What is autoimmune diabetes, particularly in adults with a personal or family history of autoimmune diseases?

What is Autoimmune Diabetes?

Autoimmune diabetes is a form of diabetes caused by cellular-mediated autoimmune destruction of pancreatic β-cells, accounting for 5-10% of all diabetes cases, and is characterized by the presence of islet autoantibodies including GAD, insulin, IA-2, IA-2b, and ZnT8 antibodies. 1

Core Pathophysiology

Autoimmune diabetes results from immune-mediated destruction of insulin-producing β-cells in the pancreas. 1 The disease process involves:

• Autoantibody markers that define the condition: glutamic acid decarboxylase (GAD65), insulin autoantibodies, islet antigen-2 (IA-2 and IA-2b), and zinc transporter 8 (ZnT8). 1
• Strong HLA associations with linkage to DQB1 and DRB1 haplotypes, where specific alleles can be either predisposing (DR3-DQ2 and DR4-DQ8) or protective (DRB11501 and DQA10102-DQB1*0602). 1
• Multiple genetic predispositions combined with poorly defined environmental factors that trigger the autoimmune process. 1

Clinical Spectrum and Presentation

The rate of β-cell destruction varies dramatically across patients:

• Rapid progression occurs particularly (but not exclusively) in infants and children, often presenting with diabetic ketoacidosis (DKA) as the first manifestation. 1
• Slow progression occurs mainly (but not exclusively) in adults who may retain sufficient β-cell function to prevent DKA for many years. 1
• Adults with autoimmune diabetes can occur at any age, even in the 8th and 9th decades of life, and may have remission or decreased insulin needs for months or years before eventually becoming insulin-dependent. 1

Staging System for Type 1 Diabetes

The American Diabetes Association defines three stages of autoimmune diabetes: 1

• Stage 1: Presence of two or more islet autoantibodies with normoglycemia and no symptoms (44% 5-year risk of progression to symptomatic diabetes). 1
• Stage 2: Islet autoantibodies (usually multiple) with dysglycemia (impaired fasting glucose, impaired glucose tolerance, or A1C 5.7-6.4%) but presymptomatic (60% risk by 2 years, 75% within 5 years). 1
• Stage 3: Overt hyperglycemia meeting diabetes diagnostic criteria with symptoms; autoantibodies may become absent at this stage. 1

Latent Autoimmune Diabetes in Adults (LADA)

LADA represents a distinct phenotype of autoimmune diabetes in adults that initially resembles type 2 diabetes but has underlying autoimmune β-cell destruction. 2

Key distinguishing features include:

• Approximately 5-10% of adults with apparent type 2 diabetes phenotype have GAD antibodies, representing LADA. 3
• Clinical risk factors that identify LADA include: age of onset <50 years, acute symptoms of hyperglycemia, BMI <25 kg/m², personal history of autoimmune disease, and family history of autoimmune disease. 4
• Presence of at least two of these distinguishing clinical features has 90% sensitivity and 71% specificity for identifying LADA. 4
• Progression to insulin dependence occurs faster in LADA patients compared to antibody-negative type 2 diabetes, with 92% positive predictive value for insulin requirement within 3 years in young adults. 5

Associated Autoimmune Conditions

Patients with autoimmune diabetes are prone to other autoimmune disorders, which is particularly relevant for adults with personal or family history of autoimmunity. 1 Common associations include:

• Hashimoto thyroiditis and Graves disease 1
• Celiac disease 1
• Addison disease 1
• Vitiligo 1
• Autoimmune hepatitis 1
• Myasthenia gravis 1
• Pernicious anemia 1

Diagnostic Approach

Standardized islet autoantibody testing is recommended in adults with phenotypic features that overlap between type 1 and type 2 diabetes, particularly when there is unintentional weight loss, ketoacidosis, younger age at diagnosis (<35 years), or rapid progression to insulin requirement. 1, 3

The diagnostic workup should include:

• GAD antibodies as the primary test, as this is the most frequently positive marker in both type 1 and type 2 diabetes presentations. 3
• IA-2 and ZnT8 antibodies if GAD is negative, as these can also indicate autoimmune etiology. 3
• Insulin autoantibodies (IAA) in patients not yet treated with insulin, as exogenous insulin renders this test unreliable. 3
• C-peptide testing primarily when the patient is already on insulin therapy to assess residual β-cell function, with interpretation: <200 pmol/L (<0.6 ng/mL) indicates type 1 diabetes, 200-600 pmol/L is indeterminate, and >600 pmol/L indicates type 2 diabetes. 3

Critical Clinical Pitfalls

Obesity does not preclude the diagnosis of autoimmune diabetes, as obesity is increasingly common in the general population and more than half of newly diagnosed Black patients with unprovoked ketoacidosis are obese. 1, 3

Approximately 5-10% of adults with true type 1 diabetes are antibody-negative, so negative autoantibodies in someone under 35 years with classic type 1 features should not change the diagnosis. 3

DKA can occur in type 2 diabetes, particularly in ethnic minorities and obese patients, which may lead to misclassification. 3

Screening Recommendations

Autoantibody-based screening for presymptomatic type 1 diabetes should be offered to those with a family history of type 1 diabetes or otherwise known elevated genetic risk. 1 When multiple islet autoantibodies are identified, referral to a specialized center for further evaluation and/or consideration of clinical trials or approved therapy (such as teplizumab) to potentially delay development of clinical diabetes should be considered. 1