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Unraveling Hyperinsulinemia: A Pathway to Metabolic Health

Explore the complex interplay between insulin resistance, adipocytokines, and inflammation in the context of diabetes and cardiovascular disease risk. Learn about novel therapeutic strategies targeting central and peripheral insulin resistance.

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Unraveling Hyperinsulinemia: A Pathway to Metabolic Health

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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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