When should C-peptide (Connecting Peptide) be ordered?

When to Order C-peptide Testing

C-peptide testing should be ordered when differentiating between diabetes types in patients with ambiguous presentation, particularly when islet autoantibody testing is negative in suspected type 1 diabetes. 1, 2

Primary Indications for C-peptide Testing

• C-peptide should be ordered after islet autoantibody testing in patients with ambiguous diabetes presentation to help distinguish between type 1 and type 2 diabetes 2
• For antibody-negative patients under 35 years with suspected type 1 diabetes but no clinical features of type 2 or monogenic diabetes 1
• For antibody-negative patients over 35 years to assist with clinical decision-making regarding treatment approach 1
• When evaluating patients with type 2 phenotype who present with ketoacidosis to determine if they have absolute insulin deficiency 2
• After at least 3 years of diabetes duration in antibody-negative patients to help confirm classification 1

Specific Clinical Scenarios for C-peptide Testing

• To differentiate between endogenous and exogenous hyperinsulinism 3
• To establish insulin requirements in patients already receiving insulin therapy 3
• To identify patients with maturity-onset diabetes of the young (MODY), who typically have persistent C-peptide production 4, 5
• To assist in patient selection for islet cell transplantation and post-transplant monitoring 4
• To identify latent autoimmune diabetes in adults (LADA), which presents clinically like type 2 diabetes but with positive autoantibodies and lower C-peptide levels 4

Interpretation of C-peptide Results

• C-peptide values <200 pmol/L are consistent with type 1 diabetes 1, 2
• Very low C-peptide levels (<80 pmol/L or <0.24 ng/mL) strongly suggest absolute insulin deficiency and type 1 diabetes 2
• C-peptide values between 200-600 pmol/L may indicate type 1 diabetes, MODY, or insulin-treated type 2 diabetes 1, 2
• C-peptide values >600 pmol/L suggest type 2 diabetes 1, 2
• High uncorrected fasting C-peptide with hyperglycemia may suggest insulin resistance 4

Important Testing Considerations

• C-peptide testing should not be performed within 2 weeks of a hyperglycemic emergency 1, 2
• For insulin-treated patients, C-peptide should be measured prior to insulin discontinuation to exclude severe insulin deficiency 1, 2
• A random C-peptide sample within 5 hours of eating can replace a formal C-peptide stimulation test for diabetes classification purposes 1, 2
• If the C-peptide result is <600 pmol/L and concurrent glucose is <4 mmol/L (<70 mg/dL), consider repeating the test 1
• Results showing very low levels (e.g., <80 pmol/L) do not need to be repeated 1

Clinical Impact of C-peptide Measurement

• Higher residual C-peptide levels (>0.400 pmol/mL) in type 1 diabetes are associated with better glycemic control, including lower mean glucose and more time in range 6
• C-peptide level may predict clinical partial remission during the first year of type 1 diabetes 4
• Low basal C-peptide can be used as a criterion for reclassifying patients initially diagnosed with type 2 diabetes to type 1 diabetes 4
• C-peptide measurement becomes most useful after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests type 2 or monogenic diabetes 5