? Robert H. Lustig, M.D. Ped Controversies, UCSF, May 18, 2013 - PDF document

• No disclosures ? Robert H. Lustig, M.D. Ped Controversies, UCSF, May 18, 2013 Past 2001 Healthy? Present Future Currently there are 30% more obese than Experts predict 165 million Americans will be obese malnourished people worldwide by 2030 (World Health Organization) (4 part obesity series in Lancet, August 26, 2011) 366 million diabetics in 2011 100 million Americans will have diabetes by 2050 (5% of the world‘s population) (CDC Division of Diabetes Translation, 2011) (International Diabetes Federation) Medicare will be broke by 2024 (General Accounting office, 2012) Insurance costs $2751 more annually per employee 1

“Exclusive” view of obesity and “Exclusive” view of obesity and metabolic dysfunction metabolic dysfunction 240 million adults in U.S. 240 million adults in U.S. 168 million 168 million Normal weight (70%) Normal weight (70%) 72 million 72 million Obese (30%) Obese (30%) Obese and sick (80% of 30%) Total: 57 million sick “Inclusive” view of obesity and “Inclusive” view of obesity and metabolic dysfunction metabolic dysfunction 240 million adults in U.S. 240 million adults in U.S. 168 million 168 million Normal weight (70%) Normal weight (70%) 72 million 72 million Obese (30%) Obese (30%) Obese and sick Normal weight, (80% of 30%) Metabolic dysfunction (40% of 70%) 57 million 67 million Total: 124 million sick The key to the kingdom: Relation between visceral and subcutaneous obesity TOFI (thin on the outside, fat on the inside) It’s not about obesity — It’s about metabolic dysfunction (anyone can get it!) of which obesity is a result, not a cause 12 Thomas et al. Obesity doi: 10.1038/oby.2011.142, 2011 2

The neuroendocrinology of energy balance PARADOX: If you give a 5 year old kid a cookie: Leptin stimulates the SNS PARADOX: 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 But if you give a 5 year old obese kid a cookie: obese kid a cookie: 3

The leptin negative feedback loop Leptin Tx in Leptin Leptin promotes weight loss in a leptin-deficient patient Deficiency Age 3.5 years Age 3.5 years Age 8 years Age 8 years Farooqi et al. N Engl J Med 341:913, 1999 O’Rahilly et al JCI Oct 2002 What’s blocking leptin from working? Obese subjects are leptin resistant If we could solve that, we could solve obesity X ? 4

What does insulin do? Anatomic leptin resistance: Hypothalamic obesity due to a brain tumor Octreotide x 1 yr Models/Hypotheses of Hypothalamic Obesity 364 lbs. 326 lbs. Damaged Ventromedial Damaged Ventromedial Nucleus Nucleus Hyperphagia Vagal Firing Rate octreotide X Obesity Insulin Secretion Insulin Secretion Glucose Utilization IGF-I Receptor Hyperphagia Growth Obesity Adapted from Adapted from Sklar. Pediatr Neurosurg. Bray and Gallagher. Medicine . 1994;21:120-123. 1975;54:301-330. Octreotide-LAR x 6 months 5

The cause of leptin resistance The cause of leptin resistance is insulin! So where did the increased insulin come from? Nature 487:27-29, Feb 1, 2012 New York Times, April 17, 2011 6

High Fructose Corn Syrup is 42-55% Fructose; Sucrose is 50% Fructose Of the 600,000 items in the American food supply, 80% have added sugar (sucrose, HFCS) Glucose Fructose Sucrose Ng et al. J Acad Nutr Diet 112:1828, 2012 10 Most Obese States 10 Most Obese States 10 Laziest States < 63% active > 30% obese > 30% obese 10 Most Obese States 10 Laziest States 10 Most Unhappy States 10 Most Obese States 10 Laziest States 10 Most Unhappy States < 63% active < 63% active > 30% obese > 30% obese 7

10 Most Obese States 10 Laziest States 10 Most Unhappy States 10 Most Obese States 10 Laziest States 10 Most Unhappy States < 63% active < 63% active > 30% obese > 30% obese Adult Heart Disease Rate Adult Heart Disease Rate Correlation is not causation Correlation is not causation But we have causation too But we have causation too Prevalence of diabetes, 2010 46 An international longitudinal analysis of An international longitudinal analysis of diet and diabetes diet and diabetes 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% (95% CI 0.03 — 1.71%, p <0.001) These data estimate that 25% of diabetes worldwide is explained by sugar Basu et al. PLoS One (in press) Basu et al. PLoS One (in press) 8

Fructose is not glucose Isocaloric fructose vs. complex carbohydrate increases intrahepatic lipid in adults • The 1 st problem: Liver fructose metabolism is different from glucose • The 2 nd problem: Fructose is 7 times more likely than glucose to bind to proteins and release hydrogen peroxide-like molecules which accelerate the aging process Elliot et al. Am J Clin Nutr, 2002 Le and Tappy, Curr Opin Clin Nutr Metab Care, 2006 Bray et al. Am J Clin Nutr, 2004 Wei et al. J Nutr Biochem, 2006 Teff et al. J Clin Endocrinol Metab, 2004 Johnson et al. Am J Clin Nutr 2007 Gaby, Alt Med Rev, 2005 Rutledge and Adeli, Nutr Rev, 2007 Brown et al. Int. J. Obes, 2008 Noworlowski et al. Proc Int Soc Mag Res Med 2699, 2009 Aging and rib cartilage The browning reaction or Maillard reaction or non- enzymatic glycation Throws off Reactive Oxygen Species (ROS) (like hydrogen peroxide) Instead of roasting 1 hour at 375 degrees we slow cook at 98.6 degrees for 75 years Courtesy Dr Baynes Is sugar addictive? The lay public seems to know…. Wise? 9

Does sugar cause dementia? The ‘Twinkie Defense’: Obesity is associated with dementia the relationship between carbonated non-diet soft drinks and Luchsinger et al. J Alz Dis Assoc Dis 2011 violence perpetration among Boston high school students Obesity alters neural projections consistent with dementia Bouret et al. Cell Metab 7:179, 2008 Adolescents who drank more than five cans of soft drinks per week (nearly Sugar generates insulin resistance 30% of the sample) were significantly more likely to have carried a weapon and hyperinsulinemia in dementia Seneff et al. Eur J Int Med 22:134, 2011 and to have been violent with peers, family members and dates (p <0.01 for Insulin resistance and high insulin carrying a weapon and p <0.001 for the three violence measures). levels are associated with dementia Craft et al. Nat Rev Neurol 8:360, 2012 Frequent soft drink consumption was associated with a 9–15% increase in Western Diet correlates with dementia Barberger-Gateau et al. Neurology 69:1921, 2007 the probability of engaging in aggressive actions, even after controlling for Fat or sugar both cause obesity in rats, gender, age, race, body mass index, typical sleep patterns, tobacco use, but only sugar caused cognitive decline alcohol use, and having family dinners. Jurdak et al. Nutr Neurosci 11:48, 2008 Causative data in animals; but to date no direct associative or causative data in humans Solnick and Hemenway, Inj Prev 18:259, 2012 Stephan et al. J Gerontol 65:809, 2010 Recognition at the American Heart Association Who’s Wealthy? Recommends reduction in sugar intake from 22 tsp/day to 9 tsp/day (males) and 6 tsp/day (females) Johnson et al. Circulation 120:1011, 2009 10

Who’s wealthy? How our food dollars have been reallocated • 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 McD Coke Pepsi S&P 500 Philpott, Mother Jones 2012 (from Bureau of Labor Statistics) Who’s wealthy? Further reading • Stock prices of various food companies compared to the S&P500, 2007-2011 Is fast food addictive? Andrea K. Garber, Robert H. Lustig Arterioscler Throm Vasc Biol 25:2451, 2005 Curr Drug Abuse Rev 4:146, 2011 Hormel Archer Daniels Midland Kraft General Mills Kraft ConAgra S&P500 Nat Rev Gastroenterol Hepatol 7:251, 2010 Proctor & Gamble/ J Am Diet Assoc 110:1305, 2010 Further reading Further reading Arterioscler Throm Vasc Biol 25:2451, 2005 Pediatric Annals 41:23, 2012 Advances in Nutrition 4:1, 2013 Andrew A. Bremer, M.D., Ph.D. a , Michele Mietus-Snyder, M.D. b , Robert H. Lustig, M.D. c * Pediatrics 129:557, 2012 Annals NY Academy of Sciences, 1, 2013 Nature 487:27, 2012 11

Further reading Current Opinion Gastroenterology, 29:170, 2013 PLoS One 8:e57873, 2013 Hudson Street Press (Penguin) 12