8 Diabetes The Metabolic Syndrome A B C D What are they Four questions Pathogenesis of the MS Molecular events leading to diabetes First some disclaimers These lectures will deal with topics with which many in our society are very sensitive Whatever you thought you knew forget Approach this topic with an open mind Take nothing personally For ALL human traits the difference within a group is always GREATER than the difference between groups 180 of individuals 150 120 90 60 Height cm of 2912 adult men 2990 adult women 30 0 135 150 165 Height in cm 180 195 3423 overlap within 2 S D 2 What is the Metabolic Syndrome Cause Chronic over nutrition Diagnostic criteria 3 of the following Blood pressure 130 85 mm Hg Fasting blood glucose 110 mg dL Elevated fasting plasma triglyceride levels Low plasma HDL Cholesterol levels High body mass index especially central visceral obesity 3 Obesity traditionally defined by body mass index mass kg BMI height2 m2 Common method for correlation health to weight Class 3 obesity 40 Morbidly obese Class 1 obesity 30 Class 2 obesity 35 Overweight 25 Normal or Healthy weight 18 5 Underweight 18 5 Devised by Lambert Adolphe Jacques Quetelet in 1840 4 Problems with BMI Overweight 6 less than Normal Class 1 Normal Better measures Waste size Waste hip ratio Gender Waist Waist Hip 20 All cause mortality 30 10 0 10 Ov er we igh t Women Men 35 in 40 in 0 86 0 95 Pear shaped better than apple Cl as s2 3 Apple men women Pear Hips waist Apple Waist hips 5 Obesity trends in the US adults with BMI 30 Placeholder left intentionally blank 6 Obesity trends in the U S 7 Obesity overweight worldwide increase 80 70 60 50 40 30 20 10 0 80 70 60 50 40 30 20 10 0 Under Under Over 80 70 60 50 40 30 20 10 0 Under Over 530 million Over 2010 1990 Developing countries 415 million 62 7 of 5 9 billion total Developed countries 250 million 21 of 1 2 billion 80 70 60 50 40 30 20 10 0 80 70 60 50 40 30 20 10 0 Under 80 70 60 50 40 30 20 10 0 Under Under Over Over Over 8 Serious medical problem Placeholder left intentionally blank 9 Placeholder left intentionally blank 10 I don t really have a solution Otherwise I d write a book But let s explore some questions 11 The questions 1 2 Why the increase in BMI Why is it difficult to lower BMI Most of the health problems related to type 2 diabetes 3 4 How is obesity related to diabetes What is the metabolic derangement of diabetes 12 1 Why the increase in BMI Not as simple as moral hazard What has changed since 1985 Energy IN calories Voluntary energy OUT activity Why Biological environmental factors Economic factors Political factors Relative contributions unclear 13 2 Why is it difficult to lower BMI Short term easy 2 year period Very hard Food abundance is recent Humans evolved in a different environment Starvation imminent Resistance to starvation selective advantage Mechanisms 14 Energy balance Ein Eout Eout Ein Stores V Feeding Absorption USE iV in Voluntary Involuntary From Ein stores Use 15 To increase stores Ein Eout iV iV V V Restore homeostatic balance V iV V iV 16 To decrease stores Ein Eout iV V iV V NOT WHAT HAPPENS 17 The issue Energy homeostasis is regulated to defend the highest weight achieved iV Energy IN Larger Stores V Energy IN Involuntary Energy OUT Protect energy stores against starvation JO Hill 2006 Endocrine Reviews 27 7 750 761 18 Sumithran P et al Long term persistence of hormonal adaptations to weight loss N Engl J Med 2011 Oct 27 365 17 1597 604 A ve ra ge w e ig ht lbs S D Clinical evidence 38 overweight men women BMI 35 metabolically normal 500 calories 8 weeks Counseled 1 year Weight 220 0 6 210 200 0 2 190 180 170 0 20 40 60 0 2 Week of study Hormones Week 10 Start Behavioral indices Week 62 150 Week 10 Week 62 150 130 110 90 70 50 30 10 10 100 50 0 Leptin Insulin Ghrelin PYY GLP 1 Amylin CCK 19 Mechanistic explanation DIET Decreasing intake Pleasure reward system Leptin normal Insulin Satiety Ghrelin E intake E stores Involuntary Energy out E intake E stores Adipose proliferation CNS pushes intake NYP AgRP Rules Intake stores Energy output Number adipose cells storage capacity POMC CART neurons Leptin Insulin NPY AgRP neurons GLP1 Satiety peptides Ghrelin 20 Why doesn t leptin maintain balance Satiety maintenance of stores Insulin resistance Physical activity POMC CART NPY AgRP Signal strength Leptin resistance Why does obesity exist at all Excess stores Other factors 21 Three steps to obesity 1 2 3 Chronic nutrient intake in excess of output Bias toward storage Leptin resistance other maladaptations Becoming obese reversing obesity are not forward reverse processes 22 Obesity Metabolic syndrome diabetes 3 How is obesity related to diabetes mellitus Diabetes Greek for siphon Mellitus Latin for honey 3500 year old Egyptian papyrus describing diabetes 23 Diabetes is defined by blood glucose concentration 300 glucose mg dL 250 Normal Diabetic IFG Diabetic 200 IGT 150 50 0 Normal Fasting 125 mg dL fasting 200 mg dL after OGT Also 100 70 110 mg dL fasting 140 mg dL after OGT Impaired Fasting Glucose Impaired Glucose Tolerance Currently using HbA1c 7 154 mg dL 2 hr OGTT 24 Two types of diabetes Type 1 later Type 2 Can be the end result of chronic obesity Slow metabolic derangement 90 of diabetes Non insulin dependent diabetes Mature onset diabetes Both inaccurate Increase mirrors obesity Causes many other ailments 4 6 8 10 10 Distinguished by insulin production Type 1 Almost none Type 2 Levels vary from very high to very low 25 Feedback between secretion resistance Healthy Resistance Secretion Insulin resistant Resistance Secretion Resistance Secretion insulin Insulin secretion Type 2 diabetes starts with insulin resistance Diabetic probably Insulin resistance Resistance Secretion Pancreatic failure Resistance Secretion 26 Possible mechanisms Hypothesis 2 Excess DAG I I VLDL LPL P TK P P P P P P P P IRS TK P P P P P P P P P P IRS P DAG Lipid Stores Insulin sensitive tissue Hypothesis 1 Adipose inflammation 27 Mechanism of insulin resistance Hypothesis 1 Obesity induced adipose inflammation The expanded adipose tissue present in obesity triggers an immune response that targets macrophages to the adipose tissue Inflammatory factors either secreted from the macrophages the adipose tissue or both it is unclear bind to a receptor that activates a kinase cascade leading to serine phosphorylation of IRS proteins inactivating therm Hypothesis 2 Obesity induced excess lipids Upon import into cells by lipoprotein lipase