Academy of Diagnostics & Laboratory Medicine - Scientific Short
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Type 1 diabetes (T1D) is often diagnosed by clinical symptoms and lab tests, many times after a life-threatening ketoacidosis event, especially in children and adolescents. However, autoimmune destruction of the pancreatic beta cells begins many years before overt clinical symptoms. Multiple, persistent islet autoantibody positivity strongly predicts progression to a clinical diagnosis (stage 3 T1D) although rates of progression vary tremendously (1). With the 2022 FDA approval of the drug Teplizumab, the need for T1D staging is no longer restricted to clinical trials. Teplizumab is a monoclonal antibody for adult or pediatric patients ≥ 8 years of age with stage 2 T1D that has been shown to delay progression to clinical symptoms (2).
The 2024 ADA Standards of Care in Diabetes still does not recommend universal screening of presymptomatic T1D, but states that “screening for presymptomatic type 1 diabetes may be done…” (3). These guidelines do, however, recommend islet autoantibody tests in adults who present with younger age, ketoacidosis, unintended weight loss or experience a short time to insulin requirement; a flow chart is provided for guidance in laboratory testing for newly diagnosed adults suspected of T1D (3). Recommendations for who and when to test C-peptide levels are also included along with cut-off guidance. A value of <200 pmol/L C-peptide is considered confirmation of T1D under certain scenarios, while values of 200-600 pmol/L are considered indeterminate.
The stages of T1D are given in various publications (3,4). Stage 1 T1D is characterized by normoglycemia with the presence of two or more of the following autoantibodies: insulin, glutamic acid decarboxylase (GAD), islet antigen 2 (IA-2) or zinc transporter 8 (ZnT8). Stage 2 T1D requires dysglycemia which is defined as impaired fasting glucose or impaired glucose tolerance in addition to islet autoantibodies. Fasting plasma glucose levels of 100-125 mg/dl (5.6 – 6.9 mmol/L) or 2-hour plasma glucose of 140-199 mg/dL (7.8 – 11.0 mmol/L) meet these definitions. A hemoglobin A1c (A1c) value in the range 5.7 – 6.4% (39-47 mmol/l) or ≥ 10% increase in A1c can also be used to diagnose dysglycemia for stage 2. Either stage 1 or 2 can be referred to as early-stage or pre-stage 3 T1D. Stage 3 requires overt hyperglycemia with clinical symptoms, but autoantibodies may no longer be present. The ADA recommends referral to a specialized center and/or consideration of approved therapy or clinical trial once multiple autoantibodies are confirmed (3).
Confirmation by repeat islet autoantibody testing with a second sample within three months of the first result, preferably by a laboratory that meets the Islet Autoantibodies Standardization Program (IASP) standards, is recommended by consensus guidelines (4). If two or more are still positive then metabolic monitoring, education, and psychosocial assessment/support is recommended. The primary purpose is to prevent diabetic ketoacidosis and minimize risk of emergency care, but patients may also be referred to clinical trials. These consensus guidelines also highlight pros and cons of various types of metabolic monitoring and give suggestions for frequency of monitoring that are based on individual risk assessment (4). A younger age, higher total number of autoantibodies, and autoantibodies against IA-2 have all been associated with a faster progression to stage 3 T1D and may call for more frequent monitoring.
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