How to differentiate between type 1, type 2, and Maturity-Onset Diabetes of the Young (MODY) in a 25-year-old patient presenting with hyperglycemia and breathlessness?

Differentiating Type 1, Type 2, and MODY in a 25-Year-Old with Hyperglycemia and Breathlessness

In this 25-year-old patient with hyperglycemia and breathlessness, immediately assess for diabetic ketoacidosis (DKA) given the respiratory symptoms, then use the AABBCC approach combined with autoantibody testing and C-peptide measurement to distinguish between type 1 diabetes (most likely if presenting with DKA and weight loss), type 2 diabetes (if obese with metabolic syndrome features), or MODY (if non-obese with strong multigenerational family history and negative autoantibodies). 1

Immediate Clinical Assessment

Address the breathlessness first, as this may indicate DKA, which occurs in approximately one-third of children with type 1 diabetes at presentation and can also occur in type 2 diabetes, particularly in ethnic minorities. 1 MODY patients typically do not present with DKA. 2, 3

Apply the AABBCC Clinical Framework

The American Diabetes Association recommends this systematic approach to avoid the 40% misdiagnosis rate in adults with new-onset diabetes: 1, 4

• Age: At 25 years, this falls in the overlap zone—type 1 diabetes and MODY are both possible (MODY classically diagnosed before age 25), while type 2 is less typical but increasingly common. 1, 4

• Autoimmunity: Check for personal or family history of autoimmune diseases (thyroid disease, celiac disease, vitiligo, polyglandular syndromes), which strongly suggests type 1 diabetes. 1, 4 Also assess for recent immune checkpoint inhibitor therapy, which can trigger acute autoimmune type 1 diabetes. 1

• Body habitus: BMI <25 kg/m² suggests type 1 diabetes, LADA, or MODY, while BMI ≥25 kg/m² with central obesity and metabolic syndrome features (hypertension, dyslipidemia) suggests type 2 diabetes. 1, 4

• Background (Family History):

  • Strong multigenerational family history in successive generations (autosomal dominant pattern—one parent affected) strongly suggests MODY. 1, 4, 5
  • Sporadic family history or family history of autoimmunity suggests type 1 diabetes. 1
  • Family history of type 2 diabetes with obesity suggests type 2 diabetes. 1

• Control: Inability to achieve glycemic goals on non-insulin therapies suggests type 1 diabetes, while stable mild hyperglycemia (A1C 5.6-7.6%) suggests MODY. 1, 4

• Comorbidities: Presence of metabolic syndrome features suggests type 2 diabetes. 1

Laboratory Testing Algorithm

First-Line Tests (Order Immediately)

1. Pancreatic Autoantibodies 4, 5

• Test for GAD65, IA-2, insulin autoantibodies, and ZnT8 antibodies
• Positive autoantibodies indicate type 1 diabetes
• Negative autoantibodies do NOT rule out type 1 diabetes but raise suspicion for type 2 or MODY
• Critical caveat: Rare cases of MODY can have positive autoantibodies, so do not assume autoantibody positivity completely rules out MODY if other features are strongly suggestive. 5

2. C-peptide Measurement 1, 4

• Obtain random C-peptide with concurrent glucose within 5 hours of eating (this replaces formal stimulation testing)
• Interpretation:
  • C-peptide >600 pmol/L (>1.8 ng/mL): Suggests type 2 diabetes regardless of testing circumstances 1
  • C-peptide 200-600 pmol/L (0.6-1.8 ng/mL): Consistent with type 1 diabetes or MODY 1, 6
  • C-peptide <80 pmol/L (<0.24 ng/mL): Indicates severe insulin deficiency, consistent with type 1 diabetes 1
• Important: If C-peptide is <600 pmol/L and concurrent glucose is <4 mmol/L (<70 mg/dL) or patient may have been fasting, repeat the test. 1
• Do NOT test C-peptide within 2 weeks of a hyperglycemic emergency. 1

Second-Line Testing (If MODY Suspected)

Consider MODY genetic testing if: 1, 4, 5

• Diabetes diagnosed before age 25 years
• Negative autoantibodies
• Non-obese (BMI <25 kg/m² or only mildly elevated)
• Strong family history in successive generations (one parent with diabetes)
• Preserved C-peptide (200-600 pmol/L)
• Stable mild hyperglycemia (A1C 5.6-7.6%)
• Specific features: renal cysts, partial lipodystrophy, maternally inherited deafness, severe insulin resistance without obesity 1

Use the MODY probability calculator at diabetesgenes.org/exeter-diabetes-app/ModyCalculator—if probability >5%, proceed with genetic testing. 1

Key Distinguishing Features by Diabetes Type

Type 1 Diabetes

• Classic triad: polyuria, polydipsia, weight loss 1, 4
• Can present with DKA (explains breathlessness) 1
• Positive autoantibodies (though may be negative in 5-10% of cases) 4
• Progressive β-cell destruction with eventual undetectable C-peptide 3
• Requires immediate insulin therapy 1, 4

Type 2 Diabetes

• Gradual onset, often asymptomatic initially 4
• BMI ≥25 kg/m², central obesity, metabolic syndrome features 1, 4
• Absence of weight loss and ketoacidosis (though ketosis-prone type 2 exists) 1
• Negative autoantibodies 4
• C-peptide >600 pmol/L indicating preserved insulin secretion with insulin resistance 1

MODY

• Diagnosed before age 25 years in non-obese individuals 4, 5
• Strong multigenerational family history (autosomal dominant pattern) 4, 5, 3
• Negative autoantibodies 4, 5
• Preserved C-peptide (200-600 pmol/L) indicating preserved β-cell function 6, 3
• Stable mild fasting hyperglycemia, A1C 5.6-7.6% 4, 5
• Does NOT typically present with DKA 2, 3
• Minimal insulin resistance 4

Common Pitfalls to Avoid

• Do not assume young age automatically means type 1 diabetes—type 2 diabetes is increasingly common in younger populations with obesity, and MODY is frequently misdiagnosed as type 1. 1, 2, 7

• Do not delay genetic testing if MODY is suspected—the average delay between initial diabetes diagnosis and MODY confirmation is 12.2 years, leading to years of inappropriate treatment. 2

• Do not assume negative autoantibodies rule out type 1 diabetes—some patients with type 1 diabetes are autoantibody-negative, and the diagnosis becomes clearer over time as β-cell deficiency progresses. 1

• Do not test C-peptide if the patient is in DKA or within 2 weeks of a hyperglycemic emergency—results will be unreliable. 1

• Do not assume autoantibody positivity completely excludes MODY—rare coexistence has been reported. 5

Treatment Implications of Correct Diagnosis

Accurate classification is critical because treatment differs substantially: 4

• Type 1 diabetes: Requires immediate insulin therapy 1, 4
• Type 2 diabetes: Initial treatment with lifestyle modification plus metformin in most cases 4
• GCK-MODY (MODY2): Typically requires no pharmacological treatment except sometimes during pregnancy 4, 5, 3
• HNF1A-MODY (MODY3) and HNF4A-MODY (MODY1): Highly sensitive to low-dose sulfonylureas as first-line therapy 4, 5, 3
• HNF1B-MODY (MODY5): Requires multidisciplinary management for associated renal cysts and organ malformations 4, 5

If classification remains unclear after initial testing, make a clinical decision about treatment and monitor closely—the diagnosis often becomes more obvious over time as the degree of β-cell deficiency becomes clear. 1 Patients with possible type 1 diabetes who are not initially treated with insulin require careful monitoring and education so insulin can be rapidly initiated if glycemic deterioration occurs. 1