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

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. 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

4. 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!!

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 OBESITY Peripheral IR OBESITY Peripheral IR Central IR Central IR Inflam- mation IR Inflam- mation IR Biome IR Biome IR Pioglitazone Metformin Bromocriptine-QR Anti- Inflam. Incretins Pro- Biotics, Pre-Biotics’ Antibiotics Weight Reduction DM MEDS- SGLT-2 inh. GLP-1 RAs Appetite suppressants

10. Natural History of Type 2 Diabetes- Insulin Secretion IR phenotype Atherosclerosis obesity hypertension  HDL,  TG Endothelial dysfunction PCO Envir.+ Other Disease Obesity Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT Type II DM Microvascular Complications DEATH d.ec 1st phase Inc 2nd phase

11. Flatbush diabetes

12. Euglycemia Healthy Subjects (n = 14)   Beta-Cell Workload   Beta-Cell Workload   Beta-Cell Response   Beta-Cell Response   Beta-Cell Workload   Beta-Cell Workload Hyperglycemia Type 2 Diabetes (n = 12)   Beta-Cell Workload   Beta-Cell Workload   Beta-Cell Response   Beta-Cell Response   Beta-Cell Workload   Beta-Cell Workload Mean (SE) The Pathogenesis of Type 2 Diabetes Beta-Cell Workload Outpaces Beta-Cell Response Carbohydrate Meal