How do you differentiate Type 1 Diabetes Mellitus (DM) from Maturity-Onset Diabetes of the Young (MODY) and Latent Autoimmune Diabetes in Adults (LADA)?

Differentiating Type 1 Diabetes from MODY and LADA

Use the AABBCC clinical approach combined with targeted autoantibody testing and C-peptide measurement to distinguish these diabetes subtypes, as misdiagnosis occurs in up to 40% of adults with new-onset diabetes. 1, 2

Initial Clinical Assessment Framework

Age at Diagnosis

• Type 1 DM: Can occur at any age, though traditionally associated with younger onset; approximately one-third of children present with DKA 1, 2
• LADA: Diagnosed after age 35 years (some sources use age 30 as cutoff) 2, 3
• MODY: Diabetes diagnosed before age 25 years in non-obese individuals 1, 2

Autoimmunity Markers

• Type 1 DM: Positive for β-cell autoantibodies (GAD, IA-2, insulin autoantibodies, zinc transporter protein) 1, 2
• LADA: Positive for islet autoantibodies, most commonly GAD antibodies; distinguishes it from type 2 diabetes 2, 3
• MODY: Negative for β-cell autoantibodies (though rare coexistence with autoimmune diabetes has been reported) 1, 2

Body Habitus and Metabolic Features

• Type 1 DM: BMI <25 kg/m², classic symptoms of polyuria, polydipsia, weight loss 1, 2
• LADA: Lower BMI, fewer metabolic risk factors, and better lipid profiles compared to type 2 diabetes; often lean body habitus 2, 3
• MODY: Non-obese individuals with stable, mild fasting hyperglycemia 1, 2

Background and Family History

• Type 1 DM: Personal or family history of autoimmune disease or polyglandular autoimmune syndromes 1, 2
• LADA: Personal or family history of autoimmune diseases 2, 3
• MODY: Strong family history across successive generations showing autosomal dominant inheritance pattern 1, 2

Control (Glycemic Pattern)

• Type 1 DM: Absolute insulin deficiency requiring immediate insulin therapy; inability to achieve glycemic goals on non-insulin therapies 1, 2
• LADA: Initially appears as type 2 diabetes but progresses to insulin dependence within months to years; glycemic control initially achieved with sulfonylureas but patients eventually become insulin dependent more rapidly than type 2 diabetes 2, 4
• MODY: Stable, mild fasting hyperglycemia with A1C between 5.6-7.6%; impaired insulin secretion with minimal or no insulin resistance 2, 5

Diagnostic Testing Algorithm

When to Test for Autoantibodies

Test all adults diagnosed with diabetes who are non-obese, <35 years old, or have atypical features for β-cell autoantibodies. 1, 2

Order the following autoantibody panel: 3

• Glutamic acid decarboxylase antibodies (GADA)
• Islet antigen-2 antibodies (IA-2A)
• Zinc transporter 8 antibodies (ZnT8A)
• Insulin autoantibodies (IAA)

C-Peptide Measurement

• Measure basal and stimulated C-peptide (6 minutes after 1 mg IV glucagon) to assess β-cell function 6
• Critical timing: Do not test C-peptide within 2 weeks of a hyperglycemic emergency 1
• For insulin-treated patients, C-peptide must be measured prior to insulin discontinuation to exclude severe insulin deficiency 1
• Interpretation: C-peptide values 200–600 pmol/L (0.6–1.8 ng/mL) are usually consistent with type 1 diabetes or MODY but may occur in insulin-treated type 2 diabetes 1
• MODY patients show significantly lower basal and stimulated C-peptide levels compared to type 2 diabetes patients 6

When to Consider MODY Genetic Testing

Consider MODY genetic testing when: 1, 2

• Diabetes diagnosed in first 6 months of life (neonatal diabetes)
• Diabetes diagnosed before age 25 years with negative autoantibodies
• Strong family history in successive generations (autosomal dominant pattern)
• Atypical diabetes with multiple family members affected

Important caveat: In most cases, the presence of autoantibodies for type 1 diabetes precludes further testing for monogenic diabetes, but the presence of autoantibodies in patients with monogenic diabetes has been reported. 1

Critical Pitfalls to Avoid

Antibody Testing Limitations

• Single positive antibody (present in 1-2% of healthy individuals) has low predictive value for diabetes progression 3
• Antibody prevalence varies by race: 85-90% in white patients with type 1 diabetes versus only 19% in black or Hispanic patients 3
• Islet autoantibodies may not be detectable in all patients and decrease with age; approximately 5-10% of type 1 diabetes patients may be antibody-negative 3
• The highest frequency is anti-GAD antibodies at 34% 6

Misdiagnosis Patterns

• Adults with type 1 diabetes are commonly misdiagnosed as having type 2 diabetes 1
• Individuals with MODY may be misdiagnosed as having type 1 diabetes 1
• LADA accounts for approximately 5-10% of adults initially diagnosed with apparent type 2 diabetes 3

Treatment Implications of Correct Diagnosis

Accurate classification is critical because treatment differs substantially: 2

Type 1 Diabetes

• Requires immediate insulin therapy 1, 2
• Absolute insulin deficiency necessitates lifelong insulin replacement 1

LADA

• Requires earlier insulin initiation to preserve β-cell function 2
• Although definitive treatment is insulin, glitazones may be useful in early stages 7
• Patients initially respond to sulfonylureas but eventually become insulin dependent more rapidly than type 2 diabetes patients 4

MODY Subtypes

• GCK-MODY (MODY 2): Typically requires no pharmacological treatment except sometimes during pregnancy; multiple studies show no complications ensue in the absence of glucose-lowering therapy 1, 2
• HNF1A-MODY and HNF4A-MODY: Highly sensitive to low-dose sulfonylureas as first-line therapy; patients respond well to low doses of sulfonylureas, which are considered first-line therapy 1, 2
• HNF1B-MODY (MODY 5): Requires multidisciplinary management for associated renal cysts, uterine malformations, and organ abnormalities 1, 2

Cost-Effectiveness Considerations

A diagnosis of the three most common forms of MODY allows for more cost-effective therapy (no therapy for GCK-MODY; sulfonylureas instead of insulin for HNF1A/HNF4A-MODY), and diagnosis can lead to identification of other affected family members. 1