How do you differentiate between Diabetes Mellitus (DM), Latent Autoimmune Diabetes in Adults (LADA), and Maturity-Onset Diabetes of the Young (MODY)?

Differentiating Between Type 1/Type 2 Diabetes, LADA, and MODY

Use the AABBCC clinical approach combined with targeted autoantibody and genetic testing to distinguish these diabetes subtypes, as misdiagnosis occurs in up to 40% of adults with new-onset diabetes. 1

Initial Clinical Assessment: The AABBCC Approach

The American Diabetes Association recommends this systematic framework for distinguishing diabetes types 1:

• Age: Onset <35 years suggests type 1 diabetes or MODY; onset >35 years suggests type 2 diabetes or LADA 1
• Autoimmunity: Personal or family history of autoimmune disease or polyglandular autoimmune syndromes suggests type 1 diabetes or LADA 1
• Body habitus: BMI <25 kg/m² suggests type 1 diabetes, LADA, or MODY; obesity with metabolic syndrome features suggests type 2 diabetes 1
• Background: Strong family history in successive generations (autosomal dominant pattern) suggests MODY; family history of type 1 diabetes suggests type 1 diabetes 1, 2
• Control: Poor glycemic control on non-insulin therapies suggests type 1 diabetes or LADA; stable mild hyperglycemia suggests MODY 1
• Comorbidities: Recent immune checkpoint inhibitor therapy can trigger acute autoimmune type 1 diabetes 1

Key Distinguishing Features by Diabetes Type

Type 1 Diabetes

• Presentation: Classic symptoms of polyuria, polydipsia, weight loss; approximately one-third present with DKA in children 1
• Age: Can occur at any age, though traditionally associated with younger onset 1
• Autoantibodies: Positive for β-cell autoantibodies (GAD, IA-2, insulin, zinc transporter protein) 1
• Insulin requirement: Absolute insulin deficiency requiring immediate insulin therapy 1

Type 2 Diabetes

• Presentation: Gradual onset, often asymptomatic; increased BMI with metabolic syndrome features 1
• Age: Typically after middle age, though increasingly seen in younger populations with obesity 1
• Autoantibodies: Negative for β-cell autoantibodies 1
• Pathophysiology: Insulin resistance with progressive β-cell dysfunction on background of insulin resistance 1

LADA (Latent Autoimmune Diabetes in Adults)

• Presentation: Initially appears as type 2 diabetes; patients are insulin-independent at diagnosis but progress to insulin dependence within months to years 1, 3, 4
• Age: Diagnosed after age 35 years 1, 3
• Autoantibodies: Positive for β-cell autoantibodies (most commonly GAD antibodies), distinguishing it from type 2 diabetes 1, 3, 4
• Body habitus: Often non-obese or less obese than typical type 2 diabetes patients 3, 4
• Clinical course: Initial response to sulfonylureas but more rapid progression to insulin requirement compared to type 2 diabetes 3, 4
• Heterogeneity: LADA shows variable degrees of insulin resistance and autoimmunity, representing a spectrum between type 1 and type 2 diabetes 4, 5

MODY (Maturity-Onset Diabetes of the Young)

• Presentation: Diabetes diagnosed before age 25 years in non-obese individuals 1, 2
• Family history: Strong family history across successive generations (autosomal dominant inheritance pattern) 1, 2, 6
• Autoantibodies: Negative for β-cell autoantibodies (though rare coexistence with autoimmune diabetes has been reported) 1, 2, 7
• Glycemic pattern: Stable, mild fasting hyperglycemia (100-150 mg/dL) with A1C between 5.6-7.6% 1, 2
• Insulin secretion: Impaired insulin secretion with minimal or no insulin resistance 1, 2

Diagnostic Testing Algorithm

Step 1: Screen for Autoimmunity

Test all adults diagnosed with diabetes who are non-obese, <35 years old, or have atypical features for β-cell autoantibodies 1:

• GAD antibodies (most sensitive for LADA) 1, 3
• IA-2 antibodies 1
• Insulin autoantibodies (if not yet on insulin) 1
• Zinc transporter protein antibodies 1

Interpretation: Positive autoantibodies indicate type 1 diabetes or LADA; negative autoantibodies suggest type 2 diabetes or MODY 1

Step 2: Consider MODY Genetic Testing When:

The American Diabetes Association recommends genetic testing in these specific scenarios 1, 2, 6:

• Diabetes diagnosed in first 6 months of life (80-85% have monogenic cause) 2
• Diabetes diagnosed before age 25 years with negative autoantibodies 1, 2
• Strong family history in successive generations (autosomal dominant pattern) 1, 2, 6
• Stable mild fasting hyperglycemia without progression 1, 2
• Non-obese without metabolic syndrome features 1, 2

Biomarker screening with urinary C-peptide/creatinine ratio and antibody testing can help identify candidates for genetic testing 2

Step 3: Differentiate LADA from Type 1 Diabetes

Both have positive autoantibodies, but distinguish by 1, 3, 4:

• Age at diagnosis: LADA >35 years; type 1 diabetes can be any age but classically younger 1, 3
• Insulin requirement: LADA remains insulin-independent for ≥6 months after diagnosis; type 1 diabetes typically requires immediate insulin 1, 3, 4
• Presentation: LADA has gradual onset without DKA; type 1 diabetes often presents with DKA or severe symptoms 1, 3
• Autoimmune intensity: LADA has less intensive autoimmune process with lower autoantibody titers 4, 5

Common Diagnostic Pitfalls

Critical caveat: Misdiagnosis is extremely common, occurring in up to 40% of adults with new-onset diabetes 1. Avoid these errors:

• Assuming all adult-onset diabetes is type 2: Always consider LADA in non-obese adults, especially if glycemic control deteriorates rapidly on oral agents 1, 3
• Missing MODY: Adults with MODY are frequently misdiagnosed as type 1 diabetes; children with MODY are often misdiagnosed as type 1 diabetes 1
• Assuming autoantibody positivity rules out MODY: Rare coexistence of autoimmune diabetes and MODY has been reported 2, 7
• Relying solely on age: Type 1 diabetes can present at any age with variable presentation in adults, including temporary remission from insulin need 1
• Ethnic minorities presenting with DKA: Type 2 diabetes can occasionally present with DKA, particularly in ethnic and racial minorities 1

Treatment Implications of Correct Diagnosis

Accurate classification is critical because treatment differs substantially 1:

• GCK-MODY (MODY2): Typically requires no pharmacological treatment except sometimes during pregnancy 1, 2, 6
• HNF1A-MODY and HNF4A-MODY: Highly sensitive to low-dose sulfonylureas as first-line therapy 1, 2, 6
• HNF1B-MODY: Requires multidisciplinary management for associated renal cysts and organ malformations 2
• LADA: Avoid sulfonylureas as they may accelerate β-cell loss; earlier insulin initiation may preserve β-cell function 3, 4
• Type 1 diabetes: Requires immediate insulin therapy 1
• Type 2 diabetes: Initial lifestyle modification plus metformin in most cases 6

Specialist consultation with a center specializing in diabetes genetics is recommended when MODY is suspected to guide genetic testing interpretation, treatment, and family counseling 2