Slide 1First: some disclaimersWhat is the “Metabolic Syndrome”?Obesity traditionally defined by body mass indexProblems with BMISlide 6Obesity trends in the U.S.Obesity/overweight worldwide increaseSlide 9Slide 10I don’t really have a solutionFour questions. One statementWhy the increase in obesity?Why is obesity so difficult to reverse?Energy balance: Ein=EoutTo increase stores: Ein>EoutTo decrease stores: Ein<Eout ???Slide 18Clinical evidenceMechanistic explanationWhy does obesity exist?Three steps to obesityWhy make such a big deal of this?How does obesity lead to Type 2 diabetes?Diabetes is defined by blood glucose concentrationType 1 diabetes: a disease of the glandType 2 diabetes: a disease of the targetType 2 diabetes starts with insulin resistancePossible mechanisms of insulin resistanceMechanism of insulin resistanceMechanism of insulin resistance (cont.)The effect of visceral obesityWhat is the metabolic derangement of diabetes?To remind you of the normal fed stateType 2 diabetic metabolismFinally insulin production failsType 2 diabetesType 2 diabetes treatmentObjective:  blood [glucose]Type 1 diabetes: disease of the glandType 1 diabetic fed state: inappropriate catabolismType 1 diabetic symptomsDiabetes vs obesityObesity may not be “our fault” but it sure is our problemNot taking it personally is not so easyReview questionsNotesNotes (cont.)Notes (cont.)PGY452/552: Endocrine physiology8. Diabetes & the Metabolic SyndromeA. Defining the problem & asking 4 questionsB. Ein ≠ Eout: a matter of balance?C. Molecular events leading to diabetesD. Diabetes: two typesFirst: 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 personally2For ALL human traits: the difference within a group is always GREATER than the difference between groupsFor ALL human traits: the difference within a group is always GREATER than the difference between groups135 150 165 180 1950306090120150180Height in cm# of individualsHeight (cm) of 2912 adult men & 2990 adult women3423 overlap within 2 S.D.3423 overlap within 2 S.D.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 nutrition3Obesity traditionally defined by body mass index4Class 2 obesity (>35)Underweight (<18.5)Normal or “Healthy” weight (>18.5)Overweight (>25)Class 1 obesity (>30)Devised by Lambert Adolphe Jacques Quetelet in ~1840Devised by Lambert Adolphe Jacques Quetelet in ~1840Class 3 obesity (>40)(Morbidly obese )BMI=mass (kg)height2 (m2)Common method for correlation health to weightCommon method for correlation health to weightProblems with BMIOverweight 6% less than “Normal”Class 1 = “Normal”Better measuresWaste sizeWaste/hip ratioPear shaped better than apple 5Gender Women MenWaist ≥35 in. ≥40 inWaist/Hip ≥0.86 ≥0.95"OverweightClass 2 & 3-10%0%10%20%30%All cause mortalityPearHips > waistPearHips > waistAppleWaist>hipsAppleWaist>hipsApplemen>womenApplemen>womenLeft intentionally blankObesity trends in the U.S.78Under Over01020304050607080Under Over01020304050607080Under Over01020304050607080Under Over01020304050607080Under Over01020304050607080Under Over0102030405060708020101990~665 millionDeveloping countries:•415 million (62%) •7% of 5.9 billion totalDeveloped countries:•250 million •21% of 1.2 billionDeveloping countries:•415 million (62%) •7% of 5.9 billion totalDeveloped countries:•250 million •21% of 1.2 billionObesity/overweight worldwide increaseLeft intentionally blankLeft intentionally blankI don’t really have a solutionOtherwise I’d write a bookBut let’s explore some questions11Four questions. One statement1. Why the increase in obesity?2. Why is obesity so difficult to reverse?3. How does obesity lead to Type 2 diabetes?4. What is the metabolic derangement of diabetes?12Most of the health problems associated with obesity are related to type 2 diabetesMost of the health problems associated with obesity are related to type 2 diabetes1. 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 unclear132. 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?14Energy balance: Ein=EoutEinEinFeedingAbsorptionFeedingAbsorptionEoutEoutVoluntaryInvoluntaryFrom Ein & storesUseVoluntaryInvoluntaryFrom Ein & storesUseStoresStoresUSEiVVin15To increase stores: Ein>Eout16iVViVVRestore homeostatic balanceiVViVVTo decrease stores: Ein<Eout ???ViViVVNOT WHAT HAPPENS!NOT WHAT HAPPENS!17The issue: “Energy homeostasis is regulated to defend the highest weight achieved”**JO Hill (2006). Endocrine Reviews, 27(7):750-761iV!V18Protect energy stores against starvationProtect energy stores against starvation Energy IN   Larger Stores Energy IN   Larger Stores Energy IN   Involuntary  Energy OUTClinical evidence38 overweight men & women BMI ~35; metabolically normal500 calories 8 weeksCounseled 1 year0 20 40 60170180190200210220-0.20.20.6WeightWeek of studyA ve ra ge w e ig h t ( lb s ) ± S DLeptin Insulin Ghrelin PYY GLP-1 Amylin CCK0%50%100%150%HormonesWeek 10 Week 62-10%10%30%50%70%90%110%130%150%Behavioral indicesWeek 10 Week 62Sumithran P, et al., Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011 Oct 27;365(17):1597-604.Sumithran P, et al., Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011 Oct 27;365(17):1597-604.19StartInvoluntaryEnergy outInvoluntaryEnergy outAdipose proliferationMechanistic explanationDIET: Decreasing intake Leptin normal Insulin Satiety GhrelinCNS:  pushes intakeNYP/AgRP Rules Intake & stores Energy output Number adipose cells →  storage