What is Latent Autoimmune Diabetes in Adults (LADA), also known as type 1.5 diabetes, in adults with a lean or normal body mass index (BMI) and a personal or family history of autoimmune diseases?

What is Type 1.5 Diabetes (LADA)?

Type 1.5 diabetes, formally known as Latent Autoimmune Diabetes in Adults (LADA), is a slowly progressive form of autoimmune type 1 diabetes that initially presents in adults with features resembling type 2 diabetes but is characterized by the presence of pancreatic beta-cell autoantibodies and eventual progression to insulin dependence over months to years. 1, 2

Core Diagnostic Features

LADA is defined by three essential clinical criteria that distinguish it from both classic type 1 and type 2 diabetes 3:

• Adult onset - Typically diagnosed after age 35 years, though can occur at any age in adulthood 1, 4
• Presence of islet autoantibodies - Positive for one or more autoantibodies including GAD65 (glutamic acid decarboxylase), IA-2 (islet antigen-2), ZnT8 (zinc transporter 8), or insulin autoantibodies 1, 2, 5
• Initial insulin independence - Does not require insulin at diagnosis, distinguishing it from classic type 1 diabetes, though insulin dependence develops within a few years 1, 3

Clinical Presentation in Your Target Population

In adults with lean/normal BMI and personal or family history of autoimmune diseases, LADA should be strongly suspected when 1, 2:

• BMI <25 kg/m² - Absence of obesity is a key discriminating feature 1
• Unintentional weight loss at presentation 1
• Personal or family history of autoimmune diseases - Including Hashimoto thyroiditis, Graves disease, Addison disease, celiac disease, vitiligo, or other autoimmune conditions 1
• Rapid glycemic deterioration despite oral antidiabetic therapy 6
• Absence of metabolic syndrome features - No hypertension, dyslipidemia, or central obesity 1

Pathophysiology and Progression

LADA represents autoimmune destruction of pancreatic beta cells that progresses more slowly than classic type 1 diabetes 1, 4:

• Beta-cell destruction occurs gradually over months to years rather than weeks to months 1
• Autoantibodies target beta-cell proteins (GAD65, IA-2, ZnT8, insulin) similar to type 1 diabetes 1, 2
• Initial insulin secretion is sufficient to avoid ketoacidosis, but deteriorates progressively 1
• Insulin dependence typically develops within 2-6 years of diagnosis 4, 3

Prevalence and Epidemiology

• LADA accounts for 2-12% of all diabetes cases initially diagnosed as type 2 diabetes 4
• Approximately 10% of adults presenting with non-insulin-requiring diabetes have LADA 3
• More common in Caucasian populations compared to other ethnicities 1

Critical Diagnostic Testing

When LADA is suspected based on clinical features, the American Diabetes Association recommends specific testing 1, 2:

• Primary test: GAD65 autoantibody - Most sensitive marker, should be tested first 2
• Secondary tests: IA-2 and/or ZnT8 autoantibodies - If GAD65 is negative but clinical suspicion remains high 2
• C-peptide measurement - Values <200 pmol/L (<0.6 ng/mL) suggest severe insulin deficiency consistent with type 1 diabetes; values 200-600 pmol/L (0.6-1.8 ng/mL) are typically consistent with LADA or MODY 1

Important Caveat on Testing

A critical pitfall: Single positive autoantibody in patients without clinical features of type 1 diabetes likely represents a false-positive result due to low disease prevalence in that population. 7 Testing should only be performed when clinical features suggest autoimmune diabetes (lean body habitus, weight loss, rapid progression, personal/family history of autoimmunity) 1, 7. In patients with typical type 2 diabetes features and no concerning clinical signs, autoantibody testing yields more false positives than true positives 7.

Heterogeneity and Classification Challenges

Recent evidence reveals LADA is not a uniform entity 7, 4:

• LADA likely represents a mixed population of true autoimmune diabetes (slow-onset type 1) and false-positive autoantibody results in actual type 2 diabetes 7
• Genetic and immunological features are intermediate between type 1 and type 2 diabetes, suggesting heterogeneity 7, 4
• The term "type 1.5 diabetes" reflects this intermediate phenotype but may be misleading as it suggests a distinct disease entity rather than a spectrum 4, 5

Clinical Implications for Management

Recognition of LADA has critical therapeutic implications 2, 6, 3:

• Sulfonylureas provide only temporary glycemic control and patients progress to insulin requirement more rapidly than true type 2 diabetes 4
• Early insulin therapy is appropriate once diagnosis is confirmed, rather than escalating through multiple oral agents 6, 3
• Patients initially treated as type 2 diabetes who show rapid deterioration despite therapy should be tested for LADA 6
• The AABBCC approach helps distinguish diabetes type: Age <35 years, Autoimmunity (personal/family history), Body habitus (BMI <25), Background (family history of type 1), Control (inability to achieve goals on non-insulin therapy), Comorbidities (other autoimmune diseases) 1

Relationship to Type 1 Diabetes Classification

The American Diabetes Association considers LADA a form of type 1 diabetes that is phenotypically similar to type 2 diabetes at presentation 2. However, it represents a slowly progressive variant with insulin dependence developing over years rather than months 1, 2. The European Society of Cardiology similarly describes LADA as a condition where "insulin dependence develops over a few years" in adults with autoantibodies to pancreatic beta-cell proteins 1.