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Unified Field Theory of Diseases of Civilization

Unified Field Theory of Diseases of Civilization. Credentials. Private Practice, Family Medicine and Bariatric Medicine in Northeast Kansas Medical Director, University of Kansas Weight Control Program (VLCD-very low calorie liquid diet) Consultant, Duke Diet and Fitness Center

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Unified Field Theory of Diseases of Civilization

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  1. Unified Field Theory of Diseases of Civilization

  2. Credentials • Private Practice, Family Medicine and Bariatric Medicine in Northeast Kansas • Medical Director, University of Kansas Weight Control Program (VLCD-very low calorie liquid diet) • Consultant, Duke Diet and Fitness Center • Consultant, Atkins Nutritionals, Inc. • Consultant, Veronica Atkins • Clinical Faculty, University of Kansas Medical School • Diplomate of the American Society of Bariatric Physicians • Past President, American Society of Bariatric Physicians • Fellow, American Society of Bariatric Physician • Co-author, lay press diet book • Co-author, “Dietary Treatment of the Obese Individual” and “Medical Treatment of Pediatric Obesity” in Handbook of Obesity Treatment. • Partner: Innovative Metabolic Solutions

  3. Credentials • Behavioral • 40 + years training animals including cats, dogs, horses, and one chicken. • I have participated in the training of 10 nationally ranked agility dogs including the #2 beagle (2 years) and #1 Norfolk Terrier (8 years) • Currently employed by Joan Meyer (Triune Training) AKC World Agility Team member 2001, 2003, 2008. • I specialize in behavior problems as well as the biomechanics of the working animal.

  4. Metabolic Health • Its not the weight, it’s the fuel source.

  5. Metabolic Syndrome • Vernon, M. • Retrospective chart review • Outpatient clinical setting • 124 patients-64 rx’d low CHO 57 rx’d low fat + anorectic Vernon, M. C., B. Kueser, et al. (2004). "Clinical Experience of a Carbohydrate-Restricted Diet for the Metabolic Syndrome." Metabolic Syndrome and Related Disorders 2(3): 180-186.

  6. Methods • Outpatient clinical setting • Low fat diet + phen/fen (n=64) • Carbohydrate restricted diet (n=57) • Diet prescription was written. • 20 grams carbohydrate/day until weight loss goal obtained or patient willing to slow weight loss. • Both groups routinely monitored with office visits and blood work.

  7. Parameters Followed • Vital Signs; Blood Pressure, TPR, Weight. • Initially used caliper measurements of Body Fat (Phen-fen). Low CHO patients followed with bio-electric impedance body composition scale. • Obtained CBC, fasting lipids, thyroid studies, chemistry panel, C-peptide and UA. • Now also obtain hs-CRP, 24 hr urine for creatinine clearance and microalbumin followed on all diabetic patients. Labs repeated at ~3 mon. intervals until stable weight –then at least yearly.

  8. LF Diet + MedsCarb Restriction mean (SD) mean (SD) n 56 66 Age, years 41.3 (8.7) 47.9 (12.7) Gender female 80.4% 71.2% Race Caucasian 94.6% 92.3% Height, inches 66.2 (3.5) 65.9 (3.7) Weight, kg 94.0 (21.1) 97.7 (28.8) Body mass index, kg/m2 38.3 (7.4) 38.7 (11.1) Family history of obesity 82.1% 65.2% Hypertension therapy 21.4% 33.3% Diabetes mellitus therapy 8.9% 22.7% Lipid therapy 16.2% 27.6% Psychiatric medical therapy 21.4% 21.2% Thyroid therapy 19.6% 6.1% Demographics

  9. Low-Fat Diet + MedicationCarbohydrate Restricted Diet VariableBaselineFollow-upChangeBaselineFollow-upChangeP value* Mean Body weight, kilograms** 108.7 94.9 -12.7% 108.2 98.7 -8.8% 0.005* Total cholesterol, mg/dl 219.9 194.8 -11.4% 213.9 203.1 -5.0% 0.39 Triglycerides, mg/dl 210.5 151.8 -27.9% 203.8 115.5 -43.3% 0.02* LDL-C, mg/dl 134.9 121.2 -10.2% 123.0 128.0 +4.1% 0.52 HDL-C, mg/dl 40.2 40.8 +1.5% 44.7 48.9 +9.4% 0.003* Total chol/HDL-C ratio 5.8 5.1 -12.1% 5.3 4.6 -13.2% 0.08 Trigycerides/HDL-C ratio 5.8 4.3 -25.9% 5.7 2.8 -50.9% 0.01* ** The mean follow-up was 20.2 wks for the LF Diet + Meds group and 15.0 wks for the Carb Restriction group Results

  10. How did these options compare? • Weight loss almost as much with CHO restriction as our best medication effort using phen/fen. • Lipid profile was markedly improved: • 51% improvementin Trig/HDL ratio (an emerging marker of cardiovascular disease).1 1 Gaziano JM, Hennekens CH, O’Donnell CJ, Breslow JL, and Buring JE “Fasting Triglycerides, high-density lipoproteins and risk of myocardial infarction.” Circulation 96: 2520-2525 (1996)

  11. Rate of Loss Very Low Carbohydrate Diet Phen/Fen and Low Calorie Diet * p = 0.04 comparing change from Week 0 to Week 24 between groups

  12. News Flash • Not all weight loss is the same in terms of metabolic state. • Metabolic outcomes are different based on the fuel source ( fat or carbohydrates)

  13. What Can You Impact? • Any condition related to hyperinsulinemia: • CAD, prediabetes, metabolic syndrome, Type 2 diabetes mellitus, hypertension, hyperlipidemia, dyslipidemia including high triglycerides and low HDL, proteinuria due to metabolic syndrome, obesity, acanthosis nigricans • Central nervous system irritability such as seizures and migraines • Ovarian dysfunction due to hyperinsulinemia manifested as polycystic ovary syndrome, irregular menses, anovulation, irregular ovulation, facial hirsuitism • GERD • Sleep apnea, Pickwician syndrome • Gestational diabetes, pre-eclampsia • Osteoarthritis • Inflammation • Some Psychiatric conditions

  14. Diseases of Civilization • Elevated carbohydrate intake (different tolerance from one individual to another) causes chronically high levels of insulin and other inflammatory mediators. • These are the drivers of the diseases of civilization-hypertension, metabolic syndrome, prediabetes, diabetes and excess fat mass gain.

  15. Mitochondrial Energy Production • This is the key to life. • No mitochondrial energy production=death • No mechanic, no oil changes, only on-site repair and oxidation must continue at all times. • That’s a challenge-and nutrition is the key.

  16. Mitochondrial Fuel Source • Mitochondrial fuel source is linked to oxidative stress • Oxidative stress is linked to tissue damage • Mitochondrial enzymes adjust to fuel source • Constant mitochondrial energy production without oxidative damage is the goal.

  17. Is Adiposity the problem? • Sunburn is the best analogy • Genetic predisposition and environmental exposure combine to cause damage. • Adiposity is a marker for hyperinsulinemia. • Excess adipose tissue is part of the pathologic process of insulin resistance and • hyperinsulinemia

  18. All calories have equal value, regardless of source Importance of each macronutrient tied to caloric density Weight gain when energy intake exceeds energy expenditure Lose weight by reducing caloric intake and/or increasing caloric expenditure Increased carbohydrate intake increases insulin production and decreases lypolysis (fat-burning) Macronutrients control metabolic hormone production, which controls storage metabolism. High carbohydrate consumption leads to hyperinsulinemia, which leads to obesity and Metabolic Syndrome Two Approaches to Understanding Human Metabolism Classic Hormonal

  19. Hormones • Insulin • Glucagon • Incretins • Epinephrine • Norepinephrine • Cortisol • Sex Steroids • Branched chain amino acids • IL-6 • Dietary Carbohydrates

  20. Visceral Adiposity Dr. Eric Freedland proposed the concept of the “critical visceral adipose threshold”-the amount of visceral fat storage that an individual could gain after which metabolic obesity ensued. This hypothesis, in conjunction with individual tissue levels of insulin resistance, may explain why one person is obese to the eye but has fewer metabolic abnormalities while an apparently thin individual is metabolically at risk. • Freedland, E. S. (2004). "Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review." Nutr Metab (Lond)1(1): 12.

  21. Physiology of Obesity Treatment • Obesity is excessive adipose tissue (fat) • “Excess” is defined by metabolic and functional parameters • The goal is to mobilize, or “burn fat” • To accomplish this goal, a change from “glucose burning” to “fat burning” is needed

  22. Fat Metabolism and Insulin • The hormonal milieu needs to be appropriate for “fat burning” • The effect of insulin to facilitate glucose uptake is linked to fat synthesis • “Fat burning” is inhibited by insulin, so insulin levels need to be around basal levels • Insulin levels can be lowered by: • Increasing energy expenditure • Reducing carbohydrate intake

  23. Insulin Promotes Fat SynthesisGlucagon Promotes Fat Burning Fatty acid synthase citrate TCA cycle Triglycerides Malonyl CoA ACCb CPT I mitochondria cytosol Intracellular and intravascular CPT I (Carnitine palmitoyltransferase I) moves long chain fatty acyl CoA groups into the mitochondria for oxidation. Inhibited by malonyl CoA. Glucose abundant-TCA producing citrate via acetyl CoA and oxaloacetate. Insulin increases availability of TCA intermediates via enzyme regulation Acetyl CoA carboxylase (ACCb ) is activated by citrate and insulin, inhibited by glucagon. Fatty acid synthase inhibited by glucagon

  24. Fuel Sources: Fatty acids, ketones, glucose • Fatty acids can be utilized by most tissues for energy. • Ketone bodies are generated by the liver from fatty acid oxidation. Ketones can be utilized by all cells except glucose obligate cells and liver. • Glucose is synthesized by the liver and renal medulla from amino acid precursors (gluconeogenesis). Cells without mitochondria (erythrocytes, cornea, lens, retina) and cells in low oxygen tension conditions (renal medulla) are obligate glucose users.

  25. Fatty Acids • Fatty acids are the main cellular fuel for all non-obligate glucose using cells • Preferred fuel of the myocyte • A large pool of fatty acids are circulating on albumin at any given time • There is nearly unlimited storage potential as triglyceride in adipose tissue

  26. Ketone bodies • Ketone bodies are molecules that deliver energy(acetoacetate, acetone, b-hydroxybutyrate) • Ketone levels • Fed state 0.1 mmol/L • Overnight fast 0.3 mmol/L • Nutritional ketosis 1 - 2 mmol/L • > 20 days fasting 10 mmol/L • Diabetic ketoacidosis > 25 mmol/L Meckling et al. Can J Physiol Pharmacol 2002;80:1095-1105.Sharman et al. J Nutr 2002;132:1879-1885.Yancy et al. Eur J Clin Nutr 2007;February 17:1-7.

  27. Glucose • Can come from diet, but also from internal sources • Excess is stored as glycogen in limited amounts, or as triglyceride • Protein (amino acids) used by liver and kidney to produce glucose (gluconeogenesis) and glycogen (glycogenesis) • Under mixed diet conditions, CNS use of glucose can be as high as 120 grams/day • However, daily glucose use is only about 30 grams/day when adapted to fat burning state (when fatty acids and ketones are available for muscle and CNS use) • This 30 grams of glucose is easily supplied by endogenous sources

  28. Caloric Content of Food • A Calorie (kcal) is the amount of heat required to raise the temperature of 1 kg of water by 1 degree Celsius • Foods can be oxidized to release energy, and the estimated caloric values using bomb calorimetry are: • Triglyceride: 9.461 kcal per gm…… 9 kcal • Protein: 4.442 kcal per gm………… 4 kcal • Carbohydrate: 4.183 kcal per gm... 4 kcal • Alcohol: 7 kcal per gram……………7 kcal • Ketones: 4.5 cal per gram………….4 kcal • The actual caloric value will depend upon what oxidation pathway is used, whether the energy has been stored, etc. • Glycogen is stored with water 1:3, so 1 gram of glycogen leads to 4 gram of weight gain

  29. Oh, Those Free Radicals • The effect of burning glucose as fast as possible overwhelms the mitochondrial electron transport chain and generates increased numbers of free radicals. • Free radicals cause tissue damage. • Control glucose/insulin metabolism=control free radical formation=control tissue destruction. Salway JG, Metabolism at a Glance. Third edition. Blackwell Publishing Ltd, 2004. Veech, R. L., B. Chance, et al. (2001). "Ketone bodies, potential therapeutic uses." IUBMB Life 51(4): 241-7.

  30. Free Radical Management Plan • “Finally there are broad therapeutic implications from the ability of ketone body metabolism to oxidize the mitochondrial co-enzyme Q couple. The major source of mitochondrial free radical generation is Q semiquinone. The semiquinone of Q, the half-reduced form, spontaneously reacts with O2 to form free radicals. Oxidation of the Q couple reduces the amount of the semiquinone form and thus would be expected to decrease O2- production.” 1 Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukotrienes Essential Fatty Acids 2004;70:309-19.

  31. Mitochondrial Ketone Metabolism Vacuums Free Radicals • In addition, the metabolism of ketones causes a reduction of the cytosolic free {NAD+}/{NADH} couple which is in near equilibrium with the glutathione couple. Reduced glutathione is the final reductant responsible for the destruction of H2O2. • Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukotrienes Essential Fatty Acids 2004;70:309-19.

  32. Ketones Improve Myocardial Function • “How ketone bodies could improve the hydraulic efficiency of heart by 28% could not be explained by the changes in the glycolytic pathway alone, but rather by the changes that were induced in mitochondrial ATP production by ketone body metabolism.” • Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukotrienes Essential Fatty Acids 2004;70:309-19.

  33. Ketotic Benefits • Chronic adaptation to fat as primary energy source may offer benefits such as improved cerebral function (treatment of seizures), improved mitochondrial ATP production, decreased oxidative stress and protection of glycogen stores during exercise. Kossoff, E. H. (2004). "More fat and fewer seizures: dietary therapies for epilepsy." Lancet Neurol 3(7): 415-20. Phinney, S. D., B. R. Bistrian, et al. (1983). "The human metabolic response to chronic ketosis without caloric restriction: preservation of submaximal exercise capability with reduced carbohydrate oxidation." Metabolism 32(8): 769-76.

  34. Dietary CHO =Insulin Secretagogue Boden, G., K. Sargrad, et al. (2005). "Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes." Ann Intern Med142(6): 403-11.

  35. Carbohydrate Signal Effects on Metabolic Hormones Ludwig, D. S., J. A. Majzoub, et al. (1999). "High glycemic index foods, overeating, and obesity." Pediatrics103(3): E26.

  36. Eat or Die Ludwig, D. S., J. A. Majzoub, et al. (1999). "High glycemic index foods, overeating, and obesity." Pediatrics103(3):E26.

  37. Lack of Postprandial Rise in Serum Glucose and Insulin After a Low Carbohydrate Meal Glucose and insulin concentrations in response to a 300 kcal meal with low- (closed circles), intermediate- (open circles), and high-carbohydrate (triangles) content after 10 d on these respective diets (n=6). Data are means (SE). Areas under the curve for insulin was different for each diet (P 0.001). Glucose area under the curve was lower in response to the low-carbohydrate diet (P 0.001 vs. other diets). Bisschop et al. J Clin Endocrinol Metab;2003:88:3801–3805.

  38. Eating Fat Equals Fasting • The importance of either carbohydrate or energy restriction in initiating the metabolic response to fasting was studied in five normal volunteers. The subjects participated in two study protocols in a randomized crossover fashion. In one study the subjects fasted for 84 h (control study), and in the other a lipid emulsion was infused daily to meet resting energy requirements during the 84-h oral fast (lipid study). Glycerol and palmitic acid rates of appearance in plasma were determined by infusing [2H5]glycerol and [1-13C]palmitic acid, respectively, after 12 and 84 h of oral fasting. Changes in plasma glucose, free fatty acids, ketone bodies, insulin, and epinephrine concentrations during fasting were the same in both the control and lipid studies. Glycerol and palmitic acid rates of appearance increased by 1.63 +/- 0.42 and 1.41 +/- 0.46 mumol.kg-1.min-1, respectively, during fasting in the control study and by 1.35 +/- 0.41 and 1.43 +/- 0.44 mumol.kg-1.min-1, respectively, in the lipid study. These results demonstrate that restriction of dietary carbohydrate, not the general absence of energy intake itself, is responsible for initiating the metabolic response to short-term fasting. Klein, S. and R. R. Wolfe (1992). "Carbohydrate restriction regulates the adaptive response to fasting." Am J Physiol 262(5 Pt 1): E631-6.

  39. The New Paradigm • Food can exert hormonal type influence on metabolic pathways • Fat is not the problem • The changes caused by excess dietary carbohydrate intake result in a shift in metabolic pathways (characterized by elevated insulin levels) which increase inflammation and tissue damage.

  40. Hyperinsulinemia and Reactive Hypoglycemia 50 yo red headed female Weight=191.3 lbs Hgt=63 inches BMI=33.9

  41. DM with elevated Insulin • 54 yo wf . 269 lb. 5’6” tall. BMI=43.4 • Multiple complaints: gluten enteropathy, vegetarian, joint aches • Meds: Synthroid 62.5 mcg/day, Accupril 40 mg po daily, HCTZ 25 mg po daily • Referred by Dr. Phinney, Dr. Westman, and Dr. Kolotkin

  42. Type 2 DM with elevated insulin levels 54 yo Caucasian female Weight=269 lbs Hgt=66 inches BMI=43.4 Stage 5 (DM) with reactive hypoglycemia and hyperinsulinemia.

  43. Type 2 DM with Elevated Insulin levels Treatment Outcomes

  44. Type 2 DM 3 hr GTT with Insulin Levels 56 yo Caucasian female Weight=276 lbs Hgt= 62 inches BMI= 50.1 Stage 5 moving to Stage 6 Insulin levels don’t adequately suppress serum glucose response to dietary carbohydrate. Insulin resistance present. Reactive hypoglycemia present

  45. Type 2 DM with Low Insulin levels Treatment Outcomes

  46. Remission of Type II Diabetes A 45 year old white female with Type II diabetes mellitus, obesity (BMI = 60.5), HTN on pioglitizone, glipizide, and metformin, lisinopril, sertraline, oral contraceptives, itraconazole, rofecoxib. DateWt (lbs)CholTrigLDLHDLHgbA1CTrig/HDLBMI 7/00 375 257 252 118 50 11.0 5 60.5 7/00 Initiation of Carbohydrate Restricted Diet 9/00 350 153 193 69 45 7.7 3 1/01 317 165 153 84 50 6.4 1.8 12/01 243 198 131 116 56 5.4 2 39.2 All hypoglycemic meds dc’d 7/00. Off all meds except setraline by 9/01

  47. Not Just For Weight • Individuals with normal BMI may exhibit the metabolic characteristics of obesity. • This is not treatment of adiposity- it is metabolic management of metabolic risk through dietary treatment/lifestyle change. • This works whether or not excess fat mass is present.

  48. Metabolic Fitness Improvement in Metabolic Fitness Without Weight Change A 48 year old WF requested dietary treatment for abnormal lipids. DateCholTrigHDLT/HDLWeight (lbs) % B F HgbA1c 9/99 256 2208 20 110 158 3/01 214 2407 ---- 158 36 5.8 3/01 Initiation of Carbohydrate Restricted Diet 11/01 162 147 31 4.7 157 29 6.0 7/02 145 127 37 3.4 153.5 31 --- 8/03 149 84 39 3.8 147 27.5 5.1

  49. What about other lipid problems? Decrease in Lp(a) Without Weight Loss A 28 year old white female with strong FH of premature CAD. Acne rosacea and hypertrophic skin over elbows. (BMI=17.5) DateLp(a)CholTrigLDLHDLWt (lbs) 3/97 215 87 171 27 98 3/00 64 214 113 154 37 109 2/01 52 243 95 197 27 112 7/01 Initiation of Carbohydrate Restricted Diet 104 11/01 44 211 66 153 45 101 2/02 36 176 52 113 52 110 (normal Lp(a) < 32)

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