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 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

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

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 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 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

U.S. Commerce Service 1822-1910, combined with Economic Research Service, USDA 1910-2010 150 Grams per day

125 Theoretical Stabilization threshold based on EtOH 100 HFCS + Sugar for Fat 75 WWII AHA threshold for CVD 50 Growth of 25 Sugar Industry

U.S. Commerce Service 1822-1910, combined with Economic Research Service, USDA 1910-2010 150 Grams per day Diabetes rise 125 In NYC 1924 Theoretical Stabilization threshold based on EtOH 100 HFCS + Sugar for Fat 75 WWII AHA threshold for CVD 50 Growth of 25 Sugar Industry

U.S. Commerce Service 1822-1910, combined with Economic Research Service, USDA 1910-2010 Emergence of 150 Grams per day Adolescent T2DM Diabetes rise as health issue 1988 125 In NYC 1924 Theoretical Stabilization threshold based on EtOH 100 HFCS + Sugar for Fat 75 WWII AHA threshold Emergence of for CVD 50 CVD as health Growth of issue 1931 25 Sugar Industry

U.S. Commerce Service 1822-1910, combined with Economic Research Service, USDA 1910-2010 Sugar and Diabetes

— Plausibility

— Human Correlation

— Human Causation Sugar and Diabetes

Plausibility: Liver fat and insulin resistance Histology of (N)AFLD

Normal Alcohol? Sugar? MRI Fat Fraction Maps

Obese Low Liver Fat = 2.6% MRI Fat Fraction Maps

Obese Obese Low Liver Fat = 2.6% High Liver Fat = 24% MRI Fat Fraction Maps

Obese Obese Thin Low Liver Fat = 2.6% High Liver Fat = 24% High Liver Fat = 23% MRI Fat Fraction Maps

Obese Obese Thin Low Liver Fat = 2.6% High Liver Fat = 24% High Liver Fat = 23% NAFLD and Metabolic Syndrome are congruent (if not the same)

Adults: Marchesini et al. Hepatology 37:917, 2003

Children: Schwimmer et al. Circulation 118:277, 2008 Epidemiology of NAFLD

Non-alcoholic fatty liver disease (NAFLD) has become epidemic

Steatosis: 45% Latinos 33% Caucasians 24% African Americans

NASH 5.5% of US Adults

Children: Steatosis in 13% of autopsy specimens ages 5-19 38% in obese autopsy specimens

Browning et al. Hepatology 40:1387, 2004; Schwimmer et al. Pediatrics 118:1388, 2006 NAFLD is a primary predictor of T2DM in Korean adults

Sung and Kim, J Clin Endocrinol Metab 96:1093, 2011 Intrahepatic fat explains metabolic perturbation better than visceral fat

Hepatic Insulin Sensitivity VLDL Index Secretion Rate

Insulin Stimulated Glucose Disposal Contribution Rate Of Free Fatty Acids Insulin To VLDL Stimulated Palmitate Suppression Rate

Fabbrini et al. Proc Natl Acad Sci 106:15430, 2009 (20%)

(80%) (80%) (100%) Inhibition of the polyol pathway inhibits liver fat and metabolic syndrome

Lyssiotis and Cantley, Nature 502:181, 2013 Inhibition of the polyol pathway inhibits liver fat and metabolic syndrome

Lyssiotis and Cantley, Nature 502:181, 2013 Isocaloric fructose vs. complex carbohydrate increases intrahepatic lipid in adults

Noworlowski et al. Proc Int Soc Mag Res Med 2699, 2009 Sugar is toxic unrelated to calories

Lustig et al. Obesity 24:453, 2016

Gugliucci et al. Atherosclerosis 253:171, 2016

Schwarz et al. Gastroenterology 153:743, 2017 Strategy

• Isocaloric fructose restriction x 9 days in children who are habitual sugar consumers • No change in weight • Substitute complex carbs for sugar • Maintain baseline macronutrient composition of the the diet • Study in PCRC at Day 0 and Day 10 • Assess changes in organ fat, de novo lipogenesis, and metabolic health Fasting Labs

Day 0 Day 10 β-coefficient p value (Adjusted Change) [95% CI] Heart rate (bpm) 83.1 ± 10.7 80.1 ± 11.3 -2.8 [-6.5, +0.9] 0.13

Systolic BP (mmHg) 122.6 ± 10.5 121.1 ± 9.9 - 1.39 [-4.9, +2.1] 0.43

Diastolic BP 68.8 ± 8.9 63.7 ± 7.5 - 4.9 [-8.1, -1.8] 0.003

Fasting lactate 1.2 ± 0.4 0.9 ± 0.3 -0.3 [-0.5, -0.2] <0.001 (mmol/L)

Lactate AUC 160.0 ± 34.5 129.0 ± 34.5 -31.2 [-41.9, -20.5] <0.001 (mM/120 min) HOMA-IR¥ 7.9 ± 4.8 5.2 ± 2.6 -2.7 [-3.8, -1.5] <0.001 AST (U/L) * 27.4 ± 14.1 23.8 ± 8.9 0.02

ALT (U/L) ¥ 28.9 ± 22.8 26.7 ± 19.6 -2.2 [-4.7, +0.3] 0.09

Fasting TG (mM) 1.4 ± 0.9 1.0 ± 0.5 -0.4 [-0.6, -0.2] 0.002

Fasting LDL-C (mM) 2.4 ± 0.6 2.1 ± 0.6 -0.3 [-0.4, -0.1] <0.001

Fasting HDL-C (mM) 1.2 ± 0.2 1.0 ± 0.2 -0.1 [-0.2, -0.1] <0.001

Fasting FFA (mM) 0.6 ± 0.2 0.7 ± 0.2 +0.1 [+0.1, +0.2] <0.001

Endocrine Society, March 5, 2015 Triglyceride-rich Lipoprotein DNL AUC (n=17)

14.00%

12.00%

10.00%

8.00% DNL AUC DNL

6.00%

4.00%

Fractional TRL – TRL Fractional 2.00%

0.00% 0 1 2 3 4 5 6 7 8 hour

D0 D10

Schwarz et al. Gastroenterology 153:743,, 2017 Changes in liver, visceral, and subcutaneous fat (n = 37) Oral glucose tolerance test before and after isocaloric fructose restriction

Lustig et al. Obesity 24:453, 2016 Changes in liver fat and CISI (n = 22) Correlation between change in CISI vs. change in ectopic (liver, visceral) fat: multivariate linear regression analysis (Spearman R)

Day 0 Day 10 Change in Fat (Absolute) Liver Fat Visceral Liver Fat Visceral Liver Fat Visceral Fraction Fat Fraction Fat Fraction Fat CISI Day 0 -0.33 -0.29

CISI Day 10 -0.33 -0.17

Change in CISI -0.63* 0.07 De novo Lipogenesis Glycerol-P DNL TG*

Ac CoA* Malonyl Fatty CoA Acid* VLDL*

warz et al. Gastroenterology doi: 10.1053/j.gastro.2017.05.043, 2017 De novo Lipogenesis Glycerol-P DNL TG*

Ac CoA* Malonyl Fatty CoA Acid* VLDL*

9 days fructose restriction LIVER DNL FAT

VLDL*

Visceral fat warz et al. Gastroenterology doi: 10.1053/j.gastro.2017.05.043, 2017 De novo Lipogenesis Glycerol-P DNL TG* Improved Ac CoA* Malonyl Fatty CoA Acid* VLDL* Insulin kinetics

9 days fructose restriction LIVER DNL FAT

VLDL*

Visceral fat warz et al. Gastroenterology doi: 10.1053/j.gastro.2017.05.043, 2017 A different model of insulin resistance

Fructose Hepatic Cytokines insulin resistance Fatty liver

Sensitivi ty A different model of insulin resistance

Fructose Hepatic Cytokines insulin resistance Fatty liver

Sensitivity Sugar and Diabetes

Plausibility: Reactive oxygen species What do these have in common? The browning reaction or Maillard reaction or non-enzymatic glycation

Instead of roasting 1 hour at 375 degrees we slow cook at 98.6 degrees for 75 years Aging and costal cartilage

Courtesy Dr Baynes

Generation of reactive oxygen species by carbohydrate

Figueroa-Romero et al. Rev Endo Metab Dis 9:301, 2008 The furan ring of fructose is more unstable, so at equilibrium, fructose exists in the linear form

Lim et al. Nat Rev Gastro Hepatol 7:251, 2010 Non-enzymatic glycation: fructose >> glucose Fructose and glycation Rates of reactivity in vitro 600

Rate Carbonyl 400 Fructose (/mM/hr) %

Glucose 0.6 0.002 200 Fluorescence Galactose 2.8 0.02 Glucose 0 Fructose 4.5 0.7 0 8 16 24 Days of in vitro glycation

Ahmed and Furth, Clin Chem 38:1301, 1992 Bunn and Higgins, Science 213:222, 1981 Association of fructose consumption with severity of steatosis and fibrosis

Grade of Steatosis Stage of Fibrosis

p =0.06p < 0.005 p < 0.0007

Non Occasional Daily Non Occasional Daily Error bar = 95%CI

Abdelmalek et al. Hepatology 51:1961, 2010 Foodstuffs and metabolic syndrome

• Transfats • Branched chain amino acids • Ethanol • Fructose

• Liver is the only site for energy metabolism • Not insulin regulated • No glycogen popoff, mitochondria are overwhelmed Toward a unifying hypothesis of metabolic syndrome

FRUCTOSE

Mitochondria Endoplasmic Cell NH2 Reticulum death UPR Cellular/ ROS metabolic dysfunction Acetyl-CoA ROS ATP ROS

ROS

ROS Acyl-CoA Lipid ROS droplet ε PKC Fat deposition JNK pSer-IRS-1 Peroxisome 1 Insulin resistance Insulin Receptor Bremer et al., Pediatrics 129:557. 2012 Sugar and Cancer

— Plausibility

— Mechanisms

— Correlation

(no causation yet: initiation vs. promotion?) Sugar and Cancer

Plausibility: The polyol pathway and the Warburg Effect Cell Energetics - All About “ATP” Cell Membrane Nutrient (Fat and Transporters Phosphate and (Sugars or Cell Signal Receptors some proteins) Fats) (Growth Hormone, Insulin) Glucose Glucose

Glycolysis

ATP NAD (108) NADH (2) ATP (2) ATP Lactate Pyruvate (30) (2)

Oxygen Acetyl CoA Fat Fat E NAD T TCA C Proteins KREBS NADH / Amino Mitochondria (lots) Acids

Courtesy Dr. Kieron Rooney Warburg’s Cancer Cell Energetics - All About “ATP” (from glycolysis only)

Warburg Hypothesis: Glucose Glucose The prime cause of cancer is the replacement Glycolysis of the respiration of oxygen in normal body 400x cells by the fermentation (Mina of sugar Bissell) NAD Although Glycolysis is NADH (2) ATP Lactate Pyruvate (2) a relatively inefficient (2) fuel supply in regard to ATP production - It can happen really Fat Fat really fast (up to 200x the rate of ? normal cells) Proteins / Amino Acids

Courtesy Dr. Kieron Rooney Glucose vital for cancer cell growth

• ATP (for energy) via glycolysis at rates far in excess to

that of normal cells and mitochondrial respiration

• Ribose - 5 - Phosphate (for DNA) via the

Pentose Phosphate Pathway

• Fat (for membranes) via both NADPH from the

Pentose Phosphate Pathway and Acetyl-CoA from

glycolysis Cancer Cells - All About “Making New Cells” Cell Membrane (Fat and Phosphate and Pentose some proteins) Phosphate Glucose Glucose Pathway Ribose-5- Phosphate

Fructose Glycolysis NADPH FAT DNA NAD Acetyl CoA NADH ATP Lactate Pyruvate (100s) (100s) (100s) NADPH Oxygen Acetyl CoA E NAD T C TCA NADH Glutamine KREBS (lots) Mitochondria

Courtesy Dr. Kieron Rooney Transketolase

Liu et al. Cancer Res 70:6368, 2010 Sugar and Cancer Mechanisms Fructose differentially induces transketolase in pancreatic cancer cells

Liu et al. Cancer Res 70:6368, 2010 Fructose increases pancreatic cancer cell proliferation

Panc-1 cell

Liu et al. Cancer Res 70:6368, 2010 Fructose increases the polyol pathway and ribose synthesis

Liu et al. Cancer Res 70:6368, 2010 Fructose-1,6-bisphosphate couples glycolytic flux to activation of ras

Peeters et al. Nat Commun 8:922, 2017 (100%) Sugar and Cancer Human Correlation Correlation between added sugar consumption and cancer risk NIH-AARP Diet and Health Study

N Added sugar Total fructose P for trend P for trend

All cancers 13,209 0.99 0.59

Lung cancer 2,008 0.83 0.03

Bladder cancer 202 0.45 0.03

Leukemia 226 0.02 0.07

Ovarian cancer 457 0.02 0.02

Tasevska et al. Int J Cancer 130:159, 2012 Dietary sugar correlates with breast cancer prevalence in Malaysia (case control, 382 pts/382 controls)

Sulaiman et al. Asian Pac J Cancer Prev 15:5959, 2014 Dietary sugar correlates with breast cancer prevalence in Malaysia (case control, 382 pts/382 controls)

Sulaiman et al. Asian Pac J Cancer Prev 15:5959, 2014 Multivariate hazard risk ratios for cancer recurrence or death according to BMI, physical activity, and SSB’s

Fuchs MA et al. PLoS ONE 9(6): e99816, 2016 doi:10.1371/journal.pone.0099816 Recognition at the American Heart Association

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

Circulation 120:1011, 2009 How our food dollars have been reallocated

Philpott, Mother Jones 2012 (from Bureau of Labor Statistics) Nutrition Facts Serv. Size 1 bottle (8 fl oz) Calories 350 Calories from Fat 100

Sugars 20 gm (Coca-Cola has 24 gm) x 4.1 cal/gm = 82 cal

Ingredients: Water, Corn Maltodextrin, Sugar, Milk Protein Concentrate, Canola Oil, Corn Oil, Soy Protein Isolate. Less than 0.5% of the Following: Whey Protein Concentrate, Natural & Artificial Flavor, Magnesium Phosphate, Potassium Citrate, Sodium Citrate, Soy Lecithin, Calcium Phosphate, Potassium Chloride, Choline Chloride, Ascorbic Acid, Salt, Carrageenan, Potassium Hydroxide, Ferrous Sulfate, dl-Alpha-Tocopheryl Acetate, Zinc Sulfate, Niacinamide, Manganese Sulfate, Calcium Pantothenate, Cupric Sulfate, Thiamine Chloride Hydrochloride, Vitamin A Palmitate, Pyridoxine Hydrochloride, Riboflavin, Chromium Chloride, Folic Acid, Sodium Molybdate, Biotin, Sodium Selenate, Potassium Iodide, Phylloquinone, Vitamin D3, and Cyanocobalamin. Summary • Obesity is associated with cancer development, but metabolic syndrome due to insulin resistance is the reason • Sugar is a cause, not the cause, of obesity • Fructose possesses unique metabolic characteristics which promote cellular damage — meets definition of toxin -De novo lipogenesis, liver fat, Browning reaction and cellular aging • Sugar is an independent risk factor for heart disease and diabetes –Plausibility, mechanism, correlation, causation –Exclusive of calories –Exclusive of obesity –Meets def. for scientific and legal proximate cause • Sugar may also be a risk factor for cancer development and/or promotion — Plausibility, mechanism (transketolase, ras), correlation • We currently consume triple our limit of added sugar • Current nutritional support for cancer provides high fructose content Further reading

Hudson Street Press Hudson Street Press Avery Press (Penguin USA) (Penguin USA) (Penguin Random House) Collaborators

UCSF UCSF Clinical/Translational Andrea Garber, Ph.D., R.D. Science Institute Patrika Tsai, M.D., M.P.H. Laura Schmidt, Ph.D. Emily Perito, M.D. Claire Brindis, Dr.P.H. Jung Sub Lim, M.D., Ph.D. Cristin Kearns, D.D.S. Stanton Glantz, M.D. Touro University Dept. of Biochemistry Jean-Marc Schwarz, Ph.D. UC Hastings Alejandro Gugliucci, Ph.D. David Faigman, J.D. Marsha Cohen, J.D. SFGH Depts. of Medicine & Radiology John Diamond, J.D. Susan Noworolski, Ph.D. Patricia Davidson, J.D. Kathleen Mulligan, Ph.D. UC Berkeley Dept. of Nutr. Sciences Pat Crawford, R.D., Ph.D. Stanford Prevention Institute Kristine Madsen, M.D., M.P.H. Sanjay Basu, M.D., Ph.D. Lorrene Ritchie, Ph.D. Paula Yoffe, B.A. Cindy Gershen Heather Millar University of Sydney Kristin Zellhart Kieron Rooney, Ph,D.