02 (0.92, 1.13) 1.17 (0.99, 1.35) 0.69 (0.47, 0.91) An international longitudinal panel analysis of diet and diabetes Diabetes prevalence rose from 5.5% to 7.0% for 204 countries An international longitudinal panel analysis of diet and diabetes Diabetes prevalence rose from 5.5% to 7.0% for 204 countries % change in diabetes for each 100kcal sugar/person/day Effect of Sugar on Diabetes Prevalence Effect of Sugar on Diabetes Prevalence Model Model # countries Countries Effect Effect (95% CI) Size (95% CI) POLS Least squares POLS with + controls controls REM Random effects FEM Fixed effects with controls FEM + controls plus period FEM + controls + period Overall Overall (0.99, 1.35) 0.95 (0.74, 1.16) 1.02 (0.92, 1.13) 0.69 (0.47, 0.91) 0.51 (0.21, 0.80) 0.58 (0.30, 0.87) 0.94 (0.87, 1.01) % change in diabetes for each 100kcal sugar/person/day Basu et al. PLoS One 8:57873, Feb Basu et al. PLoS One 8:57873, Feb An international longitudinal panel analysis of diet and diabetes prevalence Change in sugar availability (kcal/person/day) coef = , (robust) se = , t = 4.78 Adjusted Association 510 of Sugar with Diabetes diabetes Prevalence Adjusted Association of Sugar with Diabetes Prevalence An international longitudinal analysis of diet and diabetes Only changes in sugar availability predicted changes in diabetes prevalence Change 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% (95% CI %, p <0.001) This study meets the Bradford Hill criteria for Causal Medical Inference for sugar as a proximate cause of diabetes: -5 dose duration directionality precedence Change in sugar availability (kcal/person/day) 300 coef = , (robust) se = , t = 4.78 We estimate that 25% of diabetes worldwide is explained by sugar Basu et al. PLoS One 8:57873, Feb Basu et al. PLoS One 8:e57873, 2013 Toward a unifying hypothesis of metabolic syndrome FRUCTOSE FRUCTOSE Mitochondria Endoplasmic Cell NH 2 Reticulum death UPR Cellular/ ROS metabolic dysfunction Acetyl-CoA ROS ATP ROS No drug target Mitochondrial overload releases ROS s, which lead to cell dysfunction, aging, and death Mitochondrial overload promotes lipogenesis, leading to hepatic insulin resistance, and metabolic syndrome ROS Acyl-CoA Lipid ROS droplet PKCε Fat deposition JNK1 pser-irs-1 Peroxisome Insulin resistance Insulin Receptor ROS NADPH oxidase INFLAMMATORY CYTOKINES Bremer, Mietus-Snyder and Lustig, Pediatrics 129:557, 2012 Only options are: - reduce substrate availability (diet) - reduce hepatic flux (fiber) - increase clearance (exercise) Bremer, Mietus-Snyder, and Lustig, Pediatrics 129:557,

17 How our food dollars have been reallocated Dollars Philpott, Mother Jones 2012 (from Bureau of Labor Statistics) 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 Who s winning the war? Stock prices of various food companies compared to the S&P Week of Oct 3, 2011: ^GSPC CAG ADM PG GIS KFT HRL Week of Oct 3, 2011: ^GSPC MCD KO PEP Hormel 60% McD Coke 100% 80% 60% 40% 40% Archer Daniels Midland Kraft 20% General Mills 0 Pepsi S&P % 0-20% Proctor & Gamble/ ConAgra Kraft S&P500-20% -40% -40% 2011 Yahoo! Inc Jul Oct 2008 Apr Jul Oct 2009 Apr Jul Oct 2010 Apr Jul Oct 2011 Apr Jul Oct Volume: 4,514,868,224 8B 6B 4B 2B 2011 Yahoo! Inc Jul Oct 2008 Apr Jul Oct 2009 Apr Jul Oct 2010 Apr Jul Oct 2011 Apr Jul Oct Volume: 4,514,868,224 8B 6B 4B 2B 1D 5D 1M 3M 6M YTD 1Y 2Y 5Y Max FROM: Jan TO: Oct % 1D 5D 1M 3M 6M YTD 1Y 2Y 5Y Max FROM: Jan TO: Oct % Societal intervention requires externalities Societal intervention requires externalities If you smoke, drink, or take drugs, it s bad for me second hand smoke car accidents declining housing prices altered work productivity and absenteeism 17

Societal intervention requires externalities If you smoke, drink, or take drugs, it s bad for me second hand smoke car accidents declining housing prices altered work productivity and absenteeism How

18 Societal intervention requires externalities If you smoke, drink, or take drugs, it s bad for me second hand smoke car accidents declining housing prices altered work productivity and absenteeism How does your obesity affect me? $274 million extra for jet fuel (?) discomfort on the subway (?) sinking of boats due to the weight (?) Societal intervention requires externalities If you smoke, drink, or take drugs, it s bad for me second hand smoke car accidents declining housing prices altered work productivity and absenteeism How does your obesity affect me? $274 million extra for jet fuel (?) discomfort on the subway (?) sinking of boats due to the weight (?) $65B reduction in work productivity 50% increase in absenteeism 50% increase in health insurance premiums $150B waste of health care resources Obesity is a threat to national security The Government pays twice We believe higher taxation on sugary food and drinks would be the best option to reduce sugar intake and help fund the fast-growing healthcare cosrts association with diabetes type II and obesity.! Summary: The Darwinian explanation for the obesity epidemic Obesity means leptin resistance, or brain starvation The starvation response causes recidivism Energy expenditure and quality of life are the same thing Defects in insulin signaling promote leptin resistance Insulin appears to be an endogenous leptin antagonist Fructose, through de novo lipogenesis, induces hepatic insulin resistance, driving metabolic syndrome, and wasting health care dollars Fructose is addictive, and drives excess food consumption Our food environment is fructosified; we have to get the insulin down The food industry has no impetus to change its practices Lancet 381:670, 2013 DISEASE VECTOR Old medicine: infections microbes New medicine: chronic multinational disease corporations 18

Further reading Further reading Arterioscler Throm Vasc Biol 25:2451, 2005 Is fast food addictive?

Lustig Curr Drug Abuse Rev 4:146, 2011 Arterioscler Throm Vasc Biol 25:2451, 2005 Pediatric Annals

Nutrition 4:1, 2013 Current Opinion Gastroenterology, 29:170, 2013 Annals NY Academy of Sciences, 1,

19 Further reading 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 Arterioscler Throm Vasc Biol 25:2451, 2005 Pediatric Annals 41:23, 2012 Nat Rev Gastroenterol Hepatol 7:251, 2010 Andrew A. Bremer, M.D., Ph.D. a, Michele Mietus-Snyder, M.D. b, Robert H. Lustig, M.D. c * Pediatrics 129:557, 2012 J Am Diet Assoc 110:1305, 2010 Further reading Further reading Advances in Nutrition 4:1, 2013 Current Opinion Gastroenterology, 29:170, 2013 Annals NY Academy of Sciences, 1, 2013 PLoS One 8:e57873, 2013 We have started a 501c3 to provide medical, nutritional and legal analysis and consultation to promote personal and public health against Big Food Institute for Responsible Nutrition Education Research Advocacy Action Hudson Street Press (Penguin USA) E-book Hudson Street Press Sept Hudson Street Press Jan 1, 2014 Please let me know if you would like more information! rlustigmd@earthlink.net 19

Fat Chance: The Bitter Truth about Sugar 6/19/13. Robert H. Lustig, MD

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.