Diagnosing Diabetes In Adults– Type 1, LADA, or Type 2?

1. Diagnosing Diabetes In Adults– Type 1, LADA, or Type 2? Part 3 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 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

2. New β-Cell Centric Construct:Implications Insulin Resistance Exposes and Exacerbates the Core β-Cell Defect • Genetically- Based • Exacerbated by Environmental issues- Diet, Activity, Biome • Includes Brain-Directed, Peripheral Insulin Resistance Loss of Dopa- Surge in SCN • 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. Simplistic Inflammatory and Non-Inflammatory Effects of Insulin Resistance IAPP boosts islet macrophage IL-1 in type 2 diabetes : Nature ...www.nature.com

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

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 1effort 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 factorswill facilitate primary prevention studies APPLY MODEL TO ALL DM • 3 • 1 Atkinson, Eisenbarth,THE LANCET • Vol 358 • July 21, 2001 225

7. New β-Cell Centric Construct:Implications Diagnosis Markers By Virtue of Family History ‘DM”, Physiogomy, hyperglycemia in Prediabetic and diabetic range • 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

8. Current TerminologyShould Reflect the β-Cell Centric Approach; or,…we need to Develop a New Terminology Older Younger ‘LADA’ Implications for Therapy

9. 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” 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 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 Egregious Eleven inflammation 5. Liver 6. Muscle 7. Fat 8. Kidney 9. Brain 10. Stomach/Intestine 11. Colon/Biome

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

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

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