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IR and Hyperinsulinemia

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.

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IR and Hyperinsulinemia

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  1. 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

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

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

  4. 3.0 2.6 2.2 1.8 1.4 1.0 0.6 Overweight and Obesity Increase the Risk of CV Disease Mortality Men Women Relative Risk of Cardiovascular Disease Mortality Normal weight Overweight Obese >18 25 30 >40 BMI, kg/m2 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.

  5. 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 * 3 -0.2 Δ HDL Cholesterol (mg/dL) Δ A1C (%) -0.4 2 -0.6 1 * -0.8 0 Systolic Diastolic 0 0 -10 -2.5 Δ Triglycerides(mg/dL) Δ Blood Pressure(mm Hg) * -20 -5.0 -30 * -7.5 * -40 Randomized, controlled trial; n = 5145; Patients with type 2 diabetes, age >18 y; Mean ± SEIntensified 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

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

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

  8. New β-Cell Centric Construct:ImplicationsInflammation Issues Initiators of inflammation Cytokines (TNFα, IL-6, IL-12, IL-1 α, IL-8) Saturated FFA Glucose 12-HETE IL-1β IAPP 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, RadhikaNarla, and Jerry P. Palmer Biomarkers and immune-modulating therapies for Type 2 diabetes Trends in Immunology November 2012, Vol. 33, No. 11

  9. New β-Cell Centric Construct:ImplicationsInflammation Issues Downstream Effects 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, RadhikaNarla, and Jerry P. Palmer Biomarkers and immune-modulating therapies for Type 2 diabetes Trends in Immunology November 2012, Vol. 33, No. 11

  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

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