Dr Johnson has a laybook (Fat Switch, mercola.com) and patents and patent applications related to this work. He is on the Scientific Advisory Board for Amway, Rivermend Health and XORT Therapeutics. He is a member of Colorado Research Partners LLC. He has grants from the NIH, VA, DOD, Danone Research, and Amway. Johnson et al Am J Clin Nutr 2007 The Metabolic Syndrome Abdominal obesity Elevated Fasting glucose (insulin resistance) Elevated triglycerides Low HDL cholesterol Elevated blood pressure Diabetes High Blood Pressure Fatty Liver Cirrhosis Chronic Kidney Disease Stroke and Heart Disease
Diabetes increased in New York City from 3 cases/100,000 in 1880 to 20 cases per 100,000 in 1920 Haven Emerson (1874-1957) New York City Health Commissioner Risk Factors Wealthy Over age 45 Sedentary Caucasian Merchants in the Food Industry Sugar consumption Arch Int Med 1924; 34:585-630 Too Many Calories Cars, TV, Internet, Elevators Too little energy used
We eat large portions since we cannot control our appetite Leptin Resistance Dopamine Pleasure Response We produce less energy since we have a defect burning Fat Reduced ATP Sugar (sucrose): fructose/glucose High fructose corn syrup (HFCS)- fructose/glucose Fructose is in honey and fruit Soft Drinks are the Major Source: One third of sugar intake is from soft drinks. * Control Mouse Fructose-fed Mouse Ishimoto T, PNAS 2012; 109:4320-5
Am J Physiol Regul Integr Comp Physiol 2008;295:R1370-5; Eur J Clin Nutr 2012;66:201-8 Baseline Change Metabolic Syndrome (NCEP-ATPIII)(%) 19% 44% P Value Triglycerides 136 ± 15 55±20 <0.001 HDL Cholesterol 46.5 ± 1.5-2.5 ± 0.7 <0.001 Insulin resistance (HOMA) 1.7 ± 0.2 0.57 ± 0.16 <0.005 Weight (kg) 84.3 ± 2.3 0.6 ± 0.2 <0.003 BMI (kg/m2) 29.0 ± 0.6 0.2 ± 0.1 <0.003 24 hr Systolic BP (mm Hg) 126±2 7 ± 2 <0.001 24 hr Diastolic BP (mm Hg) 75 ± 2 5 ± 3 <0.001 Perez-Pozo et al Int J Obes 2010 Rats were fed the same number of calories for 5 months Sirirat Reungjui et al JASN 2007; 18:2624
Oil Red O Stain for Fat Starch Fed Rat Sugar Fed Rat Sprague Dawley rats fed sucrose or starch diet for 4 months at 90% of normal intake Roncal -Jimenez et al Metabolism 2011; 60: 1259-1270 Fructose ATP Fructokinase Fructose-1-P AMP AMPD Uric acid Fructose Depletes ATP Glycogen Glucose Triglycerides Block Fructokinase Fructose ATP Fructose-1-P Block AMPD the ATP Degradation Pathway AMP Uric acid Glycogen Glucose Triglycerides
Ishimoto T et al PNAS 2012; 109: 4320-4325 Fructose No ATP Fructokinase A Depletion ATP AMP AMPD Uric acid Fructose-1-P Glycogen Glucose Triglycerides Fructokinase A and fructose Fructokinase C and fructose Ishimoto T et al PNAS 2012; 109: 4320-4325
Fructose ATP Block Fructokinase Fructokinase A Fructose-1-P AMP AMPD Uric acid Fructokinase C is still Active Glycogen Glucose Triglycerides Normal Liver Fructose-fed Fructose +Fructokinase-A Knockout Ishimoto T et al PNAS 2012; 109: 4320-4325 Ishimoto T et al PNAS 2012; 109: 4320-4325
Fructose ATP Fructokinase Fructose-1-P AMP Blocking AMP Deaminase AMPD Uric acid Glycogen Glucose Triglycerides Triglycerides Human HepG2 cells silenced for AMPD are protected from fructose (5 mm) induced Triglyceride Accumulation, 72 h Lanaspa et al PLOS One 2012 Fructose Activates AMPD Lanaspa et al, PLOS One 2012; 7(11):e48801
Control Fructose Fructose + Allopurinol Lanaspa MA PLOS One 2012 Control Uric Acid Lanaspa MA and Kang DH, J Biol Chem 2012; 287:40732-44 Lanaspa MA et alj Biol Chem 2012
NO X4 Mitochondria Inhibit Aconitase in Kreb Cycle Inhibit ECOH In β-fatty acid cycle Citrate Enters Cytoplasm Increased Fat Synthesis Block Fat Oxidation Lanaspa MA et al, J Biol Chem 2012 Obesity 60-80% Hypertension 50-60% Metabolic Syndrome 70-80% Chronic Kidney Disease 50-100% Cardiovascular Disease in 90% Uric Acid Control Inflammation (MCP-1) Angiotensin II Oxidants Nitric Oxide Hypertension 2003; 41: 1287-93 Kidney Int 2005; 267: 1739-42 Am J Physiol 2002;282: F991-7, J Hypertens 2010; 28: 1234-42
18 of 19 studies found Uric Acid to Independently Predict the Development of Hypertension Man and Apes Mutation Uric Acid Uricase Most mammals Allantoin Uricase inhibitor Oxonic acid (OA) Normal Rat Uric Acid (0.5-1.4 mg/dl) Hyperuricemic Rat Uric Acid (2.0-3.0 mg/dl)
Systolic BP (mm Hg) ** * LSD = 0.125% NaCl, ** p<0.05 ** ** ** Time (weeks)) Mazzali M et al Hypertension 2001; 38:1101-1106 Serum Uric Acid (mg/dl) 9 8 7 6 5 4 3 2 1 Primary Hypertension N=64 Mean = 6.7mg/dl Secondary Hypertension N=39 Mean = 4.3 mg/dl White Coat Hypertension N=22 Mean = 3.5 mg/dl Controls N=41 Mean = 3.6mg/dl Feig and Johnson, Hypertension 42:247-252, 2003 Systolic BP (mm Hg) R= 0.80 Uric Acid (mg/dl) Feig and Johnson Hypertension 2003; 42:247-252
Double-blind placebo controlled Cross-over 30 Hypertensive Adolescents Baseline Uric Acid 6.9 mg/dl Allopurinol or placebo In Subjects whose Uric acid was reduced to < 5 mg/dl, 86% (19/22) became normotensive versus 3% (1/30) controls Feig et al, JAMA 2008 Aug 27;300(8):924-32 Study Population F/U Indep? RR (C.I.) Author, Year Israel 10,000 men 5 YRS Yes 1.35 Medalie 1975 ` and Herman 1976 USA 5,209 adults 26 YRS Men 2.3 (men), (women) Brand, 1985 2.1 Nauru 266 adults 6 YRS Women Not given Balkau, 1985 Sweden 766 men 13.5 YRS Yes 5.8 (2.2-16.0) Ohlson, 1988 Britain 7,735 men 12.8 YRS Yes 1.5 (0.9-2.5) Perry, 1995 Kinmen 654 high risk 3 YRS Yes 1.7 (1.2-2.6) Chou, 1998 Mauritius 2,605 adults 5 YRS Yes 1.37 (1.20-1.57) Boyko, 2000 Japan 6,356 men 9 YRS No 1.24 (0.9-1.7) Taniguchi, 2001 Germany 6,166 adults 3-14YRS Women 1.6 (1.34-1.91) Meisinger, 2002 USA 9,020 adults 11 YRS Yes 1.3 (1.2-1.4) Carnethon, 2003 Japan 2,310 men 6 YRS Yes 1.78 (1.11-2.85) Nakanishi, 2003 China 641 adults 7 YRS Women 1.44 (1.13-2.25) Lin, 2004 USA 60 adults with MI 6 MOS Yes 5.47 (1.6-17.7) Nakagawa, 2005 Finland 522 adults 4.1 YRS Yes 1.87 (1.07-3.26) Niskanen, 2006 Netherlands 4,536 adults 10 YRS Yes 1.68 (1.22-1.30) Dehgan, 2008 Mauritius 4,259 adults 5 YRS Men 1.37 (1.11-1.68) Nan, 2008 China 2,609 adults 9 YRS Yes 1.4 (1.02-1.92) Chien, 2008 USA 9,689 adults 5.7 YRS Yes 1.6 (1.3-1.9) Sui, 2008 USA 566 adults 13 YRS Yes 1.75 (1.1-2.9) Kramer, 2009 USA 9,175 adults 26-28 YRS Yes 1.71 (1.24-2.36) Bhole, 2010 Korea 4,779 men 3 YRS Yes 1.41 (1.08-1.84) Ryu, 2011 Japan 12,643 adults 5 YRS Women Yamada, 2011 China 924 adults 3.5 YRS Yes (women) Wang, 2011 2.45 (men),and 1.39 Italy 758 hypertensive 3 YRS Yes 2.78 (1.35-5.70) Viazzi, 2011 adults 23 of 24 studies found Uric Acid to Independently Predict the Development of Diabetes or Insulin Resistance Johnson et al Diabetes 2013 Serum Uric acid Blood Pressure mg/dl 2 1.5 1 0.5 0 P<0.05 P<0.01 Control Fr Fr + AP Systolic BP (mmhg) 160 150 140 130 120 110 100 Control Fr # Fr + AP # 0 4 8 Weeks * Allopurinol Nakagawa et al, Am J Physiol 2006; 290:F625-631
Triglyceride Fasting insulin # 2500 P<0.01 P<0.05 300 2000 mg/dl 200 pg/ml 1500 1000 100 500 0 Control Fructose Fruc + AP 0 Control Fructose Fruc + AP Nakagawa et al, Am J Physiol 2006; 290:F625-631 Man and Apes Mutation Uric Acid Uricase Most mammals Allantoin
Early Miocene Apes were Fruit Eating and Lived in Lush Tropical Rain Forests in Africa (22-17 MYA) Crossing the landbridge into Eurasia across the Tethys Sea Begun DR Science 2000; 287; 2375 Andrews and Kelly Folia Primatol 2007: 78:328-343
Repetitive Linear Enamel Hypoplasia shows recurrent periods of Food Shortage (stress) from Seasonal Change Johnson and Andrews, Scientific American 2014 European Great Apes 8 to 13 MYA Asian Great Apes African Apes and Humans Begun DR Science 2000; 287; 2375 Fat stores (fatty liver, triglycerides) Fruit Summ er Autum n Effect of Longer Winters Spring Fat stores depleted Starvation and Death
Uricase Mutation More Fat stores (fatty liver, triglycerides) Autumn Less Fruit Available Summer Effect of Longer Winters More Survive Spring Johnson and Andrews Evol Anthropol 2010 Rats were given soft drinks consisting of 7% Fructose and 3% glucose Tapia E and Sanchez-Lozada LG, Am J Physiol 2013; 304:F727-36 Intracellular Uric acid Intracellular Triglycerides Triglycerides (mg/dl) Con Hum Pig Kenya Fructose Con Hum Pig Kenya Fructose J Kratzer, M Lanaspa et al PNAS 2014
Diabetes develops in the individual who is in the habit of taking sweet liquids Sushruta 1400 A.D 950 A.D 500 A.D 500 A.D 1500 A.D 700 A.D 600 A.D 500 B.C
King Edward I of England ordered 1877 pounds of sugar for the royal household in 1287 and 6,258 pounds of sugar in 1288 One pound of sugar equaled 28 pounds of cheese or 34 dozen eggs Sugar intake per year 1700 4 lbs 1800 18 lbs 1900 90 lbs 2000 155 lbs Johnson et al Am J Clin Nutr 86:899-906, 2007
WWI and II James Neel, Anthropologist, with Yanomamö Indian, 1978 Am J Hum Genetics 1962; 14:353-362 Fructose is in added sugars, including sucrose and high fructose corn syrup Fructose induces metabolic syndrome in animals. These effects can even be observed with caloric restriction Fructose causes metabolic syndrome due to its ability to cause ATP depletion, uric acid generation, and mitochondrial dysfunction A mutation in uricase led to higher uric acid levels that increase our sensitivity to fructose and sugar The marked increase in sugar and HFCS was the perfect storm for making us obese and diabetic IN CONCLUSION: EXCESSIVE INTAKE OF FRUCTOSE HAS A MAJOR ROLE IN THE OBESITY EPIDEMIC
Peter Andrews PhD Miguel Lanaspa PhD Takuji Ishimoto MD, PhD Gaby Sanchez- Lozada, PhD And to all of my collaborators, past and present Glucose Polylol Pathway Fructose Rice can be converted to Sugar in the Body Lanaspa, Ishimoto et al, Nature Comm 2013 Fructose Level in the Liver Normal diet Glucose-rich diet Lanaspa and Ishimoto, Nature Com, 2013
Insulin Levels Normal Mouse Fed Glucose (Carbs) Mouse Fed Glucose that cannot metabolize Fructose Normal Mouse Mouse cannot metabolize fructose Mice That cannot Metabolize Fructose are Protected Lanaspa, Nature Com 2013 HFCS introduced WWI and II Based on Disappearance Data Sugar intake Obesity rate Johnson et al Am J Clin Nutr 86:899-906, 2007 Relatively Lower Content of Fructose Have other good components (vitamin C, antioxidants, flavonols, fiber, potassium, etc)
Overweight Adults were given 25% of calories as either glucose or fructose for 10 weeks Total Subcut Visceral Total Subcut Visceral Glucose Fructose Stanhope et al, J Clin Invest 2009; 119: 1322-1334