Morbidity: Prevalence of Diabetes in the United States

1. Insulin ResistanceMortality/Morbidity, Diagnosis & TreatmentMartin P Albert, MD and Peggy A. Wright, PhD, RD

2. “The trend in the life expectancy of humans during the past thousand years has been characterized by a slow, steady increase….Unless effective population-level interventions to reduce obesity and chronic disease associated with it are developed, the steady rise in life expectancy observed in the modern era may soon come to an end and the youth of today may, on average, live less healthy and possibly even shorter lives than their parents”. Olshansky SJ et al. A potential decline in life expectancy in the United States in the 21st century. NEJM. 2005;352(11):1138-1145.

3. Morbidity: Prevalence of Diabetes in the United States • An estimated 17 million have diabetes mellitus • 90-95% have Type 2 diabetes mellitus (T2D) • 20 million have impaired glucose tolerance (FG 110-120), and have a 10% yearly risk of progressing to DM • 5-fold increase in T2D in the latter half of the 20th century • 10-fold increase among children and adolescents in the last decade. • Lifetime risk of DM for individuals born in 2000 • 32.8% for males and 38.5% for females. Females have higher residual lifetime risks at all ages. • Highest estimated lifetime risk: Hispanics (males, 45.4% and females, 52.5%). • Loss of life-years if diagnosed with DM at 40 years • Men: 11.6 life-years and 18.6 quality-adjusted life-years • Women: 14.3 life-years and 22.0 quality-adjusted life-years. • Narayan KM - JAMA - 8-OCT-2003; 290(14): 1884-90

4. Morbidity/Mortality: Adding Insulin (Resistance) to Injury • Metabolic Syndrome • Endothelial dysfunction • Congestive heart failure • Treatment Resistant Hypertension • Nonalcoholic fatty liver disease • Alzheimer’s disease • Cancer (colorectal, breast, prostate)

5. Morbidity: Metabolic Syndrome As An American Crisis • High prevalence of metabolic syndrome among obese children and adolescents. Biomarkers of increased CV risks already exist in this population. Weiss, R at al. Obesity and the metabolic syndrome in children and adolescents. NEJM. 2004;350(23):2362-2374. • “These results from a representative sample of US adults show that the metabolic syndrome is highly prevalent (24%) …..the large numbers of US residents with the metabolic syndrome may have important implications for the health care sector”. Ford ES, Giles WH, Dietz WH. J Am Med Assoc 2002;287: 356 • The underlying problem of metabolic syndrome is insulin resistance.

6. Mortality/Morbidity: Insulin Resistance & Cancer Risk & Survival • Colorectal • Keku TO et al. Insulin resistance, apoptosis, and colorectal adenoma risk. 2005. Cancer Epidemiol Biomarkers Prev;14(9):2076-81. • Higginbotham S et al. Dietary glycemic load and risk of colorectal cancer in the Women's Health Study. 2004. J Natl Cancer Inst;96(3):229-33. • Breast • Borugian MJ et al. Insulin, macronutrient intake, and physical activity: are potential indicators of insulin resistance associated with mortality from breast cancer? 2004. Cancer Epidemiol Biomarkers Prev;13(7):1163-72 • Bozcuk H et al. Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy. 2004. Cytokine;27(2-3):58-65. • Ovarian • Augustin LS et al. Dietary glycemic index, glycemic load and ovarian cancer risk: a case-control study in Italy. 2003. Ann Oncol;14(1):78-84. • Prostate • Hsing AW et al. Insulin resistance and prostate cancer risk. 2003. J Natl Cancer Inst;95(1):67-71.

7. Morbidity: Insulin Resistance & Cognitive Decline • Alzheimer’s Disease • Friedrich MJ. Insulin effects weigh heavy on the brain. JAMA 2006:296(14):1717-1718. • Fishel MA et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. 2005;62(10):1539-1544. • Steen E et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is the type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80. • Cognitive decline in elderly with metabolic syndrome • Yaffe K et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292(18):2237-2242.)

8. Morbidity: NASH, HBP, & CHF • Close association between insulin resistance and nonalcoholic fatty liver disease.(McCullough, AJ. Thiazolidinediones for nonalcoholic steatohepatitis—promising but not ready for prime time. NEJM. 2006;355(22):2361-2363.) • Hyperinsulinemia may directly contribute to elevated blood pressure by enhancing sympathetic nervous system activity and promoting renal sodium retention. INS may also indirectly increase blood pressure by decreasing the signaling processes that are important for vascular relaxation. (Sowers, J. R. and E. D. Frohlich (2004). "Insulin and insulin resistance: impact on blood pressure and cardiovascular disease." Med Clin North Am88(1): 63-82. • Insulin resistance predicted congestive heart failure incidence independently of established risk factors. Ingelsson E. Insulin resistance and risk of congestive heart failure. JAMA - 20-JUL-2005; 294(3): 334-41.

9. Mechanism of Insulin Resistance • Positive net energy balance • Hypertrophic adipocytes • Metabolic byproducts result in phosphorylation and glycosylation of insulin receptor, which terminates the insulin signal. • GLUT4 no longer moves to the cell membrane to let in insulin. • Instead of glycogen storage, get circulation of free fatty acids, lipid storage, inflammation (TNF-alpha, IL-6), and reactive oxidative products from fatty acid metabolism..

10. Mechanism of Insulin Resistance • Where does plasma glucose go under ideal circumstances? • 80-85% to muscle • 5-10% to liver • <=5% to adipose tissue • Where does the fatty acid “spill over” in IR? • Blood (hypertriglyceridemia) • Adipocyte (central obesity) • Muscle (intramyocellular lipid deposition) • Liver (NASH) • Pancreas (Beta cell apoptosis and loss of insulin secretory ability) • Endothelial cells (hypothesis)

11. Mechanisms: Adipose Tissue & Insulin Sensitivity • What is the largest endocrine organ of the human body? • Adipose tissue—even the very lean will have 10-15 pounds of adipose that contributes at least 25 different adipokines. • The adipokines or adipocytokines are a group of cell-to-cell signaling proteins secreted by adipose tissue.

12. Adipocyte Products • ADIPOKINES ASSOCIATED WITH INSULIN SENSITIVITY • ADIPONECTIN (ACRP) • LEPTIN • ADIPOKINES ASSOCIATED WITH INSULIN RESISTANCE • RESISTIN (FOR RESISTANCE TO INSULIN) • TUMOR NECROSIS FACTOR (TNF) • INTERLEUKIN –6 (IL-6) • ADIPOCTYE PROTEINS AND LIPID METABOLISM • ADIPSIN • ACYLATION STIMULATING PROTEIN (ASP) • AQUAPORIN ADIPOSE (AQPap)

13. Adipocyte Products ADIPOKINES AND HEMOSTASIS 9. PLASMINOGEN ACTIVATOR INHIBITOR –1 (PA1-1) 10. ADIPOCYTE RENIN–ANGIOTENSIN SYSTEM (RAS) ADIPOSE AROMATASE AND INTRAADIPOSE GLUCOCORTICOIDS 11. AROMATASE 12. 11 HYDROXYSTEROID DEHYDROGENASE (11 HSD-1) OTHER ADIPOCYTE PROTEINS 13. METALLOTHIONEIN AND ITS GENES (MT-1; MT-2) 14. FASTING–INDUCED ADIPOSE FACTOR (FIAF) 15. LIPOPROTEIN LIPASE; CHOLESTERYL ESTER TRANSFERANCE: 16. APOLIPOPROTEIN E; RETINOL BINDING PROTEIN

14. Causes of Insulin Resistance: Dietary Factors 1 • The primary cause is our food supply and meal habits. Secondary is change in exercise habits. • Glucose “overload” • Fiber “shortage” • Refined grains in breads, pasta, crackers, etc. • Fewer legumes & legumes bred for less fiber (soluble fiber) • Fewer high fiber fruits and vegetables

15. Causes of Insulin Resistance: Dietary Factors 2 • Fat “overload” • Marbled meat from inactive/immoblized feedlot animals • Vegetable oils (corn, soy, safflower, etc.) • Eating out: gourmet, family, and fast-food restaurants • Large portion sizes • Insufficient vitamins, minerals, and micronutrients from eating too few whole grains, fruits and vegetables, and insufficient sunlight. • Insufficient phytonutrients (fruits and vegetables) • Additives that interfere with cell signaling mechanisms and structures.

16. Causes of IR: Responsiveness to Dietary Composition • Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasians. • Compared with the traditional diet, the modern diet was associated with a decrease in oral glucose tolerance and higher plasma cholesterol concentrations in both ethnic groups. • This occurred in the 14-day study time. • “Since glucose-mediated glucose disposal, beta-cell function, and glucose tolerance deteriorated on the modern diet, it is likely that diet composition affects the prevalence of noninsulin-dependent diabetes mellitus in both Pimas and Caucasians.” Swinburn B et al.Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasians. J Clin Endocrinol Metab. 1991 Jul;73(1):156-65.

17. Useful Diagnostic findings associated with Insulin Resistance • Visceral obesity and BMI : • over 40 in a man • over 35 in a woman • The total TGL to HDL ratio. If it is greater than 3, there's a 70% chance or better that the patient is insulin resistant. • Lipoprotein subgroup analysis: • dense LDL, • associated with increased triglyceride levels, • low HDL, and a • shift toward high VLDL levels.

18. Diagnosis: Fasting Insulin and BS • Advantages: • Usual testing: part of the CMET, inexpensive, and relatively easy. • Will screen for persons with relatively advanced insulin resistance. • Useful for following the change in insulin resistance of a given patient: • Used in research studies, such as the Diabetes Prevention Program. • Disadvantages • Will miss a large number of people with early impaired insulin resistance and glucose intolerance. • Problem: Early “ain’t” early enough

19. Diagnosis: Glucose Tolerance Test with Insulin Levels • “…post-challenge glucose levels provide additional information which may be helpful in the prediction of CVD.” • “Debate continues whether such testing should be undertaken, because administering glucose tolerance tests is troublesome, results vary, and the clinical benefit is not definite.” • Disadvantage: Time, cost, discomfort. • Estimating cardiovascular disease risk and the metabolic syndrome: a Framingham view. Endocrinology and Metabolism Clinics - Volume 33, Issue 3 (September 2004)

20. Diagnosis: HgbA1C (Glycosylated hemoglobin) • Advantages • Independent Predictor of risk of all cause mortality • Easy and inexpensive • Functional (physiological) Reflection of all factors affecting blood sugar and insulin resistance. • Easy concept for patients to understand • Serial comparisons helpful for patient education • Disadvantages • Problems with insurance payment for screening • Ideal level: Below 5%

21. Diagnosis: IR & All-cause Mortality • The European Prospective Investigation of Cancer and Nutrition-Norfolk study, found a continuous relationship between all-cause mortality and glycosylated hemoglobin even for values in the nondiabetic range in men ages 45-79 years. • An increase of 1% in HbA1c was associated with a 28% (P < 0.002) increase in risk of death independent of age, blood pressure, serum cholesterol, body mass index, and cigarette smoking. • This effect remained (RR, 1.46; P = 0.05 adjusted for age and risk factors) after men with known diabetes, a HbA1c concentration greater than 7%, or a history of myocardial infarction or stroke were excluded. • Srikanth S, Deedwania P. Comprehensive risk reduction of cardiovascular risk factors in the diabetic patient: an integrated approach. Cardiology Clinics - Volume 23, Issue 2 (May 2005)

22. Diagnosis: 2 hr postprandial testing • 2 hr post-prandial insulin, BS, and lipid panel • Advantages • Relatively easy and inexpensive • Physiologic, functional test. Reflects what is actually happening to that patient in real life. • Useful for patient coaching and feedback. • Different outcomes for different meals • Serial values show results of lifestyle change • Identifies insulin resistance years earlier than fasting studies • Disadvantages • Not using standard meal, results will vary • If LDL is calculated, fasting triglycerides are needed

23. Treatment Strategies: Overview • Downstream • Pharmacological Treatment of Consequences: Statins, antihypertensives, platelet-aggregation inhibitors, hypoglycemics, appetite suppressing drugs • Botanical treatment: Lipid lowering agents, platelet-aggregation inhibitors, hypoglycemics • Upstream • Treatment strategies based on primary causes, not downstream effects. • Recognize the social-environmental aspects of primary causes. • Support a change in lifestyle for the community. • Model a change in lifestyle for the patient.

24. Treatment of IR: Upstream Choices • Problem: Refined grains and sweeteners • Foods are not only “fast” foods but “fast release” foods • American diet is high in calorie-dense, insulin-provoking refined carbohydrates (e.g., flour, sugar, corn syrup) • Loss of blood-glucose moderating fiber • 98% of grain products consumed in the US are refined • Refined grains: blood sugar and insulin responses 2-3 times greater than whole grains or coarse-milled products • Loss of micronutrients involved in glucose regulation • vanadium, zinc, chromium, copper, iron, and nickel

25. White versus Whole Wheat(Source: Nutrition Action Newsletter, May 2006) • Whole Wheat 100 % • White: % of nutrients, compared to whole wheat • Vitamin E 7% • Vitamin B6 13% • Riboflavin 19% (230%)* • Niacin 20% (93%)* • Magnesium 16% • Fiber 22% • Zinc 24% • Potassium 26% • Thiamine 27% (176%)* • Iron 30 % (120%)* • Copper 36% • Selenium 48% • Folate 59% (416%) * • *Added in “enriched products”

26. Treatment of IR: Upstream Choices • Treatment: Eat minimally processed foods. • Use only whole grains • 100% whole wheat bread, oatmeal, barley, brown rice, quinoa, millet, stone-ground corn meal, etc. • Cut out sugar. Use whole fruit for sweetness. • Replace animal protein with legumes (soluble fiber, protein, vitamins, minerals) • 3-bean salad, hummus, lentil and minestrone soups, veggie chili, etc.

27. Upstream Treatment of IR: Whole Grains • A diet high in rapidly absorbed carbohydrates and low in cereal fiber has been found to be associated with an increased risk of type 2 diabetes. Schulze MB et al. Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle-aged women. AJCN. 2004;80:348-356. • Increasing whole grain foods to 3-servings daily may reduce the risk of developing type 2 DM by as much as 30%. McKeown NM. Whole grain intake and insulin sensitivity: evidence from observational studies. Nutr Rev. 2004;62(7):286-291. • A high CHO intake from low glycemic index sources may be superior in terms of increasing fat oxidation and improving overall glucose regulation than reducing CHO and increasing protein and fat. Postprandial glycemia should be avoided even when fasting glucose is normal. Brand-Miller JC. Postprandial glycemia, glycemic index, and the prevention of type 2 diabetes. AJCN. 2004;80:243-244.

28. Treatment of IR: Upstream Choices • Problem: Imbalanced fat intake • High intake of transfats (crackers, bakery goods, etc.)Lefevre, M., J. C. Lovejoy, et al. (2005). "Comparison of the acute response to meals enriched with cis- or trans-fatty acids on glucose and lipids in overweight individuals with differing FABP2 genotypes." Metabolism54(12): 1652-8. • High intake of saturated fats (meats)Haag, M. and N. G. Dippenaar (2005). "Dietary fats, fatty acids and insulin resistance: short review of a multifaceted connection." Med Sci Monit11(12): RA359-67. • Low omega-3 fats.Mostad, I. L., K. S. Bjerve, et al. (2006). "Effects of n-3 fatty acids in subjects with type 2 diabetes: reduction of insulin sensitivity and time-dependent alteration from carbohydrate to fat oxidation." Am J Clin Nutr84(3): 540-50. • Feedlot beef, poultry, and fish have few omega-3 fatty acids, which help normalize insulin signaling. • Increased use of corn oil, safflower oil, soy oil, which are omega-3 poor. • Affects inflammation and signal transduction

29. Treatment of IR: Upstream Choices • Solution: Healthy fats • Eliminate all trans fats-- bakery goods, partially hydrogenated oils in margarines, many commercial crackers and cookies. • Less than 0.5 g need not be labeled, so look at contents: i.e. partially hydrogenated oil • Severely limit high-saturated fat meats (beef, pork, bacon, etc.) • Avoid deep-fried foods. • Include high omega-3 fish or fish oil. (2 grams of EPA/DHA daily average) • Use monounsaturated olive oil (preferably extra virgin) as primary oil.

30. Insulin Resistance: Upstream Treatment choices • Problem: • Meal patterns that “starve” people during the day and “gorge” at night. The Sumo wrestler effect. • Meal habits with oversize portions, small hi-carb breakfasts, few fruits and vegetables, & large dinners. • Solution: • 3 meals per day • Larger high-protein, moderate fat breakfast (see handout) • Smaller dinners • No evening snacking • Increase fruits and vegetables • DASH and Mediterranean diets • Minimum of 5, preferably 10 servings per day

31. Insulin Resistance: Upstream Treatment choices • Problem: Addition of additives that interfere with cell signaling mechanisms and structures. • trans fats • artificial sweeteners • increases appetite and causes weight gain • gelatinous starches & sugary syrups in “fat-free” food • flavor enhancers (example: MSG) • Solution: • Eat food, not “food like substances.” • Avoid items with more than a few ingredients, or whose contents sound like a chemical catalogue • Avoid trans fats completely • Avoid foods with added sugars, corn syrup and artificial sweeteners

32. Insulin Resistance: Upstream Treatment choices • Problem: Lack of Exercise • Mechanism: Exercise reduces IR by increasing GLUT-4 mediated transport of glucose into target tissues. • Solution: • Regular exercise: starting with whatever is do-able: example walk 15 minutes every day • Make lifestyle more active: Avoid elevators, park at corner of lot, etc.

33. Treatment: Diabetes Prevention Program Research Group • “Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at risk. The lifestyle intervention was more effective than metformin”. Exercise and weight loss also improve endothelial function. • A moderate diet and 150 minutes of walking each week decreased the incidence of new diabetes by 58% in subjects with impaired glucose tolerance, and was effective in all age groups, whereas metformin treatment was associated with a 31% decreased risk of diabetes, but was not effective in subjects older than 60 years Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. NEJM. 2002;346:393-403.

34. Treatment:Finnish Diabetes Prevention Study • People at risk for Type 2 DM • Lifestyle intervention • Weight loss • Reduced total and saturated fat • Increased dietary fiber • Increased physical activity • 7-year follow-up • Reduction in DM incidence sustained after lifestyle counseling was stopped • Lindstorm J et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006; 368:1673-1678.

35. Treatment: Adequate 25-OH vitamin D • “The data show a positive correlation of 25-hydroxyD3 with insulin sensitivity and a negative effect of hypovitaminosis D on beta cell function. Individuals with hypovitaminosis D are at higher risk to insulin resistance and metabolic syndrome”. Am J Clin Nutrition 2004; 79: 820-25. • “The recommended adequate intakes for vitamin D areinadequate, and, in the absence of exposure to sunlight,a minimum of 1000 IU vitamin D3 is required to maintain a health concentration of 25-hydroxyvitamin D3 in the blood”. (greater than 50 nmol/L) Am J Clin Nutrition 2004; 39; 362-71.

36. Vitamin D Levels in 58 patients in Buckingham County 2006 • Vitamin D Level Number of patients • <10 ng/ml 8 (14%) • 10-20 29 (50%) • 21-30 10 (17%) -------------------------------------------------- • 31-40 6 (10%) • >41 5 (7%)

37. Botanical Hypoglycemics: Metformin • Galega officinalis has been known since the Middle Ages for relieving the symptoms of diabetes • Also known as Goat's Rue, French Lilac, Italian Fitch or Professor-weed.

38. Insulin Resistance: Downstream Treatment choices: Botanicals • Botanical hypoglycemics: examples • Fiber: glucomannon • Spices: Cinnamon: Cinnamon – Stimulates cellular glucose uptake and glycogen synthesis to a similar level as insulin (Jrnl of American College of Nutr 2001;20(4);327-36) • Aryuvedics: gymnema, fenugreek • Hops/acacia– Insinase • Silymarin (milk thistle) • TCM: bitter melon

39. IR Downstream Treatment Choices: Nutritional Antioxidants • Anti-oxidants: • Alpha lipoic acid (Alpha-lipoic acid – Stimulates glucose transport very effectively. Diabetes 2001; 50:1464-1471) • Green tea – increased glucose metabolism in adipocytes (fat cells) (Experimental and Molecular Medicine 2003; 35(2): 136-139) Epigallocatechin gallate. ECGC Standardized catachins. Reduces oxidation of LDL Reduces APO b. Reduces mycellar absorption of cholesterol from GI tract. Shunts to TI3K pathway. Increases insulin sensitivity through 2 or 3 pathways • Olive leaf, olive oil (monounsaturated) prevent oxidation of LDL, raise nitrous oxide levels, and improve insulin resistance (Mark Houston, MD. What Your Doctor May Not Tell You About Hypertension. 2003. New York: Warner Books.)

40. Problem: Wrong dietary recommendations for CHD • “Based on current evidence, replacement of total, unsaturated, and even possibly saturated fats with refined, high-glycemic index carbohydrates is unlikely to reduce CHD risk and may increase risk in persons predisposed to insulin resistance.” • Solution: Correct dietary recommendations. • 1) rich in whole grains and other minimally processed carbohydrates; • 2) includes moderate amounts of fats particularly unsaturated fats and omega-3 polyunsaturated fats from seafood and plant sources; • 3) is lower in refined grains and carbohydrates; and • 4) eliminates packaged foods, baked goods, and fast foods containing trans fatty acids • Mozaffarian, D. (2005). "Effects of dietary fats versus carbohydrates on coronary heart disease: a review of the evidence." Curr Atheroscler Rep7(6): 435-45.

41. Insulin Resistance and Diet: 10 word summary • From Michael Pollan: • Eat Food • Don’t eat a lot • Eat mostly vegetables • New York Times Magazine Jan 28, 2007. (Also See Michael Pollan’s book: The Omnivore’s Dilemma)