Fructose and metabolic syndrome: Fructose and metabolic syndrome: • No disclosures Is there a link? Is there a link? Robert H. Lustig, M.D., M.S.L. Robert H. Lustig, M.D., M.S.L. Division of Endocrinology, Department of Pediatrics Division of Endocrinology, Department of Pediatrics Institute for Health Policy Studies Institute for Health Policy Studies University of California, San Francisco University of California, San Francisco Adjunct Faculty Adjunct Faculty UC Hastings College of the Law UC Hastings College of the Law Baptist Health South Florida, Feb. 6, 2014 Past Past Present Present Currently there are 30% more obese than undernourished people worldwide 2001 (World Health Organization) 371 million diabetics in 2012 (5% of the world‘s population) (International Diabetes Federation) Future Future Obesity is the problem Obesity is the problem (?) Experts predict: 165 million Americans will be obese by 2030 (4 part obesity series in Lancet, 8/26/11) 42% of Americans will be obese by 2030 (Finkelstein et al. Am J Prev Med epub 5/7/12) 100 million Americans will have diabetes by 2050 (CDC Division of Diabetes Translation, 2011) Medicare Medicare will will be be broke broke by by 2026 2026 1
Obesity is the problem (?) Obesity is the problem (?) Obesity is the problem (?) Obesity is the problem (?) Basu et al. PLoS One 8:e58783, 2013 “Exclusive Exclusive” view of obesity and view of obesity and Obesity is the problem (?) Obesity is the problem (?) metabolic dysfunction metabolic dysfunction 240 million adults in U.S. 168 million Normal weight (70%) 72 million • Obesity is increasing worldwide by 1% per year Obese (30%) • Diabetes is increasing worldwide by 4% per year “Exclusive Exclusive” view of obesity and view of obesity and “Inclusive Inclusive” view of obesity and view of obesity and metabolic dysfunction metabolic dysfunction metabolic dysfunction metabolic dysfunction 240 million adults in U.S. 240 million adults in U.S. 168 million 168 million Normal weight (70%) Normal weight (70%) 72 million 72 million Obese (30%) Obese (30%) Obese and sick (80% of 30%) Total: 57 million sick 2
Relation between visceral and subcutaneous obesity: Relation between visceral and subcutaneous obesity: “Inclusive Inclusive” view of obesity and view of obesity and (thin on the outside, fat on the inside) (thin on the outside, fat on the inside) metabolic dysfunction 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 Thomas et al. Obesity doi: 10.1038/oby.2011.142, 2011 Obesity is not the problem Obesity is not the problem Obesity is not the problem Obesity is not the problem Metabolic Syndrome: where all the money goes Metabolic Syndrome: where all the money goes (75% of all healthcare dollars) (75% of all healthcare dollars) Metabolic syndrome is difficult to define in adults Metabolic syndrome is difficult to define in adults Obesity is not the problem Obesity is not the problem • WHO 1998 • AACE 2003 Metabolic Syndrome: where all the money goes Metabolic Syndrome: where all the money goes (75% of all healthcare dollars) (75% of all healthcare dollars) • EGIR 1998 • IDF 2005 • NCEP/ATPIII 2001 • AHA 2005 Diabetes Diabetes Hypertension Hypertension Lipid abnormalities Lipid abnormalities Cardiovascular disease Cardiovascular disease Non-alcoholic fatty liver disease Non alcoholic fatty liver disease Polycystic ovarian disease Polycystic ovarian disease Cancer Cancer Dementia Dementia 3
Metabolic syndrome is difficult to define in adults Metabolic syndrome is difficult to define in adults • WHO 1998 • AACE 2003 Because each of these definitions sought to define the Because each of these definitions sought to define the • EGIR 1998 • IDF 2005 metabolic syndrome phenomenologically, with cutoffs metabolic syndrome phenomenologically, with cutoffs • NCEP/ATPIII 2001 • AHA 2005 And even more difficult to define in children And even more difficult to define in children Circulation 119:628, 2009 The standard model of insulin resistance The standard model of insulin resistance Because each of these definitions sought to define the Because each of these definitions sought to define the metabolic syndrome phenomenologically, with cutoffs metabolic syndrome phenomenologically, with cutoffs Cytokines It is easier to define the metabolic syndrome mechanistically It is easier to define the metabolic syndrome mechanistically Where Where’s the insulin resistance? s the insulin resistance? Familial Partial Lipodystrophy: Dunningan or Type 2 Familial Partial Lipodystrophy: Dunningan or Type 2 Comparison between lipodystrophy and obesity Comparison between lipodystrophy and obesity •X-linked or autosomal dominant obesity LD •Absence of limb fat • Fat mass � Easily visible veins � Defined musculature • Leptin •Normal or excess facial fat • Adiponectin •Cushingoid facies (moon facies) • Inflam. Cytokines •Dorsocervical fat pad ± ++ • Metabolic Syndrome •Acanthosis nigricans •Metabolic Syndrome Asterholm et al. Drug Disc Today Dis Models 4:17, 2007 Peters et al. Nature Genet 18:292, 1998 4
Obesity and lipodystrophy share insulin resistance Obesity and lipodystrophy share insulin resistance Comparison between lipodystrophy and obesity Comparison between lipodystrophy and obesity Obesity Lipodystrophy obesity LD • Fat mass • Leptin Insulin • Adiponectin Resistance • Inflam. Cytokines ++ ± • Metabolic Syndrome So the metabolic syndrome can arise from too much, or too little fat So the metabolic syndrome can arise from too much, or too little fat i.e. it i.e. it’s not the fat that counts s not the fat that counts Asterholm et al. Drug Disc Today Dis Models 4:17, 2007 Chehab, Endocrinol 149:925, 2008 Relation between obesity, T2DM, and Metabolic Syndrome Relation between obesity, T2DM, and Metabolic Syndrome REFRAMING THE DEBATE REFRAMING THE DEBATE Steinberger et al. Circulation 119:628, 2009 REFRAMING THE DEBATE REFRAMING THE DEBATE REFRAMING THE DEBATE REFRAMING THE DEBATE Obesity doesn’t CAUSE metabolic syndrome Obesity doesn t CAUSE metabolic syndrome Obesity doesn Obesity doesn’t CAUSE metabolic syndrome t CAUSE metabolic syndrome Obesity is a MARKER for metabolic syndrome Obesity is a MARKER for metabolic syndrome Obesity is a MARKER for metabolic syndrome Obesity is a MARKER for metabolic syndrome OBESITY IS A OBESITY IS A “RED HERRING RED HERRING” RYONE IS AT RISK OF METABOLIC SYNDR RYONE IS AT RISK OF METABOLIC SYNDR 5
Intrahepatic fat explains metabolic perturbation Intrahepatic fat explains metabolic perturbation better than visceral fat better than visceral fat Obesity isn’t enough! Obesity isn t enough! Hepatic Insulin Sensitivity Insulin resistance isn Insulin resistance isn’t enough! t enough! VLDL Index Secretion Rate What kind of obesity? What kind of obesity? Insulin Stimulated What kind of insulin resistance? What kind of insulin resistance? Glucose Disposal Contribution Rate Of Free In which tissue? In which tissue? Fatty Acids Insulin To VLDL Stimulated Palmitate Are all insulin pathways affected? Are all insulin pathways affected? Suppression Rate Fabbrini et al. Proc Natl Acad Sci 106:15430, 2009 Insulin has two effects on the liver Insulin has two effects on the liver Insulin Receptor Knockouts (IRKO) Insulin Receptor Knockouts (IRKO) Kahn Lab, Kahn Lab, Joslin Joslin 1998 1998-present present Obesity, Metabolic Syndrome Liver (LIRKO) Brain (NIRKO) Protected from Obesity Muscle (MIRKO) White Adipose Tissue (FIRKO) Brown Adipose Tissue (BATIRKO) β -cell ( β IRKO) Vascular Smooth Muscle (VSMCIRKO) Glomerular Podocyte (PODIRKO) Biddinger and Kahn , Ann Rev Physiol 68:123, 2006 Brown and Goldstein, Cell Metab 7:95, 2008 Result: Obesity Result: Obesity Hyperglycemia, hyperinsulinemia, DM Hyperglycemia, hyperinsulinemia, DM Low TG, VLDL High TG, VLDL Normal BP Low BP NOT Metabolic Syndrome Metabolic Syndrome 6
U.N. General Assembly U.N. General Assembly In order to explain Metabolic Syndrome: Sept 20, 2011 Sept 20, 2011 • We are looking for a ubiquitous factor that • Non-communicable disease is now a bigger problem – promotes obesity (preferably visceral) than acute infectious diseases worldwide – promotes hypertension • Plan to target, tobacco, alcohol, and diet – induces selective hepatic insulin resistance • blocks Foxo1 to promote gluconeogenesis (hyperglycemia, hyperinsulinemia, and diabetes) • stimulates de novo lipogenesis (dyslipidemia, atherosclerosis) U.N. General Assembly U.N. General Assembly Sept 20, 2011 Sept 20, 2011 • Non-communicable disease is now a bigger problem than acute infectious diseases worldwide • Plan to target, tobacco, alcohol, and diet • But exactly what about diet? Total calories? Fat? Red meat? Dairy? Carbohydrate? The Fiction 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 7
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