When should C-peptide (Connecting peptide) be ordered in patients with diabetes mellitus?

When to Order C-peptide in Diabetic Patients

C-peptide testing should be ordered in adults with diabetes who have phenotypic risk factors that overlap with type 1 diabetes, in patients with uncertain diabetes classification, and when C-peptide values <1.51 ng/mL can provide a 96% negative predictive value for type 1 diabetes. 1

Primary Indications for C-peptide Testing

• To differentiate between diabetes types:

  • When clinical presentation is ambiguous between type 1 and type 2 diabetes 1, 2
  • In suspected Latent Autoimmune Diabetes in Adults (LADA), which represents 5-10% of adults initially diagnosed with type 2 diabetes 1
  • When monogenic diabetes is suspected, especially after 3-5 years from diagnosis when substantial insulin secretion persists 2

• To assess beta-cell function:

  • To determine residual insulin secretion capacity 1, 3
  • To guide treatment decisions, particularly regarding insulin therapy 1, 2
  • To track disease progression in patients with diabetes 1

Interpretation of C-peptide Values

According to the American Diabetes Association's 2024 Standards of Care 1:

C-peptide level	Clinical interpretation
<0.6 ng/mL (<200 pmol/L)	Type 1 diabetes pattern
0.6-1.8 ng/mL (200-600 pmol/L)	Indeterminate status
>1.8 ng/mL (>600 pmol/L)	Type 2 diabetes pattern

Specific Clinical Scenarios for C-peptide Testing

1. Newly diagnosed diabetes with unclear classification:

   • Young adults with features of both type 1 and type 2 diabetes
   • Normal or overweight patients with ketosis
   • Patients with strong family history but atypical presentation 1, 2

2. Insulin-treated patients:

   • To determine absolute insulin requirement 2
   • To assess appropriateness of type 1 diabetes management strategies regardless of apparent etiology 2
   • When considering insulin discontinuation or addition of non-insulin therapies 1, 3

3. Suspected LADA:

   • In combination with autoantibody testing (particularly GADA) 1
   • In adults initially diagnosed with type 2 diabetes who show poor response to oral agents 1

4. Treatment guidance:

   • Patients with C-peptide >1.8 ng/mL may benefit from non-insulin approaches 1
   • Patients with low C-peptide (<0.6 ng/mL) require insulin therapy 1
   • To determine appropriate initial insulin dosing (0.3-0.4 units/kg/day for LADA patients) 1

Timing and Type of C-peptide Test

• Most valuable 3-5 years after diagnosis when persistence of substantial insulin secretion suggests type 2 or monogenic diabetes 2
• Fasting C-peptide: Reflects baseline beta-cell function
• Stimulated C-peptide (after glucagon or meal): Better reflects maximum beta-cell secretory capacity 4
• Postprandial C-peptide to glucose ratio: May better reflect beta-cell function than fasting measurements 4
• Urine C-peptide:creatinine ratio: A reliable alternative when blood sampling is challenging 2

Common Pitfalls and Caveats

• C-peptide results should be interpreted in conjunction with clinical presentation and other tests (e.g., autoantibodies) 1, 3
• C-peptide is more stable in blood than previously thought but proper sample handling remains important 2
• Insulin resistance can confound C-peptide interpretation in type 2 diabetes 3
• Absent C-peptide at any time confirms absolute insulin requirement 2
• Standardization issues between laboratories may affect result interpretation 3
• Renal impairment can elevate C-peptide levels due to reduced clearance 5

C-peptide measurement provides valuable clinical information about beta-cell function, which is fundamental to diabetes classification and treatment decisions. Its utility is greatest in cases where diabetes classification is unclear or when determining the appropriate treatment approach in insulin-treated patients.