Child born in year /3 will die before parents in US (diabetes)

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Erik Bridges
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1 Child born in year /3 will die before parents in US (diabetes)

ATP III identified 6 components of the metabolic syndrome that

Atherogenic dyslipidemia (elevated triglycerides, small LDL

Insulin resistance with or without glucose intolerance 5.

Prothrombotic state USA today 7/23/2009 He weighs 555 pounds at

2 ATP III identified 6 components of the metabolic syndrome that relate to CVD 1. Abdominal obesity 2. Atherogenic dyslipidemia (elevated triglycerides, small LDL particles, low HDL cholesterol 3. High blood pressure 4. Insulin resistance with or without glucose intolerance 5. Proinflammatory state 6. Prothrombotic state USA today 7/23/2009 He weighs 555 pounds at age 14 Central obesity- measured as waist circumference > 40 inches in males or 35 inches in females National Health Statistics Report: Number 13 May 5, 2009

2006 34% of adults met the criteria for metabolic syndrome 60 50 40 30 20

3 Prevalence of Metabolic Syndrome Among Adults % Prevalence Of Metabolic Syndrome By Age 3,423 adults, 20 years of age and over, from NHANES % of adults met the criteria for metabolic syndrome Age National Health Statistics Report: Number 13 May 5, 2009

4 Cellular Abnormalities Involved in Metabolic Syndrome ABC cassettes Proinflammatory Procoagulants Insulin resistance Cell Senescence Clock Endothelium Cellular crosstalk CCR2 others Wall Stress (BP) HDL Endothelial lipase Adiponectin Adipocytes Macrophages Chemokines Interleukin (IL)-6 MCP-1 TNF 5-10 micron resolution Common Soil from the capillaries to large vessels ChiltonECM08

5 Basic Science of Metabolic Syndrome High Triglycerides/Low HDL Pre-diabetes Insulin resistance Leptin resistance Wall stress Inflammation

Median (mmol/l) Hazard ratio TOTAL DEATH Remnant lipoprotein cholesterol (mmol/l) Elevated Nonfasting Triglycerides Increase Cardiovascular Disease 18 16 14 12 10 Age-adjusted HRs and

6 Median (mmol/l) Hazard ratio TOTAL DEATH Remnant lipoprotein cholesterol (mmol/l) Elevated Nonfasting Triglycerides Increase Cardiovascular Disease Age-adjusted HRs and multifactorially adjusted HRs (ahrs) for each respective category Female Male < Nonfasting triglycerides (mmol/l) Copenhagen General Population Study (N = 10,284) Triglycerides Remnant lipoprotein cholesterol > 441 Nonfasting triglycerides (mg/dl) F Time since last meal (hours) Nordestgaard BG, et al. JAMA. 2007;298:

7 Microparticles Cause Significant Endothelial Progenitor Loss MP/EPC HC= high cholesterol EMP Microparticles originate from damage endothelial cells Arterioscler Thromb Vasc Biol. 2006;26:2530

with the supply of l-arginine Free Radicals Metabolic

8 Oxy-LDL-induced impairment of endothelial NO production NO production attenuated in the presence of oxy- LDL by interfering with the supply of l-arginine Free Radicals Metabolic syndrome-high triglycerides/low HDL Small dense LDLs Acta Physiol 2009, 196,

9 Basic Science of Metabolic Syndrome High Triglycerides/Low HDL Pre-diabetes Insulin resistance Leptin resistance Wall stress Inflammation

10 Many Faces of Metabolic Syndrome Wall stress/rupture 43 Hispanic women FBS 155 BP 143/80 BMI 36 TRG 321 Thrombus Ruptured Plaque Vasoactive microparticles

11 Endothelial mechanoreceptors sense changes in shear stress Shear stress to cytoskeleton ESS = endothelial shear stress Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:

12 Activation Activation Shear stress rapidly activates endothelial signal transduction and gene expression Inter-relationships between HT and atherosclerosis Signal Transduction Gene Expression Maximum activation Maximum activation Basal activity Basal activity Ras ERK JNK C-fos mrna MCP-1 mrna min min Shear stress activates---small GTPases in endothelial cells (eg, Ras) and mitogen-activated protein kinases (eg, extracellular signal-regulated kinase [ERK] and c-jun N-terminal kinase [JNK]) Proto-oncogene activation c-fos and monocyte chemotactic protein-1 (MCP-1) Chien S et al. Hypertension. 1998;31[part 2]:162-9.

13 Basic Science of Metabolic Syndrome High Triglycerides/Low HDL Pre-diabetes Insulin resistance Leptin resistance Wall stress Inflammation Temperature C ATVB Oct 1999;19:2348

14 CRP Accelerates Atherosclerosis Human CRP transgene (tg) expression CRPtg/0/apoE-/- mice Causes accelerated aortic atherosclerosis in apoe-/- 29 weeks CRPtg 0/0 CRPtg+ /0 Aortic Sinus CRP-Brown ET1 & AT1R NOS CRP activates Classic complement pathway CRP Stained Circulation 2004;109:r43-51

15 MMP-1 ng/ug DNA CRP Stimulates MMP- 1 Plaque Destabilization? MMP 10 8 Human Macrophages Control MMP P<0.01 Northern Blot-mRNA P< Control CRP - 24Hrs 15 Incubated with 100 ug/ml of CRP Cell Culture P< Hours 48 Hours MMP Control ATVB Jan 2004;24:61

Fasting Insulin Level Chronic Inflammation Initiated by Macrophages in White Adipose Tissue Mice Ob/Ob Wild type High fat diet Histology @ 15 weeks, 3 & 5 months Measurement of inflammatory markers

16 Fasting Insulin Level Chronic Inflammation Initiated by Macrophages in White Adipose Tissue Mice Ob/Ob Wild type High fat diet 15 weeks, 3 & 5 months Measurement of inflammatory markers Wild Type White Adipose Tissue Transcriptional regulation of inflammatory genes Low Fat Diet Ob/Ob High Fat Diet MCP Baseline 6 wks 9wks 12 wks 26 wks High Fat Low Fat JCI Dec 2003;112:1821

17 Basic Science of Metabolic Syndrome High Triglycerides/Low HDL Pre-diabetes Insulin resistance Leptin resistance Wall stress Inflammation

A1C Associated with Risk for Diabetes and Stronger Risk for CV Events Glycated Hemoglobin (%) Atherosclerosis Risk in Communities (ARIC) study Glycated hemoglobin in whole-blood sample Adjusted

18 A1C Associated with Risk for Diabetes and Stronger Risk for CV Events Glycated Hemoglobin (%) Atherosclerosis Risk in Communities (ARIC) study Glycated hemoglobin in whole-blood sample Adjusted Hazard Ratio for Stroke 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease Self reported events Median f/u 14 years Adjusted Hazard Ratio for CHDx ARIC NEJM selvin AIC and CV Events pdf N Engl J Med 2010;362:800-11

Type 2 Diabetes: Insulin resistance state blocks

Genetics Toxic environment IRS Glut 4 PI3K Shc

Lipid synthesis Glycogen synthesis Protein

Insulin Resistant Toxic Free Fatty Acids Insulin

19 Type 2 Diabetes: Insulin resistance state blocks normal pathway Insulin Sensitive Insulin Receptor Genetics Toxic environment IRS Glut 4 PI3K Shc Mitogen activated protein (MAP) kinase pathway Lipid synthesis Glycogen synthesis Protein synthesis Mitogenesis / Atherogenesis Normal Insulin Resistant Toxic Free Fatty Acids Insulin Receptor NFkb Nucleus IRS PI3K Genes Inhibit insulin signaling (i.e., serine kinases) Inflammatory Growth Endothelial dysfunction Adapted from DeFronzo RA. Atheroscler Suppl. 2006;7:11-15.

C-Reactive Protein Inhibits Insulin Activation of Endothelial Nitric Oxide Synthase Insulin

by endothelial NO synthase (enos), which it stimulates via Akt kinase which phosphorylates

2-fold increase in enos phosphorylation by insulin, and full inhibition of this process by

20 C-Reactive Protein Inhibits Insulin Activation of Endothelial Nitric Oxide Synthase Insulin promotes the cardiovascular protective functions of the endothelium including NO production by endothelial NO synthase (enos), which it stimulates via Akt kinase which phosphorylates enos CRP inhibits-immunoreceptor Tyrosine-Based Inhibition Motif of FcRIIB and SHIP fold increase in enos phosphorylation by insulin, and full inhibition of this process by CRP SHIP-1 knockdown by small interfering RNA prevents CRP antagonism of insulin Circ Res. 2009;104:

Metabolic Considerations in Insulin Resistance Endothelial cells VLDL trig/ HDL Obesity Genetics Sick fat cells NO Endothelial dysfunction Increased PAI-1 High PAI1-negates antithrombotic benefit of

21 Metabolic Considerations in Insulin Resistance Endothelial cells VLDL trig/ HDL Obesity Genetics Sick fat cells NO Endothelial dysfunction Increased PAI-1 High PAI1-negates antithrombotic benefit of factor XIII by inhibiting fibrinolysis HT Insulin Resistance Glucose intolerance / T2DM Insulin Level Insulin resistant cells Skeletal Muscle Liver cells FOX1 Loss of gene downregulation for gluconeogenesis --- glucose Insulin -activate the transcription factor SREBP-1c, - enhances transcription of genes required for fatty acid and triglyceride biosynthesis Kohler NEJM 2000;342:1792 Brown/Goldstein Cell Metabolism 2008;7:95

INSULIN meets Insulin Resistant Cells By brute force treatment of type 2 diabetes patients with large doses of insulin, we can overwhelm the insulin resistance and control the

22 INSULIN meets Insulin Resistant Cells By brute force treatment of type 2 diabetes patients with large doses of insulin, we can overwhelm the insulin resistance and control the blood sugar Concerns Is it possible that high doses of insulin further enhance hepatic triglyceride synthesis and increase lipotoxicity? Brown/Goldstein Cell Metabolism 2008;7:95

Molecular Benefits of Global Risk Reduction in

primarily) Thrombosis Plaque stability MMP9, TBx,

Lipid Core Foam Cells Cholesterol Efflux ABCA1,

23 Molecular Benefits of Global Risk Reduction in Metabolic Syndrome (caloric restriction primarily) Thrombosis Plaque stability MMP9, TBx, PAF, TF Fibrous cap Cell Recruitment & Activation MCP1, CCR2, VCAM- 1, ICAM-1, chemokines Vasoconstriction Cell migration ET-1, MMPs, TBx Lipid Core Foam Cells Cholesterol Efflux ABCA1, SR-BI, CD36 Inflammatory Response TNF, CRP, COX-2, VCAM, TF, Fibrinogen

Primary Prevention of CV Disease: Less CV events with Rosuvastatin in Women JUPITER study: Women subgroup Justification for the Use of Statins in Prevention: An Intervention Trial Elevated hscrp

24 Primary Prevention of CV Disease: Less CV events with Rosuvastatin in Women JUPITER study: Women subgroup Justification for the Use of Statins in Prevention: An Intervention Trial Elevated hscrp Randomized asymptomatic individuals MS HR (p=ns) 0.65 Women >60 years of age N= 6801) Without prior history of coronary disease, stroke, or diabetes mellitus who had LDL cholesterol <130 mg/dl and hscrp >2.0 mg/l HR 0.19 No MS MS=Metabolic syndrome Composite end point defined as the combined end point of myocardial infarction, stroke, and hospitalization for unstable angina, arterial revascularization, or CV death Jupiter for women Circ pdf Courtesy of Mora et al CIRCULATION 2010 ;121;1069

Adipose Tissue as an Endocrine Organ. Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University

Adipose Tissue as an Endocrine Organ Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University Functions of Adipose Tissue Adipose tissue expresses and secretes a variety of bioactive peptides,