IR and Hyperinsulinemia Insulin Resistance A Survival Mechanism

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

The Adipocytokine Syndrome: A New Model for Insulin Resistance and ßCell Dysfunction Atherothrombosis Liver FFA , TN Adi pon Fa ect in Obesity IR Diabetes ASVD Artery CRP, PAI-1 -6 , IL AI-1 a P F TN gen, , A FF nsino ctin ote pone i g i An Ad FFA tin Lep Sns Visceral fat cells Resistin, TNFa FFA, TNFa, Leptin Brain Muscle Pancreas

“Sick” Dysfunctional, Adiposopathic Fat Cell ASP & Adipsin FFA MIF IL-6 ADIPOCYTE Leptin TNFa Resistin PAI-1 Adiponectin Bays H, Mandarino L, De. Fronzo RA. J Clin Endocrinol Metab. 2004; 89: 463 -78. Angiotensinogen

Overweight and Obesity Increase the Risk of CV Disease Mortality Relative Risk of Cardiovascular Disease Mortality 3. 0 Men Women 2. 6 2. 2 1. 8 1. 4 1. 0 Normal weight 0. 6 >18 Overweight 25 BMI, kg/m 2 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. 30 Obese >40

Weight Loss Reduces Cardiometabolic Risk Factors in Patients With Type 2 Diabetes Intensified Lifestyle Intervention, 8. 6% Weight Loss Diabetes Support and Education, 0. 7% Weight Loss 4 -0. 6 * -0. 8 0 Δ Blood Pressure (mm Hg) Δ HDL Cholesterol (mg/d. L) -0. 2 Systolic Diastolic -2. 5 * -5. 0 -7. 5 * * 3 2 1 0 0 Δ Triglycerides (mg/d. L) Δ A 1 C (%) 0 -10 -20 -30 -40 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 *

Implications for Therapy · Treat Central Mechanisms IR · Treat Peripheral IR- fat, liver, muscle · Treat Inflammation · Treat Biome

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

New β-Cell Centric Construct: Implications Inflammation Issues Initiators of inflammation Glucose Saturated FFA IL-1β Cytokines (TNFα, IL-6, IL-12, IL-1 α, IL-8) 12 -HETE IAPP Yumi Imai 1, Anca D. Dobrian 2, Margaret A. Morris 1, 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 Yumi Imai 1, Anca D. Dobrian 2, Margaret A. Morris 1, 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

Implications for Therapy · Treat Central Mechanisms IR · Treat Peripheral IR- fat, liver, muscle · Treat Inflammation · Treat Biome

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