The Carbohydrate Hypothesis

1. The Carbohydrate Hypothesis Advanced Healing Methods GCU Holistic Health Fall 2009

2. Diseases of Civilization • Tribal and indigenous populations tend to have low levels of “diseases of civilization” • When exposed to Western diet- including sugar, molasses, white flour, white rice- these diseases appear • Obesity, diabetes, CVD, HTN, stroke, CA, cavities, periodontal dz, appendicitis, ulcers, diverticulitis, gallstones, hemorrhoids, varicose veins, constipation • When any of them appear, they eventually all do • Stress, other factors also important • Carb Hypothesis: The dietary cause of these diseases is the consumption of refined carbohydrates • Rejected in the 1970’s- incompatible with fat-chol idea

3. Reports • F.P. Fouche, South Africa, 1925, British Medical Journal • “I never saw a single case of gastric or duodenal ulcer, colitis, appendicitis, or cancer in any form in a native, although these diseases were frequently seen among the white or European population.” • Smithsonian Institution, 1908 • “Malignant diseases, if they exist at all… must be exceedingly rare.” • As were CVD, appendicitis, peritonitis, ulcer, etc. • The Native Americans (SW US and Mexico) lived as long as or longer than local whites • Isaac Levin, Columbia U, 1910- survey of 107 physicians • Buchanan- 15 yr practice, 2000 Indians, avg lifespan 55-60, one case of CA • Goodrich- 13 years, 3500 Indians, zero cases of CA • Total- 115,000 Indians, treated for a few months to 20 years, 29 total cases of malignant tumor

4. Early Studies • The Natural History of Cancer, 1908 • Many continents and regions • Fiji- 120,000 tribal people, 2 deaths from CA • Borneo- Dr. Pagel- 10 years, zero cases of CA • In NYC, 32 deaths per 1000 people in 1864, 67 in 1900 • Philly- 31 in 1861, 70 in 1904 • “The negative evidence is convincing that in the opinion of qualified medical observers cancer is exceptionally rare among primitive peoples” • Fredrick Hoffmann, later a founder of the ACS

5. Why is this? • Paleolithic diet high protein (19-35%), low carb (22-40%), high fat (28-58%) in one estimate • Carbs (cereal grains, dairy, drinks, veggie oils, sugar, candy) are over 60% of calories in modern diet, but virtually absent in Paleo • White flour and sugar increase in late 19th century in Western diets right along with the rise in CA mortality (and DM, appendicitis, etc) • Stress levels also?

6. Refining Foods • The more refined, the whiter • The lower the vitamin, mineral, protein, and fiber • But- “more attractive to the eye” • Better baking properties • Bran (and molasses) sold for livestock and industry • Better “digestibility” (i.e., a higher glycemic index) • Less liable to infestation (!) • Mid-19th century • White flour less expensive- invention of roller mill • Sugar less expensive- sugar-beet cultivation spread • White rice- mechanical rollers mid-20th century • WWI England- 90 lbs. sugar per year- 500% increase in a century- Americans 80 lbs.

7. Debate • Early 20th century: Do the digestibility and pleasing white color outweigh the removal of nutrients? • By WWII, US law: white flour must be enriched with vitamin B, iron, and niacin • Britain also • White flour, sugar, and rice problematic because they have the nutrients and fiber taken out • Is this the only explanation?

8. Diabetes • High blood glucose • Glycosuria, frequent urination • Constant hunger for sugar and refined carbs • Urine smells and tastes like sugar (DM aka “sugar sickness”) • Absent in isolated populations eating traditional diets • Rise in Western societies coincides with rise in consumption of sugar and white flour • Death rate from DM up 400% btw 1900 and 1920 in US, up 15X since Civil War, similar in Britain and France • “Rises and falls in the sugar consumption are followed with fair regularity within a few months by similar rises and falls in the death rates from diabetes.” • -H. Emerson, Columbia U, 1924

9. Diabetes • Of the 13 countries highest in consumption of sugar, 11 are found among the 13 highest in death rate from diabetes • Elliott Joslin- Joslin’s Diabetes Mellitus • 1920’s- pioneered insulin as DM Tx • Insulin discovered in 1921 • DM from obesity, decrease in exercise, and fat-rich low-carb diet • Mainstream view

10. Outside the US • Israel 1954- immigrants from Yemen, in 1930’s and 1949 • 3 cases of DM in 1949 cohort, incidence 50X greater in 1930’s group, comparable to Jewish populations in NYC, Israel, etc • Also greater CVD, HTN, high cholesterol • Carbs in both diets about the same, but almost no sugar consumption in Yemen • New Zealand 1964- isolated Maori population • Physically active, but lots of diseases of civ • Bread, flour, cereals, sugar, potatoes, etc • South Africa 1950’s- George Campbell • Whites and urban Zulus had diseases of civ, not rural Zulus • Fat in diet <20% in both, but 6# sugar per year vs. 80# • Natal Indians- 6200 diabetics in 250K, but 1% in the rest of India, so genetic explanation not meaningful here • Fat in diet low for both, but 12# sugar/year vs. 80# • 1600 calories/day, but obese and diabetic • Sugarcane workers, oddly, little DM despite chewing cane all day • Evidence against sugar hypothesis • But this sugar not yet refined, and high physical activity

11. Peter Cleave • 1966- Diabetes, Coronary Thrombosis, and the Saccharine Disease • Diseases of civ- CHD, obesity, DM, ulcers, appendicitis- all symptoms of an underlying saccharine disease • Adding sugar, flour, and white rice to any diet leads to chronic disease- same dz no matter the previous diet • Dental caries the “canary in the coal mine” • Weston Price- dental dz correlates with diet • Law of Adaptation: species require time to adapt to a new feature in the environment • Refining carbs the most drastic dietary change since agriculture • Overconsumption- deception of appetite control • Removal of protein • Increased rate of digestion, blood sugar spikes

12. Confound • Affluence- meat consumption tends to go up, grains down along with total carbs, but refined carbs up, often drastically • A confound • In US, 15# sugar/year in 1830’s to 100# by 1920’s and 150# by 2000 (including HFCS) • Keys- Japan- low fat, low HD • But also very low sugar and flour consumption • Seven Countries Study • Crete and Corfu- Mediterranean diet- attributed to fish, olive oil, and veggies • But 16# sugar per year, no white flour at all • Sugar predicts HD mortality as well as fat did • Doll and Armstrong- 1975- the higher the sugar intake (in several nations), the higher the incidence and mortality from CA of colon, rectum, breast, ovary, uterus, prostate, kidney, NS, and testes

13. John Yudkin • Queen Elizabeth College, London • Fed sugar and starch to different animals • Raised cholesterol, TG’s, insulin • High-sugar diets to college students • Raised cholesterol, TG’s, insulin, blood cells stickier • Sugar responsible for the diseases of civilization • Early 1970’s- Europe open-minded, not US • By the late 1970’s, to study the dietary harm of sugar was to endanger your reputation • All potential causes of CVD (and other chronic diseases) had to coexist with the idea that dietary fat caused CVD

14. Metabolic Syndrome • Imbalances common to obesity, DM, CVD • Abdominal obesity • Elevated triglycerides • Low HDL, high LDL (small, dense LDL) • High blood pressure • Hyperinsulinemia • Insulin resistance/glucose intolerance • Prothrombotic state • Proinflammatory state- elevated C-reactive protein • Elevated uric acid- precursor of gout • All worsened by refined carbs

15. Insulin • Homeostasis • Endocrine control- hypothalamus • Reproduction, growth, homeostasis, energy metabolism • All hormones affect fuel partitioning • Insulin • Regulates fat, carb, and protein metabolism • Glycogen synthesis • Fat synthesis and storage • Synthesis of protein, RNA, DNA • Coordinates homeostasis and energy metabolism • Carb and fat metabolism, kidney and liver fcnout of balance in metabolic syndrome- hyperinsulinemia • The most dramatic disruption (arguably) of homeostasis in human history has been the introduction of sugar and refined carbsinto the diet, including fructose

16. Hypertension • BP greater than 140/90 • Risk factor for CVD, stroke, obesity, DM • And DM and obesity risk factors for HTN • HTN accounts for up to 85% of extra CVD risk in DM • Salt as the dietary cause of HTN • Water retained along with the salt, blood volume up • Body normally excretes the salt • But evidence ambiguous, effect small • Cutting salt intake in half lowers BP by <5 mm Hg

17. Hypertension • Insulin elevated in HTN • HTN as an insulin-resistant state • The higher the BP, the higher the chol and TG levels, the greater the body weight, and the greater the risk of DM and CVD • Carbs inhibit salt excretion, so we retain water • Insulin encourages the kidneys to hold on to sodium • Joslin’s DM: chronically elevated insulin “the major pathogenetic defect initiating the hypertensive process” in type 2 DM

18. Hypertension • Carbs encourage the kidneys to retain Na • Insulin stimulates the SNS, stress response • Increases HR, constricts blood vessels = higher BP • Conventional: obesity causes high insulin • Obesity caused by calorie imbalance • Alternative: carbs raise insulin levels, leading to HTN, obesity, other diseases of civilization

19. Lipids and CVD • Fat-free fatty acids and triglycerides • Cholesterol • Lipoproteins • HDL- high-density lipoprotein • LDL- low-density lipoprotein • VLDL- very low-density lipoprotein • TG’s mainly found in VLDL • Cholesterol mainly in LDL

20. Lipids and CVD • 1950- ultracentrifuge fractionates lipoproteins • LDL higher in atherosclerosis • LDL not consistently related to blood cholesterol • Gofman: LDL and VLDL can predict CVD, but atherogenic index combining both even better • Majority opinion- lipoproteins not important

21. Lipids and CVD • LDL elevated by saturated fats • VLDL elevated by carbs • When LDL declines, VLDL rises disproportionately • So… low-fat, high carb diet could increase risk of CVD • Recommending low-fat diet for everyone? • Ahrens 1955- carbohydrate-induced lipemia • Test tubes • Joslin: “The percent of fat (in the blood) rises with the severity of the disease (diabetes)… and is especially related to the quantity of carbohydrate, … rather than with the fat administered.”

22. Lipids and CVD • 1961- Ahrens and Margaret Albrink • Elevated TG’s in • 5% of healthy young men • 38% of middle-aged men • 82% of coronary patients • Elevated TG’s assoc with CVD risk, and low-fat, high-carb diets raise TG’s • High TG’s much more strongly associated with CVD than high blood cholesterol • AHA embracing Keys hypothesis at the time • NIH funding- testing chol hypothesis only • 1967 JAMA: “This fervent embrace of cholesterol to the exclusion of other biochemical alterations resulted in a narrow scope of study.” (p. 159)

23. Lipids and CVD • 1967- NIH finally studies lipoproteins • 4 categories • LDL- carries most cholesterol • VLDL- carries most triglycerides • HDL • Chylomicrons- carry dietary fat from intestines to fat cells • Since TG’s, different lipoproteins, and the chol in each could now be measured, more tests follow

24. Lipids and CVD • 5 studies- results 1977 • Total blood cholesterol not predictive of CVD • LDL a “marginal” risk factor • TG’s predict CVD • HDL the strongest predictor of all • The higher the HDL, the lower the TG’s, and the lower the risk of heart disease • HDL the largest impact, and the only good predictor for age >50 • So… since TG’s tend to move with obesity, DM, and HDL, TG’s as not important by themselves, so no need to focus on dietary carbs (!) • MRFIT and LRC trials focused on total cholesterol • No room left over in the dogma or the funding • One drug study (1999)- CVD prevented by raising HDL • The drug also lowered VLDL, TG’s • No dietary studies yet

25. Lipids and CVD • HDL revelations • NHLBI and AHA • Keep the science simple for the public • Reconcile this with fat-cholesterol hypothesis • So… a small increase in risk from elevated LDL chol • And 70% of total chol as LDL chol • Now the effort shifted to lowering LDL cholesterol, not total cholesterol • A “marginal” risk factor becomes, using the same data, a “powerful” and “significant” risk factor • NCEP (National Cholesterol Education Program) in 2003: “Robust relationship between total cholesterol and (CVD)… implies that an elevated LDL is a powerful risk factor.” • HDL still the dominant predictor, though, along with TG’s

26. Lipids and CVD • Dietary carbs lower HDL • Typically not mentioned • Advice- lower HDL through exercise and weight loss • Low-fat, high-carb diets to lose weight • Saturated fats raise HDL and LDL • Carbs lower HDL and LDL • 1985- monounsaturated fats lower LDL, raise HDL • Oleic acid- the main fat in olive oil

27. Lipids and CVD • Oleic acid also the main fat in meat, eggs, bacon, lard • Porterhouse steak with ¼ inch layer of fat • 51% monounsaturated, 90% of this is oleic acid • 45% saturated • 1/3 of this is stearic acid, which metabolizes to oleic acid • 4% polyunsaturated- lowers LDL, no effect on HDL • So- 70% of the fat in meat raises HDL and lowers LDL, while the other 30% will raise HDL and LDL • Bacon instead of bread to reduce CVD risk?

28. LDL Subtypes • 1980- R. Krauss- 7 subtypes of LDL • Different amounts of cholesterol • Different effects on CVD • Different responses to dietary carbs and fats • Smallest, densest LDL • Strong negative correlation with HDL • Elevated in CVD • Small, dense LDL • Squeezes more easily through damaged artery walls • Structural changes in protein facilitating adhesion • Remains in bloodstream longer • Oxidizes more easily • Oxidation potentiates LDL’s role in atherosclerosis

29. Lipids and CVD • LDL in the population in two patterns • Pattern A- large, fluffy LDL, low CVD risk • Pattern B- small, dense LDL, high CVD risk • High TG’s, low HDL (not in pattern A) • This pattern (the atherogenic profile) also found in DM • The lower the fat in the diet and the higher the carbs, the smaller and denser the LDL, the more likely the appearance of pattern B, and the greater the CVD risk • The more saturated fat in the diet, the larger and fluffier the LDL

30. Carbs and CVD • 1931- high-fat diet for DM • Only 9 of 79 pts with high cholesterol • Atherosclerosis in 10% • 1962- carbs double in diabetic diet • Fat calories from 60% to 40% • TG’s up 40% • Atherosclerosis in 56% • Weight gain- the greater the body fat, the greater the TG’s • 50% increase with 10 lb gain in middle age • MI survivors- high TG’s, glucose intolerance • Also high TG’s in DM

31. Insulin • Carbohydrate-induced lipemia • TG levels up with dietary carbs • Down when replaced by fat • Insulin stimulates TG synthesis and secretion to fat cells • Insulin resistance exacerbates this • 1987- Reaven- Syndrome X- later metabolic syndrome • Observational and prospective studies link hyperinsulinemia, insulin resistance, and type 2 DM to high TG’s, CVD, obesity, stroke, HTN-the higher the insulin levels, the greater the CVD

32. Insulin and CVD • 2005, Joslin’s DM: “the effects of insulin (on CVD)… are related to both systematic metabolic abnormalities and the direct effect of insulin on the vasculature” • 1960’s- insulin enhances transport of cholesterol and fat into the arterial wall • And stimulates chol and fat synthesis in artery wall • Insulin also enhances smooth muscle cell proliferation in artery walls • Insulin as an “atherogenic hormone”?

33. Sugar Toxicity • Reactive oxygen species • Free radicals and other oxidants – oxidative stress • Burning glucose transforms oxygen • Neutralized by antioxidants • Advanced glycation end-products (AGE’s) • Glycation- sugar attaches to protein without enzyme • Random reaction, leading to more of same • The sugar disengages in low blood sugar • In high blood sugar, continuing process = AGE’s • AGE’s cross-link with each other and other proteins

34. Sugar Toxicity • AGE’s accumulate in eye, kidney, arterial lining, nerve endings • All of which are damaged in DM • AGE accumulation normal • Accelerated in high blood sugar • Collagen- most abundant protein, structural • AGE version ages skin- diabetics look older • Also stiffening of joints, arteries, heart, lungs- leather

35. Sugar Toxicity • LDL particularly susceptible to glycation • As is HDL, making them both more atherogenic • And oxidation by ROS • Oxidized LDL trapped in artery wall more effectively, along with its cholesterol • Also more resistant to removal from blood • Oxidized LDL elevated in CVD patients • With or without DM • And particularly in the plaques • Anti-AGE compounds (AGE breakers) reverse arterial stiffness (in animals) • Help CV and renal changes of HTN

36. Sugar • Sucrose- table sugar • Glucose and fructose • Glycemic index- rate of digestion, absorption, and conversion of carbs to blood sugar • The higher the GI, the higher the blood sugar spike • And the higher the resulting insulin rise • Glucose = 100 • Fat and protein decrease GI, refined carbsraise it • GI of sucrose (69) lower than flour and starches • Fructose metabolized in the liver, so little immediate effect on blood sugar • So… it’s healthy! (p. 198)

37. Fructose • Fructose-induced lipogenesis • Fructose stimulates TG synthesis in liver • Fructose also blocks glucose metabolism in the liver • And glycogen synthesis • So more insulin secreted • Fructose-induced HTN greater than glucose • Sucrose and HFCS the worst of both worlds- p. 201 • Fructose way more reactive in AGE formation than glucose • And 10x more effective at cross-linking • And the AGE’s and cross-linked proteins more resistant to degradation • Fructose greatly increases the oxidation of LDL’s, too • Two enzymes (acyl-CoA and acyl-carnitine) suppressed by fructose- this tells cells to store fat, not burn it • Fructose increases pyruvatedehydrogenase (PDH, another enzyme) synthesis in liver • Cells burn sugar, not fat- metabolism skewed toward fat storage • Fatty liver disease, like in alcoholics

38. HFCS • HFCS-55: high-fructose corn syrup • 55% fructose, 45% glucose • US- 110-120# of caloric sweeteners per capita per year • Up in 1960’s, coinciding with HFCS precursors • HFCS-55 introduced in 1978 • Cheaper substitute for sugar in US • Corn subsidies and sugar tariffs • Lower cost encourages consumption • Liquid- easier to blend and transport • It’s natural! “Fruit sugar” • 124# sugars 1975-79 • 150# in 2000, almost completely due to HFCS • Paralleling the rise in obesity

39. Fructose and HFCS • Sucrose- broken down to fructose and glucose by the enzyme sucrase • This regulates the amount the body can digest • HFCS- no need for sucrase, no regulation • HFCS soft drinks 10x richer in carbonyl compounds than diet soda control • Involved in AGE formation • Elevated in diabetics and implicated in foot ulcers, retinopathy, neuropathy • HFCS induces leptin (satiety signal) resistance • People keep eating and don’t feel full- hungry ghosts! • HFCS tainted with mercury- 1/3 of products tested • Caustic soda and HCl used in production

40. Fructose and HFCS • Continuing systemic denial • Several studies: HFCS no different than other energy sources • Funded by American Beverage Institute, Corn Refiners Association • "I don't think there should be a perception that high-fructose corn syrup has caused obesity until we know more.“-Dr. Barry M. Popkin • "There's no substantial evidence to support the idea that high-fructose corn syrup is somehow responsible for obesity .... If there was no high-fructose corn syrup, I don't think we would see a change in anything important.“ • Walter Willett, chair of the nutrition department of the Harvard School of Public Health • "Doubt is our product since it is the best means of competing with the 'body of fact' that exists in the mind of the general public." • 1969 memo written for cigarette maker Brown & Williamson • “It is difficult to get a man to understand something when his salary depends upon his not understanding it.” • Upton Sinclair

41. Cancer • At least 75-80% preventable with diet and lifestyle • Some role for pollution and chemicals • Diet the largest role • Increasing incidence in CA • GI- colon, rectal, gall bladder • Endocrine- breast, endometrial, ovarian, prostate • These are the cancers related to diet and lifestyle • Incidence patterns similar to CVD, DM, obesity • Another disease of civilization

42. Cancer • Late 1970’s- 5 countries with highest sugar intake also the 5 countries with the highest breast CA mortality • 5 lowest = 5 with least mortality • Sugar intake correlated with incidence and mortality • In colon, rectal, breast, ovarian, prostate, kidney, nervous-system, and testicular CA • GI and endocrine CA tend to increase with obesity • Breast and endometrial CA- estrogen • Obesity increasing estrogen production

43. Cancer • Tumors can get energy anaerobically • Burn way more sugar than normal cells • Insulin • Link btw CA and glucose intolerance • Insulin acts a growth promoter, normally and in CA • Breast CA tumors- more receptors for insulin • Fuel and growth signals to cells, including CA cells

44. Cancer • IGF- insulin-like growth factor • Prominent hormone in growth regulation • Secreted by liver and local tissues • Many classes of IGF • Can mimic effects of insulin, and vice versa • Intermediary between growth hormone from pituitary and actual food available for cells • IGF levels change with food availability • More slowly than insulin- days to weeks

45. Cancer • IGF receptors necessary for tumor growth • IGF enhances tumor growth • Particularly with estrogen • Tumors can secrete their own IGF • Tumor cells have more IGF receptors • Insulin unbinds IGF to enter cells • So extra insulin and extra blood sugar along with extra IGF and extra signals to proliferate • IGF also overrides the cell suicide program • Mice with reduced IGF have slower tumor growth • Accelerates with IGF injection • Insulin and IGF both cause benign tumors to metastasize

46. Cancer • Hyperinsulinemia and elevated IGF in breast, prostate, colorectal, and endometrial CA • Genetic mutations happen normally, and the body effectively fixes them • Insulin and IGF accelerate the process of the cell becoming cancerous, and keep it alive and multiplying • They don’t cause the CA, but they encourage the transformation into malignancy • An ideal environment for CA growth

47. Alzheimer’s Disease • Progressive and fatal brain disease • Most common form of dementia • Plaques- beta-amyloid protein between cells • Tangles- protein inside dying nerve cells • Both disrupt nerve cell communication • Both accumulate in most people • Risk factors- age, genetics, family history, smoking • Also- HTN, CVD, stroke, DM, metabolic syndrome • Hyperinsulinemia too • Another disease of civilization • Incidence patterns similar to CVD, DM, obesity • 2x increased risk in diabetics • 4x if on insulin

48. Alzheimer’s • Amyloid- normal protein in brain • Healthy brains clear it out, but not in AD • AGE’s found in plaques and tangles • Nobody knows for sure what causes AD • Theory- AD starts with glycation • Proteins stick to themselves and each other • Disposal mechanisms don’t work, so they accumulate • Cross-linking leads to AGE’s • Glycation also generates ROS (free radicals) • Damaging neurons further

49. Alzheimer’s • Insulin-degrading enzyme (IDE) • Clears both amyloid and insulin • Insulin can monopolize it • In animals- the less IDE available, the more amyloid • Mice without IDE gene get AD and type 2 DM • Insulin given to healthy elderly volunteers • Amyloid increased proportionately • The older the person, the greater the increase • Decreasing insulin increases amount of IDE