Should C-peptide (Connecting peptide) testing for type 1 diabetes mellitus (DM) be done in a fasting state?

C-peptide Testing for Type 1 Diabetes Diagnosis: Fasting vs. Non-fasting

For C-peptide testing to diagnose type 1 diabetes, a random sample within 5 hours of eating can replace a formal fasting C-peptide test, though fasting testing is recommended when plasma glucose is ≤220 mg/dL. 1

When to Use C-peptide Testing

• C-peptide measurement helps distinguish type 1 from type 2 diabetes in ambiguous cases, such as individuals with type 2 phenotype presenting with ketoacidosis 1
• Testing is most useful after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests type 2 or monogenic diabetes 2
• Absent C-peptide at any time confirms absolute insulin requirement and appropriateness of type 1 diabetes management strategies 2

Fasting vs. Non-fasting Testing Guidelines

Non-fasting Testing Approach

• A random C-peptide sample (with concurrent glucose) within 5 hours of eating can replace a formal C-peptide stimulation test for diabetes classification 1
• If the C-peptide result is >600 pmol/L (>1.8 ng/mL), the circumstances of testing do not matter 1

When Fasting Testing is Recommended

• If required by payers for coverage of insulin pump therapy, measure fasting C-peptide level when simultaneous fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L) 1
• If a non-fasting C-peptide result is <600 pmol/L (<1.8 ng/mL) and the concurrent glucose is <4 mmol/L (<70 mg/dL) or the person may have been fasting, consider repeating the test 1

Interpretation of C-peptide Results

• C-peptide values <200 pmol/L (<0.6 ng/mL) are consistent with type 1 diabetes 1
• C-peptide values 200–600 pmol/L (0.6–1.8 ng/mL) are usually consistent with type 1 diabetes or maturity-onset diabetes of the young, but may occur in insulin-treated type 2 diabetes, particularly in people with normal or low BMI or after long duration 1
• C-peptide values >600 pmol/L (>1.8 ng/mL) suggest type 2 diabetes 1
• Results showing very low levels (e.g., <80 pmol/L [<0.24 ng/mL]) do not need to be repeated 1

Important Considerations and Caveats

• Do not test C-peptide within 2 weeks of a hyperglycemic emergency 1
• Where a person is insulin-treated, C-peptide must be measured prior to insulin discontinuation to exclude severe insulin deficiency 1
• Stimulated C-peptide (via mixed-meal tolerance test) may detect residual beta cell function in an additional 10% of individuals compared to fasting in those with >5 years of diabetes duration 3
• C-peptide levels decrease over time in type 1 diabetes, with significant reduction observed even at one-year follow-up 3
• Advances in assays have made C-peptide measurement both more reliable and inexpensive, with newer point-of-care tests showing strong correlation (r = 0.98) with laboratory methods 2, 4

Clinical Algorithm for C-peptide Testing in Type 1 Diabetes Diagnosis

1. For patients with ambiguous presentation (e.g., type 2 phenotype with ketoacidosis):

   • Measure islet autoantibodies first 1
   • If antibody-negative, proceed to C-peptide testing 1

2. For C-peptide testing:

   • If testing for insurance coverage of insulin pump: Use fasting C-peptide when glucose ≤220 mg/dL 1
   • For diagnostic classification: Random C-peptide within 5 hours of eating is acceptable 1

3. Interpret results:

   • <200 pmol/L: Type 1 diabetes 1
   • 200-600 pmol/L: Indeterminate (likely type 1 or MODY) 1

   • 600 pmol/L: Type 2 diabetes 1