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Diagnosing Diabetes In Adults– Type 1, LADA, or Type 2? Part 1 of 4 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.D Children’s Hospital of Philadelphia Associate Professor, University of Pennsylvania Vanessa Guy Children’s Hospital of Philadelphia Senior Clinical Research Coordinator Co-Investigators NIH RO-1, Genes in LADA OR Since Confusion Abounds, Isn’t it Time for… A New Classification/Approach to the Diagnosis of Diabetes 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 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 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 Current Diabetes Classification Note the OVERLAP Diagnosis is Often IMPRECISE 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 ‘Definitions of LADA’ A. The Immunology of Diabetes Society –LADA, and Action LADA 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 B. ADA recognizes LADA as a variation of T1DM 1. Also called: Type 1.5 ‘Slowly’ progressive Type 1D Latent-onset Type 1D Implies: insulin-dependent antibody-positive adults Visualization of the Overlap IMMUNITY AGE GENES BMI INSULIN THERAPY T1DM In children Strong +++ child HLA++ low Intermediate Immediate T1DM In adults ++ adult HLA+ normal Immediate LADA + adult HLA normal Variable T2DM weak adult ? high Infrequent Adapted from Leslie et al. Diabetes Metab Res Rev. 2008 Oct;24(7):511-9 Characteristics Frequently Overlap ‘LADA’ T1D Typical Age of Onset All Ages % of all Diabetes T2D Usually Age >30 10% MODY Adults 10% Usually Age <25 75% Mostly Overweight or Obese All 5% Typical BMI Ethnicity Mostly Normal or Mostly Normal or Thin Overweight All All Progression to insulin Dependence Fast (Days/Week) Latent (Months/Years) Slow (Years) Depends on MODY type Insulin Resistance Mostly no; ~10% ,yes Some Yes Depends on MODY type Presence of Autoantibodies Yes (ICA, IA2, GAD65, Yes (mostly GAD65), IAA) Some not No No T cell reponses to islet proteins Yes Yes No No Insulin/ C-peptides Level at diagnosis Ketoacidosis Insulin Secretion Islet Inflammation HLA Link TCF7L2 Link Undectable or extermely low Yes Low/null Chronic Inflammation High None Low Yes, many not all Varies Chronic Inflammation Low Greater than T2DM Normal to High Rare Varies Chronic Inflammation None ?5% Normal Rare Varies None None None PTPN22; INS; CTLA4; PPARG; JAZF1; KCNJ11; NOTCH2; WFS1; IGF2BP2; FTO; SLC30A8; HHEX Non-Insulin, Insulin required, Non-Insulin or insulin, diet & increased diet & exercise helpful diet & exercise helpful activity Other Genes Involved CCR5; FOXP3; PTPN22; INS HNF1A; IL2RA; IL6; ITPR3; OAS1; SUMO4 Early Treatment Late Treatment Insulin, diet, exercise Insulin, pills, diet, exercise Insulin, pills, diet, exercise Mostly normal All HNF4A; GCK; HNF1A; IPF1; HNF1B; NEUROD1 Gene Specific Gene Specific Characteristics Frequently Overlap ‘LADA’ T1D Typical Age of Onset All Ages % of all Diabetes Typical BMI Ethnicity T2D Usually Age >30 Adults Usually Age <25 10% 75% T1D ‘LADA’ T2D Mostly Normal or Mostly Overweight or 10% Mostly Normal or Thin Overweight All All Insulin Secretion Progression to MODY Obese All Low/null Varies Mostly normal All Varies insulin Dependence Fast (Days/Week) Latent (Months/Years) Slow (Years) Depends on MODY type Insulin Resistance Mostly no; ~10% ,yes Some Depends on MODY type Presence of Autoantibodies Yes (ICA, IA2, GAD65, Yes (mostly GAD65), IAA) Some not T cell reponses to islet proteins Yes T1D Yes Chronic Insulin/ C-peptides Undectable or Islet Inflammation Level at diagnosis extermely Inflammation low Low Ketoacidosis Insulin Secretion Islet Inflammation HLA Link TCF7L2 Link Yes Low/null Chronic Inflammation High None Early Treatment Late Treatment No ‘LADA’ No T2D No T1D Rare Varies Chronic Inflammation None ?5% ‘LADA’ PPARG; JAZF1; Rare Varies None None None Insulin, diet, exercise Greater than T2DM Insulin, pills, diet, exercise Insulin, pills, diet, exercise Varies MODY None T2D MODY ? 5% None HNF4A; GCK; HNF1A; KCNJ11; NOTCH2; IPF1; HNF1B; WFS1; IGF2BP2; FTO; NEUROD1 SLC30A8; HHEX Non-Insulin, Insulin required, Non-Insulin or insulin, diet & increased diet & exercise helpful diet & exercise helpful activity Gene Specific None MODY No Chronic Chronic Normal to High Normal Inflammation Inflammation Yes, many not all Varies Chronic Inflammation Low Greater than T2DM PTPN22; INS; CTLA4; Other Genes Involved CCR5; FOXP3; PTPN22; INS HNF1A; IL2RA; IL6; ITPR3; OAS1; SUMO4 TCF7L2 Link Yes 5% Gene Specific • • • • 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