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Diabetes Mellitus 101 for Cardiologists (and Alike): 2015

Diabetes Mellitus 101 for Cardiologists (and Alike): 2015. An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye. Part 10. Stan Schwartz MD,FACP Affiliate, Main Line Health System

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Diabetes Mellitus 101 for Cardiologists (and Alike): 2015

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  1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015 An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye Part 10 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. 6105472000

  2. Weight Gain With TZD Use- a Common (‘core’) Effect • TZDs can increase weight (not edema) • 2-8 lbs • But 50% with no increased weight or even weight loss- on eucaloric or hypocaloric diet (EVIDENT trial) • Obviated with combination with exenatide- no weight gain; actually combination causes nearly as much weight LOSS (~4 lb) as with exenatide alone (~5 lbs/ 30 weeks)

  3. 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

  4. 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

  5. Potential Immunomodulatory Therapy to Prevent /Treat/Reverse Diabetes- (and not just Type 1D) www.thelancet.com Published online July 26, 2013 http://dx.doi.org/10.1016/SO140-6736(13)60591-7 A promising approach is the use of pharmacological agents, such as orally active chemical chaperones, which can stabilize protein conformation, improve ER folding capacity,and facilitate the trafficking of mutant proteins.110–113 Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2014:7 25–34 CLAUDIA CAVELTI-WEDER, Effects of Gevokizumab on Glycemia and Inflammatory Markers in Type 2 DiabetesDiabetes Care 35:1654–1662, 2012 C. Levitan,,Proposal for generating new beta cells in a muted immune environment for type 1 diabetes [cyclosporin/PPI] Diabetes Metab Res Rev 2013; 29: 604

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

  7. Metabolic Derangement, and Insulin Resistance Associated with Microbiome Lipopolysaccharides LPS Fasting-induced adipocyte factor Pioglitazone Treats Secondary Adverse Effects of Abnormal Biome

  8. Probiotic, Prebiotic and Antibiotic Treatment of Abnormal Gut Biome

  9. Multiple Causes of Insulin Resistance-Multiple Therapies Central IR Weight Reduction DM MEDS- SGLT-2 inh. GLP-1 RAs Appetite suppressants Bromocriptine-QR Biome IR OBESITYPeripheral IR Inflam- mation IR Anti- Inflam. Incretins Pro- Biotics, Pre-Biotics’ Antibiotics Pioglitazone Metformin

  10. Natural History of Type 2 Diabetes-Insulin Secretion Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity Poor Diet Inactivity IR phenotypeAtherosclerosisobesityhypertensionHDL, TG Endothelial dysfunctionPCO Disability Insulin Resistance MICVAAmp DEATH IGT Type II DM  Beta Cell Secretion d.ec 1st phase Inc 2nd phase BlindnessAmputationCRF EyeNerveKidney Risk of Dev. Complications ETOHBPSmoking Disability Microvascular Complications

  11. Flatbush diabetes

  12. Balancing Beta-Cell Response and Beta-Cell WorkloadInsulin Is Enhanced and Glucagon Is Suppressed Healthy Subjects (n = 14) Type 2 Diabetes (n = 12) Carbohydrate Meal Beta-Cell Response  Beta-Cell Response Beta-Cell Workload  Beta-Cell Workload The Pathogenesis of Type 2 DiabetesBeta-Cell Workload Outpaces Beta-Cell Response  Beta-Cell Workload Beta-Cell Workload Hyperglycemia Euglycemia Euglycemia Mean (SE)

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