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Sugar, Metabolic Syndrome, and Cancer

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Sugar, Metabolic Syndrome, and Cancer Sugar, metabolic syndrome, and cancer Robert H. Lustig, M.D., M.S.L. Emeritus Professor Division of Endocrinology, Department of Pediatrics Institute for Health Policy Studies University of California, San Francisco Adjunct Faculty UC Hastings College of the Law U. Nevada-Reno, November 6, 2017 Disclosures Obesity and Cancer Obesity is a risk factor for cancer Lustig and Bradlow, In: Gagel et al. Int Medicine and Cancer, 2011 Obesity is a risk factor for certain cancers Lustig and Bradlow, In: Gagel et al. Int Medicine and Cancer, 2011 Relative risk of individual cancers due to obesity in 5.2 million UK adults, with smoking removed Bhaskaran et al. Lancet 14 Aug 2014, doi:10.1016/S0140-6736(14)60892-8 International Agency for Research on Cancer Lauby-Secretan et al. N Engl J Med 375:794, 2016 • Education and awareness • Clinical guidance, tools, resources • Research promotion • Policy and advocacy • Weight management in cancer survivors J Clin Oncol Oct 1, 2014 But is it just about the calories? Obesity is the problem (?) Obesity is the problem (?) It’s about calories and obesity — or is it? Basu et al. PLoS One 8:e58783, 2013 It’s about calories and obesity — or is it? Basu et al. PLoS One 8:e58783, 2013 It’s about calories and obesity — or is it? Basu et al. PLoS One 8:e58783, 2013 It’s about calories and obesity — or is it? Basu et al. PLoS One 8:e58783, 2013 Diabetes is NOT a subset of obesity • Obesity is increasing worldwide by 1% per year • Diabetes is increasing worldwide by 4% per year Secular trend in diabetes among U.S. adults, 1988-2012 JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029 Secular trend in diabetes among U.S. adults, 1988-2012 25% increase in obese JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029 Secular trend in diabetes among U.S. adults, 1988-2012 25% increase in obese 25% increase in nl wt JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029 “Exclusive” view of obesity and metabolic dysfunction 240 million adults in U.S. 168 million Normal weight (70%) 72 million Obese (30%) “Exclusive” view of obesity and metabolic dysfunction 240 million adults in U.S. 168 million Normal weight (70%) 72 million Obese (30%) Obese and sick (80% of 30%) Total: 57 million sick “Inclusive” view of obesity and metabolic dysfunction 240 million adults in U.S. 168 million Normal weight (70%) 72 million Obese (30%) “Inclusive” view of obesity and metabolic dysfunction 240 million adults in U.S. 168 million Normal weight (70%) 72 million Obese (30%) Obese and sick Normal weight, (80% of 30%) Metabolic dysfunction (40% of 70%) 57 million 67 million Total: 124 million sick 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 Obesity is not the problem Metabolic Syndrome: where all the money goes (75% of all healthcare dollars) Obesity is not the problem Metabolic Syndrome: where all the money goes (75% of all healthcare dollars) Diabetes Hypertension Lipid abnormalities Cardiovascular disease Non-alcoholic fatty liver disease Polycystic ovarian disease Cancer Dementia Macronutrients and cancer Promotion: Dietary fat: colon, mammary, pancreatic Dietary protein: colon, mammary Dietary starch: ovarian, prostate Prevention: Dietary fiber: colon Reddy et al. in: Micozzi and Moon, CRC Press, 1992 Macronutrients and cancer Promotion: Dietary fat: colon, mammary, pancreatic Dietary protein: colon, mammary Dietary starch: ovarian, prostate Prevention: Dietary fiber: colon Reddy et al. in: Micozzi and Moon, CRC Press, 1992 ASCO position statement doesn’t even mention dietary composition High Fructose Corn Syrup is 42-55% Fructose; Sucrose is 50% Fructose Glucose Fructose Sucrose Sugar and Obesity Sugar and obesity do not correlate perfectly White, Adv Nutr 4: 246, 2013 Sugar and obesity do not correlate perfectly Fruit Juice White, Adv Nutr 4: 246, 2013 150 Grams per day 125 100 75 50 25 0 U.S. Commerce Service 1822-1910, combined with Economic Research Service, USDA 1910-2010 150 Grams per day 125 Stabilization 100 HFCS + Sugar for Fat 75 WWII 50 Growth of 25 Sugar Industry 0 U.S. Commerce Service 1822-1910, combined with Economic Research Service, USDA 1910-2010 Foods that cause weight gain Mozaffarian et al. N Engl J Med 364:2392, 2011 Foods that cause weight gain Mozaffarian et al. N Engl J Med 364:2392, 2011 Foods that cause weight gain Mozaffarian et al. N Engl J Med 364:2392, 2011 Sugar sweetened beverages and weight gain in 2-5 year old children Correlative Prospective DeBoer et al. Pediatrics Aug 5, 2013 Faith et al. Pediatrics 118:2066, 2006 Fast food transactions predict change in age-adjusted BMI in the OECD DeVogli et al. Bull WHO, 92:99-107A, 2014 Soft drink transactions are a partial mediator of the effect of fast food transactions on change in BMI in the OECD DeVogli et al. Bull WHO, 92:99-107A, 2014 Soft drink transactions are a partial mediator of the effect of fast food transactions on change in BMI in the OECD DeVogli et al. Bull WHO, 92:99-107A, 2014 Soft drink transactions are a partial mediator of the effect of fast food transactions on change in BMI in the OECD DeVogli et al. Bull WHO, 92:99-107A, 2014 Effects of sugar on obesity (meta-analysis) Lowering sugar Raising sugar Te Morenga et al. BMJ 345:e7492, 2013 Conflicts of interest with food companies and conclusions on SSB consumption vs. weight gain Bes-Rastrollo M, et al. PLoS Med 10(12): e1001578. doi:10.1371/journal.pmed.1001578 60 studies (28 trials and 32 systematic reviews/meta-analyses) Food Company Positive Negative RR; 95% CI; P Sponsorship Association Association Yes (n=26) 0 26 RR 34.0 No (n=34) 33 1 [4.9-234.5] P<0.001 Schillinger et al. Annals Int Med epub Nov 1, 2016 A randomized trial of cessation of sugar-sweetened beverages and body weight Ebbeling et al. N Engl J Med 367:1407, 2012 Does sugar cause weight gain? Yes Is sugar a cause of obesity? In some, likely Is sugar the cause of obesity? Not even close Mechanisms by which obesity can predispose to cancer 1. Adipose tissue as a storehouse for toxins 2. Estrogen synthesis and metabolism 3. Oxidative stress and reactive oxygen species* 4. Hyperinsulinemia, IGF-1, and IGFBP-1* *(Specific for dietary sugar) Effects of Insulin on the Adipocyte Stimulates Glut4 mRNA and protein Stimulates Acetyl-CoA Carboxylase Stimulates Fatty Acid Synthase Stimulates Lipoprotein Lipase Sciacca et al. Nutr Metab Cardiovasc Dis 23:808, 2013 Micic et al. Hormones, 10:5, 2011 Metabolic syndrome is difficult to define in adults • WHO 1998 • AACE 2003 • EGIR 1998 • IDF 2005 • NCEP/ATPIII 2001 • AHA 2005 Metabolic syndrome is difficult to define in adults • WHO 1998 • AACE 2003 • EGIR 1998 • IDF 2005 • NCEP/ATPIII 2001 • AHA 2005 And even more difficult to define in children Circulation 119:628, 2009 Because each of these definitions sought to define the metabolic syndrome phenomenologically, with cutoffs Because each of these definitions sought to define the metabolic syndrome phenomenologically, with cutoffs It is easier to define the metabolic syndrome mechanistically Where’s the insulin resistance? The standard model of insulin resistance Hepatic Cytokines insulin resistance Sensitivi ty The standard model of insulin resistance Hepatic Cytokines insulin resistance Sensitivity Familial Partial Lipodystrophy: Dunningan or Type 2 •X-linked or autosomal dominant •Absence of limb fat Easily visible veins Defined musculature •Normal or excess facial fat •Cushingoid facies (moon facies) •Dorsocervical fat pad •Acanthosis nigricans •Metabolic Syndrome Peters et al. Nature Genet 18:292, 1998 Comparison between lipodystrophy and obesity LD obesity • Fat mass • Leptin • Adiponectin • Inflam. Cytokines • Metabolic Syndrome ++ ± Asterholm et al. Drug Disc Today Dis Models 4:17, 2007 Comparison between lipodystrophy and obesity LD obesity • Fat mass • Leptin • Adiponectin • Inflam. Cytokines • Metabolic Syndrome ++ ± So the metabolic syndrome can arise from too much, or too little fat i.e. it’s not the fat that counts Asterholm et al. Drug Disc Today Dis Models 4:17, 2007 Obesity and lipodystrophy share insulin resistance Obesity Lipodystrophy Insulin Resistance Chehab, Endocrinol 149:925, 2008 REFRAMING THE DEBATE REFRAMING THE DEBATE Obesity doesn’t CAUSE metabolic syndrome Obesity is a MARKER for metabolic syndrome REFRAMING THE DEBATE Obesity doesn’t CAUSE metabolic syndrome Obesity is a MARKER for metabolic syndrome OBESITY IS A “RED HERRING” EVERYONE IS AT RISK OF METABOLIC SYNDROME Obesity isn’t enough! Insulin resistance isn’t enough! What kind of obesity? What kind of insulin resistance? In which tissue? Are all insulin pathways affected? Insulin Receptor Knockouts (IRKO) Kahn Lab, Joslin 1998-present Obesity, Metabolic Syndrome Liver (LIRKO) Brain (NIRKO) Protected from Obesity Muscle (MIRKO) White Adipose Tissue (FIRKO) Brown Adipose Tissue (BATIRKO) β-cell (βIRKO) Vascular Smooth Muscle (VSMCIRKO) Glomerular Podocyte (PODIRKO) Biddinger and Kahn, Ann Rev Physiol 68:123, 2006 Insulin has two effects on the liver Brown and Goldstein, Cell Metab 7:95, 2008 Result: Obesity Hyperglycemia, hyperinsulinemia, DM Low TG, VLDL Normal BP NOT Metabolic Syndrome Result: Obesity Hyperglycemia, hyperinsulinemia, DM High TG, VLDL Low BP Metabolic Syndrome In order to explain Metabolic Syndrome: • We are looking for a ubiquitous factor that – promotes obesity (preferably visceral) – promotes hypertension – induces selective hepatic insulin resistance • blocks Foxo1 to promote gluconeogenesis (hyperglycemia, hyperinsulinemia, and diabetes) • stimulates de novo lipogenesis (dyslipidemia, atherosclerosis, liver fat accumulation) 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 • Some Calories Cause Disease More than Others • Different Calories are Metabolized Differently • A Calorie is Not A Calorie – Fiber – Protein – Fat – Fructose 150 Grams per day 125 Stabilization 100 HFCS + Sugar for Fat 75 WWII 50 Growth of 25 Sugar Industry 0 U.S.
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