1. IR and Hyperinsulinemia Insulin Resistance: A Survival Mechanism, Gone Awry Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. stschwar@gmail.com Part 4

2. The Adipocytokine Syndrome: A New Model for Insulin Resistance and ß- Cell Dysfunction Muscle Pancreas Liver Brain Visceral fat cells FFA, TNF  Leptin Leptin Sns FFA, TNF  IL-6 Angiotensinogen, PAI-1 Adiponectin CRP, PAI-1 Atherothrombosis FFA, TNF  Adiponectin Artery FFA Resistin, TNF  ObesityIRDiabetesASVD

3. “Sick” Dysfunctional, Adiposopathic Fat Cell ADIPOCYTE ASP & Adipsin FFA TNF  MIFIL-6LeptinPAI-1 Resistin Angioten- sinogen Adiponectin Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78.

4. Overweight Overweight and Obesity Increase the Risk of CV Disease Mortality Data are from 1 million men and women (average age, 57 years) followed for 16 years who never smoked and had no history of disease at enrollment. Calle EE, et al. N Engl J Med. 1999;341:1097-1105. Normal weightObese Relative Risk of Cardiovascular Disease Mortality 0.6 3.0 2.6 2.2 1.8 1.4 1.0 >18 25 30 >40 BMI, kg/m 2 Women Men

5. Weight Loss Reduces Cardiometabolic Risk Factors in Patients With Type 2 Diabetes -0.8 -0.6 -0.4 -0.2 0 Δ A1C (%) * Δ HDL Cholesterol (mg/dL) * Intensified Lifestyle Intervention, 8.6% Weight Loss Diabetes Support and Education, 0.7% Weight Loss Randomized, controlled trial; n = 5145; Patients with type 2 diabetes, age >18 y; Mean ± SE Intensified lifestyle intervention (n = 2496) vs diabetes support and education (n = 2463) therapy; *P<0.001 between groups Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383 -40 -30 -20 -10 0 Δ Triglycerides (mg/dL) * -7.5 -5.0 -2.5 0 Δ Blood Pressure (mm Hg) * * 0 1 2 3 4 SystolicDiastolic

6. Implications for Therapy  Treat Central Mechanisms IR  Treat Peripheral IR- fat, liver, muscle  Treat Inflammation  Treat Biome

7. Gene(s) Environment Amylin B-Cell function/ mass GLP-1 resistance, incretin effect Insulin resistance Appetite SCN ( dopa surge) BRAIN- insulin glucagon cells ‘complain’ not getting enough glucose Ppg--- HYPERGLYCEMIA lipotoxicity Up-regulates SGLT-2 glucotoxicity Gene/ envir inter- action!! Colon biome B-Cell-Centric Construct for Pathogenesis of All Diabetes-Implications for RX - EGREGIOUS ELEVEN Inflammation Kidney Fat Liver Muscle Stomach Fast emptying INSURES its GETTING ENOUGH GLUCOSE TO WORK!! *

8. Yumi Imai1, Anca D. Dobrian2, Margaret A. Morris1,3, and Jerry L. NadlerIslet inflammation: a unifying target for diabetes treatment? Trends in Endocrinology and Metabolism 2013:1- 10 ; Barbara Brooks-Worrell, Radhika Narla, and Jerry P. Palmer Biomarkers and immune-modulating therapies for Type 2 diabetes Trends in Immunology November 2012, Vol. 33, No. 11 New β-Cell Centric Construct: Implications Inflammation Issues Initiators of inflammation IAPP Glucose Saturated FFA IL-1β Cytokines (TNFα, IL-6, IL-12, IL-1 α, IL-8) 12-HETE

9. Yumi Imai1, Anca D. Dobrian2, Margaret A. Morris1,3, and Jerry L. Nadler,Islet inflammation: a unifying target for diabetes treatment? Trends in Endocrinology and Metabolism 2013:1- 10 ; Barbara Brooks-Worrell, Radhika Narla, and Jerry P. Palmer Biomarkers and immune-modulating therapies for Type 2 diabetes Trends in Immunology November 2012, Vol. 33, No. 11 New β-Cell Centric Construct: Implications Inflammation Issues Downstream Effects

10. Implications for Therapy  Treat Central Mechanisms IR  Treat Peripheral IR- fat, liver, muscle  Treat Inflammation  Treat Biome

11. Metabolic Derangement, Insulin Resistance Associated with Microbiome Lipopolysaccharides LPS Fasting-induced adipocyte factor