PGY452 552 Endocrine physiology 8 Diabetes the Metabolic Syndrome A Defining the problem asking 4 questions B Ein Eout a matter of balance C Molecular events leading to diabetes D Diabetes two types 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 0 135 150 165 180 195 3423 overlap within 2 S D Height in cm 2 What is the Metabolic Syndrome 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 Cause Chronic over nutrition 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 20 All cause mortality 30 10 0 10 Waste size Waste hip ratio Gender Women Men Waist 35 in 40 in Waist Hip 0 86 0 95 Pear shaped better than Ov er we igh t Cl as s2 3 Apple men women Pear Hips waist Apple Waist hips 5 Left intentionally blank 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 665 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 Left intentionally blank Left intentionally blank I don t really have a solution Otherwise I d write a book But let s explore some questions 11 Four questions One statement 1 2 3 4 Why the increase in obesity Why is obesity so difficult to reverse How does obesity lead to Type 2 diabetes What is the metabolic derangement of diabetes Most of the health problems associated with obesity are related to type 2 diabetes 12 1 Why the increase in obesity 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 obesity so difficult to reverse 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 Clinical evidence 38 overweight men women BMI 35 metabolically normal 500 calories 8 weeks Counseled 1 year A ve ra ge w e ig ht lbs S D Sumithran P et al Long term persistence of hormonal adaptations to weight loss N Engl J Med 2011 Oct 27 365 17 1597 604 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 Anorexigenic intake stores Involuntary Energy out Orexigenic intake stores CNS pushes intake NYP AgRP Rules Intake stores Energy output Number adipose cells storage capacity Adipose proliferation POMC neurons Leptin Insulin AgRP NPY neurons GLP1 Ghrelin Satiety peptides 20 Why does obesity exist Insulin Insulin Satiety peptides resistance Physical activity POMC Not homeostatic No advantage for caveman Defends highest weight achieved NOT weight yet to be acquired NPY AgRP Signal strength Leptin resistance 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 Why make such a big deal of this Chronic over nutrition obesity metabolic syndrome type 2 diabetes Heart disease and stroke 65 of deaths in people with diabetes The risk for stroke is 2 to 4 times higher High blood pressure Kidney disease Diabetes is the leading cause of kidney failure 44 400 people began treatment for end stage kidney disease Blindness Nervous system disease Amputations Dental disease Complications of pregnancy Lot of other conditions 23 3 How does obesity lead to Type 2 diabetes Diabetes Greek for siphon Mellitus Latin for honey Two major types 3500 year old Egyptian papyrus describing diabetes 24 Diabetes is defined by blood glucose concentration Normal 300 glucose mg dL 250 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 25 Type 1 diabetes a disease of the gland Definition Fasting blood glucose 125 mg dL Also called Insulin dependent diabetes IDDM Juvenile diabetes Neither appropriate Fast onset Auto immune disease that destroys pancreatic cells Quick death if untreated Treatment Insulin careful monitoring 10 of all cases We ll cover it in a bit 26 Type 2 diabetes a disease of the target Also called Can be the end result of chronic obesity Slow metabolic derangement 90 of diabetes Non insulin dependent diabetes mellitus Mature onset diabetes Both terms are inaccurate Increase mirrors obesity Causes many other ailments Distinguished from type 1 by insulin production 4 6 8 10 10 Type 1 Almost none Type 2 Levels vary from very high to very low 27 Feedback between secretion resistance Healthy Resistance Secretion Insulin resistant Resistance Secretion