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 2 2

2. PROPOSAL: ‘β-Cell Centric’ Classification of Diabetes  Intuitively obvious approach  Didn’t we know that all along! It can help define diagnosis and therapy better, especially as our knowledge-base increases

3. EPIGENITICSEPIGENITICS Pathogenic, β-Cell-Centric Construct for All Diabetes Implications for Classification, Diagnosis, Prevention, Therapy, Research Inflammatory; Abnormal Immune Modulation β-Cell secretion/mass Polygenic - other Monogenic (HLA) Polygenic Monogenic - MODY − Mitochondrial Resistance inflammatory adipokines Resistance-FFA Poor diet, inactivity Non Inflammatory Environmental Inflam. Triggers eg: viral,endocrine disruptors, food AGE’s, biome Gene EPIGENITICSEPIGENITICS endocrine disruptors, food AGE’s,biome Environmental Triggers PHENOTYPE

4. 100% − − 0% − I I I I I / ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Increasing Age % β−Cell Function Critical β−Cell Mass The Age at presentation = tipping point when the combined Gene Effect Environmental trigger is exposed as phenotypic hyperglycemia. The ‘Severity’ at presentation: Reflects the β-cell loss-function/mass- at presentation The Slope = Progressive ‘Natural History’ over time ie: = Rate of β-cell loss Phenotypic Presentation, dependent on :

5. The Age at presentation = tipping point when the combined Gene Effect Environmental trigger is exposed as phenotypic hyperglycemia. The ‘Severity’ at presentation: Reflects the β-cell loss-function/mass- at presentation The Slope = Progressive ‘Natural History’ over time ie: = Rate of β-cell loss Phenotypic Presentation, dependent on : 100% − − 0% − Pre-Diabetes = FBS ≥100, PPG ≥140 T2D = FBS ≥126, PPG ≥200 I I I I I / ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Increasing Age % β−Cell Function Critical β−Cell Mass

6. Phenotype: is DEPENDENT ON Genotype: 1. Number of Genes, which genes-their nature, even Epigenetics recent article on epigenetics in T1DM-DCCT/EDIC ie: Genes influencing: insulin secretory dynamics, insulin resistance, sites of susceptibility of β-Cell to destruction by Endogenous/Exogenous Triggers eg: inflammation, etc. i.e. Genetics is: Which genes, how many different ones, the ‘severity/intensity’ of expression! New β-Cell Centric Construct: Implications Genetics 101 for Diabetes

7. Genotyping Should Be a Standard Diagnostic Marker to be obtained For DX of DM : (Cost now $100) eg: Pharmacogenetics Pick right drug for right patient Find Gene action/ Function- Leads to understanding mechanisms  eg: TCF7L2-Potential Therapy  PARP-1 Inhibitor??, incretin  Or Gene/Mechanism/ Therapy  low BMR- results in morbid obesity  Asian/ Eastern Europeans- store more Visceral Fat at Lower BMI

8. Genetics of ‘LADA’ R01DK085212 HLA TCF7L2 Typical age of onset SPIDDM Antibody + T2DM No genes in common ~25-40 yrs 40 yrs Type 1 Diabetes ~60 genes ‘LADA’ Late onset type 1 diabetes? Type 2 Diabetes ~60 genes <10 yrs We are looking for LADA-Specific Genes

9. New β-Cell Centric Construct: Implications β-cell Issues  Usual use of Glycemic Criteria  Usual/Occasional Use of C-Peptide  Try to Determine Mono-Genetic Causes  Development of therapies aimed at Improving β-cell function: Reduce Glucotoxicity Reduce Lipotoxicity Reduce IR (treat inflammation, gut biome change)

10. Be aware of all the Secretory Dynamic Pathways involved, AND GENES INVOLVED

11. 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, 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 Initiators of inflammation IAPP Glucose Saturated FFA IL-1β Cytokines (TNFα, IL-6, IL-12, IL-1 α, IL-8) 12-HETE

12. 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, 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

13. Potential Immunomodulatory Therapy to Prevent / Treat / Reverse Diabetes- (and not just Type 1DM) 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