1. Diagnosing Diabetes In Adults– Type 1, LADA, or Type 2? Stanley Schwartz MD, FACE, FACP Affiliate Main Line Health Emeritus, Clinical Assoc. Prof. of Medicine Perlman School of Medicine, University of Pennsylvania Struan F.A. Grant, Ph.DVanessa Guy Struan F.A. Grant, Ph.D Vanessa Guy Children’s Hospital of Philadelphia Children’s Hospital of Philadelphia Associate Professor, University of Pennsylvania Senior Clinical Research Coordinator Co-Investigators NIH RO-1, Genes in LADA Part 3

2.  Genetically- Based  Exacerbated by Environmental issues- Diet, Activity, Biome  Includes Brain-Directed, Peripheral Insulin Resistance Loss of Dopa- Surge in SCN New β-Cell Centric Construct: Implications Insulin Resistance Exposes and Exacerbates the Core β-Cell Defect  IR Impairs β-Cell Function by: Lipo and gluco-toxicity Inflammatory Mechanisms Adipocytokine effect on β-cell  IR is NOT a Core Defect (as only ~1/3 of IR patients have Diabetes) (but CLEARLY, IR is a focus of therapy in patients with vulnerable β-cells)

3. IAPP boosts islet macrophage IL-1 in type 2 diabetes : Nature...www.nature.com Simplistic Inflammatory and Non-Inflammatory Effects of Insulin Resistance

4. Multiple Causes IR- Multiple Potential Therapies Peripheral IR Peripheral IR Central IR/ Appetite Central IR/ Appetite Inflam- mation IR Inflam- mation IR Biome IR Biome IR TZD (Pio-), Metformin Bromocriptine-QR Anti- Inflam. Pro- Biotics, Pre-Biotics Weight Reduction

5. New β-Cell Centric Construct: Implications Environmental Risk Factors in T1D/T2D, ? ‘LADA’ T1D  Seasonality at diagnosis  Migrants assume risk of host country  Risk factors from case-control studies Hormones Vitamin D Stress Cow’s Milk Improved Hygiene Gut-microbial Balance – Biome Infant/childhood diet Lack of Physical Activity Viruses – exposures as early as in utero T2D  Obesity-Diet  Lack of Physical Activity  AGE ingestion LADA  Coffee  More Educated

6. Going Forward: New Focus of Care: Primary Prevention: ? For All DM in New Classification  Genetic / antibody screening 1 effort to identify eligible subjects  Potential Immune Modulators 2  Environmental Modulation 3 – Especially as we learn more- vaccination, endocrine disruptors, diet, exercise  Intervention needs to be extremely safe  Defining risk factors will facilitate primary prevention studies Atkinson, Eisenbarth,THE LANCET Vol 358 July 21, 2001 225 APPLY MODEL TO ALL DM 2 3 1

7.  Genes Family History Genotype- HLA, TCF7L2, etc  β-Cell FBS, 2hr ppg, HgA1c, ? C-peptide, ?other  Inflammation Antibodies, Inflammatory Markers, T-Cell function, ?other  Insulin Resistance BMI, Adiponectin, Adipocytokines, ? Other Abilities to get what/which above data will be cost-dependent- each patient, insurers, formulary, government New β-Cell Centric Construct: Implications Diagnosis Markers By Virtue of Family History ‘DM”, Physiogomy, hyperglycemia in Prediabetic and diabetic range

8. Current Terminology Should Reflect the β-Cell Centric Approach; or,…we need to Develop a New Terminology T2DMODY, monogenic T1DSPIDDMAutoimmune T2D Genes - mono+,which - poly+,which Inflammation+/- ─ +++ Resistance+/- ─ Environment+,which ‘LADA’ Older Implications for Therapy Younger

9. Egregious Eleven 1. β-CELL 5. Liver 2. α cell Glucagon defect 6. Muscle 3. ↓ INCRETIN EFFECT-Incretin 7. Fat 4. Inflammation 8. Kidney 9. Brain 10. Stomach/Intestine 11. Colon- Biome β-Cell (Islet Cell) Classification Model- Implications for Therapy : (Not Core Defects)-Targets for Therapies GIVES US ‘PERMISSION’ TO USE ANY LOGICAL THERAPY for ANY DIABETIC ‘TYPE” With Appropriate, on bent-knee, thanks and appreciation, to my ( Renal fellow when I was an intern ) friend and collaborator, Dr. Ralph DeFronzo

10. β-Cell (Islet Cell) Classification Model- Implications for Therapy: 1. β- Cell 2. α- Cell 3. Incretin 4. Inflammation inflammation Egregious Eleven 8. Kidney 9. Brain 10. Stomach/Intestine 11. Colon/Biome 5. Liver 6. Muscle 7. Fat

11. Gene(s) Environment Insulin resistance Cells ‘complain’ not getting enough glucose Lipotoxicity Glucotoxicity β-Cell Centric Construct For Pathogenesis of All Diabetes: Implications for RX - EGREGIOUS ELEVEN Inflammation INSURES it’s GETTING ENOUGH GLUCOSE TO WORK!! PPG-HYPERGLYCEMIA ↓ Amylin ↓ Incretin effect ↑ GLP-1 resistance ↓ β-Cell function ↓ β-Cell mass ↑Glucagon BRAIN ↑Appetite SCN ↓Dopa surge ↓Insulin Gene/ Envir inter- Action!! CORE ISSUES Teach CROSSTALK

12. Gene(s) Environment Insulin resistance Cells ‘complain’ not getting enough glucose Lipotoxicity Glucotoxicity β-Cell Centric Construct For Pathogenesis of All Diabetes: Implications for RX - EGREGIOUS ELEVEN Inflammation Fat Liver Muscle INSURES it’s GETTING ENOUGH GLUCOSE TO WORK!! PPG-HYPERGLYCEMIA ↓ Amylin ↓ Incretin effect ↑ GLP-1 resistance ↓ β-Cell function ↓ β-Cell mass ↑Glucagon BRAIN ↑Appetite SCN ↓Dopa surge ↓Insulin Gene/ Envir inter- Action!! CORE + IR ISSUES

13. Gene(s) Environment Insulin resistance Cells ‘complain’ not getting enough glucose Lipotoxicity Up-regulates SGLT-2 Glucotoxicity Colon biome β-Cell Centric Construct For Pathogenesis of All Diabetes: Implications for RX - EGREGIOUS ELEVEN Inflammation Kidney Fat Liver Muscle Stomach Fast emptying INSURES it’s GETTING ENOUGH GLUCOSE TO WORK!! PPG-HYPERGLYCEMIA ↓ Amylin ↓ Incretin effect ↑ GLP-1 resistance ↓ β-Cell function ↓ β-Cell mass ↑Glucagon BRAIN ↑Appetite SCN ↓Dopa surge ↓Insulin Gene/ Envir inter- Action!! ALL ISSUES