What investigations are recommended for patients suspected of having Latent Autoimmune Diabetes in Adults (LADA)?

Recommended Investigations for Latent Autoimmune Diabetes in Adults (LADA)

Standardized islet autoantibody testing is the primary recommended investigation for diagnosing LADA in adults who present with clinical features that overlap between type 1 and type 2 diabetes. 1

Primary Diagnostic Tests for LADA

1. Islet Autoantibody Testing

• First-line autoantibody tests (in recommended order):

  • Glutamic acid decarboxylase antibodies (GADA) - most common in LADA 1, 2
  • Islet antigen-2 antibodies (IA-2A) 1, 2
  • Zinc transporter 8 antibodies (ZnT8A) 1, 2
  • Insulin autoantibodies (IAA) - only useful in patients not previously treated with insulin 2

• Clinical significance:

  • Presence of multiple islet autoantibodies has 92% positive predictive value for requiring insulin within three years 1
  • Approximately 5-10% of adults presenting with type 2 diabetes phenotype have islet autoantibodies, particularly GADA 1
  • Autoantibody testing is most valuable at or near diagnosis, as antibodies may disappear over time 2

2. C-peptide Measurement

• When to measure: After glucose challenge or randomly with concurrent glucose measurement (within 5 hours of eating) 2
• Interpretation:
  • <0.6 ng/mL (<200 pmol/L): Type 1 diabetes pattern - requires insulin therapy
  • 0.6-1.8 ng/mL (200-600 pmol/L): Indeterminate - may need additional testing

  • 1.8 ng/mL (>600 pmol/L): Type 2 diabetes pattern 2

• Timing considerations: Most informative after 3-5 years from diagnosis 2

Additional Diagnostic Tests

1. Standard Glucose Tests

• Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 1
• 2-hour post-load glucose (OGTT) ≥200 mg/dL (11.1 mmol/L) 1
• Random glucose ≥200 mg/dL with symptoms 1
• HbA1c ≥6.5% (48 mmol/mol) 1

2. Tests to Rule Out Other Types of Diabetes

• Consider genetic testing for monogenic diabetes if:
  • A1C <7.5% at diagnosis
  • One parent with diabetes
  • Specific features like renal cysts
  • C-peptide >200 pmol/L 2

Clinical Assessment Factors

When laboratory results are indeterminate, consider these clinical factors that suggest LADA:

• Age <35 years at diagnosis 2
• Personal/family history of autoimmune disease 2
• BMI <25 kg/m² (though 66% of LADA patients may be overweight/obese) 3
• Family history of type 1 diabetes 2
• Inability to achieve glycemic control on non-insulin therapies 2
• Presence of other autoimmune conditions (particularly thyroid disease) 3

Staging LADA (Based on Type 1 Diabetes Staging)

LADA can be staged similar to type 1 diabetes:

1. Stage 1:

   • Multiple islet autoantibodies
   • Normoglycemia
   • No symptoms 1

2. Stage 2:

   • Islet autoantibodies (usually multiple)
   • Dysglycemia (IFG: FPG 100-125 mg/dL, IGT: 2-h PG 140-199 mg/dL, or HbA1c 5.7-6.4%)
   • No symptoms 1

3. Stage 3:

   • Autoantibodies may become absent
   • Overt hyperglycemia meeting diabetes criteria
   • Symptomatic 1

Common Pitfalls and Caveats

1. Misdiagnosis is common - up to 40% of adults with new-onset type 1 diabetes are initially misdiagnosed as having type 2 diabetes 2

2. Antibody limitations:

   • Negative autoantibodies do not rule out LADA (5-10% of type 1 diabetes patients are autoantibody negative) 2
   • Autoantibodies may disappear over time, making early testing crucial 2
   • The prevalence of any antibody marker in healthy persons is 1-2%, which may lead to false positives 1

3. C-peptide considerations:

   • C-peptide levels may remain stable in LADA patients who achieve tight metabolic control 4
   • C-peptide tends to decrease in LADA patients who subsequently require insulin 4

4. Clinical presentation variability:

   • LADA patients may present with features of both type 1 and type 2 diabetes
   • About half of LADA patients may be insulinopenic 3
   • LADA patients often have poorer long-term glycemic control compared to antibody-negative patients 3

By following this systematic approach to investigation, clinicians can more accurately diagnose LADA and initiate appropriate management strategies to preserve beta-cell function and optimize glycemic control.