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 1 of 4

2. OR Since Confusion Abounds, Isn’t it Time for … A New Classification/Approach to the Diagnosis of Diabetes

3. Disclosures Vanessa Guy- none Struan Grant- None Stanley Schwartz – Ad boards- Janssen, Merck, Santarus, AZ-BMS, BI-Lilly – Speaker’s Bureaus- Takeda, Janssen, Merck, Novo, Salix, BI-LILLY

4. Purely Clinical Answer Empiric, Pragmatic Approach At this point in time, it doesn’t matter which label is applied Insulin Requiring  DKA: ketosis prone, die without insulin Everyone else – Independent of Age,  “Label” Patient, ‘best guess’  Treat ‘as needed’ to get glycemic control

5. But Need to be More Than Pragmatic!! ’Diagnosis’: Has Many Functions  Plan care − eg: imply ‘cause-specific’ studies and therapies  Predict − who else might get disease  Prevent − disease development and progression  Proliferate Scientific Knowledge − about diabetes

6. Current Diabetes Classification  Note the OVERLAP  Diagnosis is Often IMPRECISE

7. Definitions: T1D, ‘LADA’, T2D Won’t belabor typical definitions- T1D and T2D! ‘LADA’ use – ambiguous Includes:  Later age, therefore, SPIDDM- Slowly progressive T1D ‘slower’ destruction of β-cells than T1D  Antibody positive T2D = ‘T1.5D’ ‘ faster’ destruction of β-cells than in T2D  T-cell abnormal SPIDDM antibody negative

8. ‘Definitions of LADA’ A.The Immunology of Diabetes Society –LADA, and Action LADA B.ADA recognizes LADA as a variation of T1DM 1. 30 years of age 2. Positive for at least one of the four antibodies commonly found in T1D 3. Not treated with insulin within the first 6 months after diagnosis Implies: antibody positive adults, that may be on insulin, but may not be insulin dependent 1. Also called:  Type 1.5  ‘Slowly’ progressive Type 1D  Latent-onset Type 1D Implies: insulin-dependent antibody-positive adults

9. Visualization of the Overlap Adapted from Leslie et al. Diabetes Metab Res Rev. 2008 Oct;24(7):511-9 T1DM In children T1DM In adults LADA T2DM IMMUNITY AGE GENES BMI INSULIN THERAPY Strong +++ ++ + weak HLA++ HLA+ HLA ? child adult low normal high Intermediate Immediate Variable Infrequent Immediate

10. Characteristics Frequently Overlap T1D‘LADA’T2DMODY Typical Age of OnsetAll AgesUsually Age >30 AdultsUsually Age <25 % of all Diabetes10% 75%5% Typical BMIMostly Normal or Thin Mostly Normal or Overweight Mostly Overweight or ObeseMostly normal EthnicityAll Progression to insulin DependenceFast (Days/Week)Latent (Months/Years)Slow (Years) Depends on MODY type Insulin ResistanceMostly no; ~10%,yesSomeYes Depends on MODY type Presence of Autoantibodies Yes (ICA, IA2, GAD65, IAA) Yes (mostly GAD65), Some notNo T cell reponses to islet proteinsYes No Insulin/ C-peptides Level at diagnosis Undectable or extermely lowLowNormal to HighNormal KetoacidosisYesYes, many not allRare Insulin SecretionLow/nullVaries Islet InflammationChronic Inflammation None HLA LinkHighLowNone TCF7L2 LinkNoneGreater than T2DM?5%None Other Genes Involved PTPN22; INS; CTLA4; CCR5; FOXP3; HNF1A; IL2RA; IL6; ITPR3; OAS1; SUMO4 PTPN22; INS PPARG; JAZF1; KCNJ11; NOTCH2; WFS1; IGF2BP2; FTO; SLC30A8; HHEX HNF4A; GCK; HNF1A; IPF1; HNF1B; NEUROD1 Early Treatment Insulin required, diet & exercise helpful Non-Insulin or insulin, diet & exercise helpful Non-Insulin, diet & increased activityGene Specific Late TreatmentInsulin, diet, exercise Insulin, pills, diet, exercise Gene Specific

11. Characteristics Frequently Overlap T1D‘LADA’T2DMODY Typical Age of OnsetAll AgesUsually Age >30 AdultsUsually Age <25 % of all Diabetes10% 75%5% Typical BMIMostly Normal or Thin Mostly Normal or Overweight Mostly Overweight or ObeseMostly normal EthnicityAll Progression to insulin DependenceFast (Days/Week)Latent (Months/Years)Slow (Years) Depends on MODY type Insulin ResistanceMostly no; ~10%,yesSomeYes Depends on MODY type Presence of Autoantibodies Yes (ICA, IA2, GAD65, IAA) Yes (mostly GAD65), Some notNo T cell reponses to islet proteinsYes No Insulin/ C-peptides Level at diagnosis Undectable or extermely lowLowNormal to HighNormal KetoacidosisYesYes, many not allRare Insulin SecretionLow/nullVaries Islet InflammationChronic Inflammation None HLA LinkHighLowNone TCF7L2 LinkNoneGreater than T2DM?5%None Other Genes Involved PTPN22; INS; CTLA4; CCR5; FOXP3; HNF1A; IL2RA; IL6; ITPR3; OAS1; SUMO4 PTPN22; INS PPARG; JAZF1; KCNJ11; NOTCH2; WFS1; IGF2BP2; FTO; SLC30A8; HHEX HNF4A; GCK; HNF1A; IPF1; HNF1B; NEUROD1 Early TreatmentInsulin required, diet & exercise helpful Non-Insulin or insulin, diet & exercise helpful Non-Insulin, diet & increased activityGene Specific Late TreatmentInsulin, diet, exercise Insulin, pills, diet, exercise Gene Specific T1D‘LADA’T2DMODY Insulin Secretion Low/null Varies T1D‘LADA’T2DMODY Islet Inflammation Chronic Inflammation Chronic Inflammation Chronic Inflammation None T1D‘LADA’T2DMODY TCF7L2 Link None Greater than T2DM ? 5%None

12. Summary Definitions are Imprecise, Ambiguous Exceptions to ‘typical’ presentations Overlapping Characteristics ( eg: T1 with T2 parents) They don’t take into account various causes of hyperglycemia that we know exist. CONCLUSION: We need to bring Nomenclature of Classification and Diagnosis in line with therapies: current and future, and vice versa