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

1. Diagnosing Diabetes In Adults– Type 1, LADA, or Type 2? Part 2 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 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. 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. Pathogenic, β-Cell-Centric Construct for All Diabetes Implications for Classification, Diagnosis, Prevention, Therapy, Research EPIGENITICS EPIGENITICS Environmental Inflam. Triggers eg: viral,endocrine disruptors,food AGE’s, biome Inflammatory; Abnormal Immune Modulation Resistance inflammatory adipokines Polygenic- other Monogenic (HLA) PHENOTYPE Gene β-Cell secretion/mass Polygenic Monogenic - MODY − Mitochondrial Resistance-FFA Poor diet, inactivity Non Inflammatory endocrine disruptors, food AGE’s ,biome Environmental Triggers

4. Phenotypic Presentation, dependent on : • 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 100% − − − − − − − − − − 0%− % β−Cell Function Critical β−Cell Mass I IIII/ ≈ / I IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII Increasing Age

5. Phenotypic Presentation, dependent on : • 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 100% − − − − − − − − − − 0%− % β−Cell Function Pre-Diabetes = FBS ≥100, PPG ≥140 T2D = FBS ≥126, PPG ≥200 Critical β−Cell Mass I IIII/ ≈ / I IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII Increasing Age

6. New β-Cell Centric Construct:ImplicationsGenetics 101 for Diabetes Phenotype: is DEPENDENT ON Genotype: • 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, sitesof susceptibility of β-Cell to destruction by Endogenous/Exogenous Triggerseg: inflammation, etc. i.e. Genetics is: Which genes, how many different ones, the ‘severity/intensity’ of expression!

7. GenotypingShould Be a Standard Diagnostic Marker to be obtained For DX of DM: (Cost now $100)eg: PharmacogeneticsPick 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. TCF7L2 HLA Genetics of ‘LADA’ R01DK085212 We are looking for LADA-Specific Genes Typical age of onset SPIDDM Antibody + T2DM 40 yrs ~25-40 yrs <10 yrs Type 1 Diabetes ~60 genes ‘LADA’ Late onset type 1 diabetes? Type 2 Diabetes ~60 genes No genes in common

9. New β-Cell Centric Construct:Implicationsβ-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. New β-Cell Centric Construct:ImplicationsInflammation Issues Initiators of inflammation Cytokines (TNFα, IL-6, IL-12, IL-1 α, IL-8) Saturated FFA Glucose 12-HETE IL-1β IAPP 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, RadhikaNarla, and Jerry P. Palmer Biomarkers and immune-modulating therapies for Type 2 diabetes Trends in Immunology November 2012, Vol. 33, No. 11

12. New β-Cell Centric Construct:ImplicationsInflammation Issues Downstream Effects 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, RadhikaNarla, and Jerry P. Palmer Biomarkers and immune-modulating therapies for Type 2 diabetes Trends in Immunology November 2012, Vol. 33, No. 11

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