1 Diagnosis of Type 1 Diabetes

2 Classifying Diabetes IAA, autoantibodies to insulin; GADA, glutamic acid decarboxylase; IA-2A, the tyrosine phosphatase insulinoma antigen; ZnT8A, zinc transporter 8; T1aD, type 1a (autoimmune) diabetes; T2D, type 2 diabetes. *Needs to be refined for non-white population groups. Rewers M. Diabetes Metab J. 2012;36:90-97.

3 A Growing Issue: Differentiating T1DM and T2DM Type 1 DiabetesType 2 Diabetes Usual clinical courseInsulin-dependentInitially non-insulin-dependent Usual age of onset<20 years (but ~50% over 20 years) >40 years but increasingly earlier Body weightUsually leanUsually obese OnsetOften acuteSubtle, slow Ketosis proneYesNo Family history  15% with 1 st -degree relative Common EthnicityPredominantly whiteMore common in minorities Frequency of HLA-DR3, DR4, DQB1*0201, *0302 IncreasedNot increased Islet autoantibodies (GADA, ICA, IA-2A, IAA) PresentAbsent IAA, autoantibodies to insulin; GADA, glutamic acid decarboxylase; IA-2A, the tyrosine phosphatase insulinoma antigen; ZnT8A, zinc transporter 8; T1aD, type 1a (autoimmune) diabetes; T2D, type 2 diabetes. *Needs to be refined for nonwhite population groups. Rewers M. Diabetes Metab J. 2012;36:90-97.

4 “Etiological” Classification of Diabetes APS1, autoimmune polyendocrine syndromes 1; IPEX, immunodeficiency, polyendocrinopathy, enteropathy, X-linked syndrome; MODY, maturity-onset diabetes of the young. Rewers M. Diabetes Metab J. 2012;36:90-97.

5 Other Specific Types of Diabetes: Genetic Defects of Beta-Cell Function Chromosome 12, HNF-1α (MODY3) Chromosome 7, glucokinase (MODY2) Chromosome 20, HNF-4α (MODY1) Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) Chromosome 17, HNF-1β (MODY5) Chromosome 2, NeuroD1 (MODY6) Mitochondrial DNA American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S67-S74.

6 Symptoms and Severity of T1DM at Presentation: EURODIAB DKA, diabetic ketoacidosis. Levy-Marchal C, et al. Diabetol. 2001;44 (Suppl 3):B75-B80.

7 Markers of Immune Destruction of the Beta Cell in T1DM Islet cell autoantibodies Autoantibodies to insulin Autoantibodies to GAD (GAD65) Autoantibodies to the tyrosine phosphatases IA-2 and IA-2b When fasting hyperglycemia is first detected, one and usually more than one of these autoantibodies are present in 85%-90% of individuals American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S67-S74.

8 Genetic Markers Strong HLA associations, with linkage to the DQA and DQB genes Influenced by the DRB genes HLA-DR/DQ alleles can be either predisposing or protective American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S67-S74.

9 Beta-Cell Destruction in T1DM Can be quite variable –Rapid in some individuals (mainly infants and children) –Slow in others (mainly adults) Children and adolescents often present with ketoacidosis as the first manifestation of T1DM Other patients have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other environmental triggers American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S67-S74.

10 Beta-Cell Destruction in T1DM Adults may retain residual β-cell function sufficient to prevent ketoacidosis for many years –These patients eventually become insulin-dependent and are at risk for ketoacidosis –They have low or undetectable levels of plasma C-peptide Immune-mediated diabetes commonly occurs in childhood and adolescence but can occur at any age American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S67-S74.

11 T1DM and BMI Although T1DM patients are rarely obese when they present, the presence of obesity is not incompatible with T1DM These patients are also prone to other autoimmune disorders –For example, Addison’s disease, autoimmune hepatitis, celiac sprue, Graves’ disease, Hashimoto’s thyroiditis, vitiligo, myasthenia gravis, pernicious anemia American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S67-S74.

12 T1DM: Clinical Course Typically characterized by the acute onset of the classic symptoms of diabetes –Polyuria, polydipsia, weight loss Course of autoimmune diabetes is characterized by ongoing β-cell destruction Patients with T1DM require exogenous insulin for survival and should be identified as soon as possible to avoid high morbidity due to a delay in insulin treatment

13 Idiopathic Diabetes Diabetes of “unknown etiology” Patients may have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity Strongly inherited, lacks immunological evidence for β-cell autoimmunity, and is not HLA associated –Most who fall into this category are of African or Asian ancestry Often suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S67-S74.