What is the role of C (connecting) peptide levels in diagnosing and managing diabetes?

Role of C-peptide in Diagnosing and Managing Diabetes

C-peptide testing is primarily indicated in insulin-treated patients to help differentiate between diabetes types when clinical presentation is ambiguous, with values <200 pmol/L consistent with type 1 diabetes, 200-600 pmol/L suggesting type 1 or MODY, and >600 pmol/L indicating type 2 diabetes. 1, 2

When to Use C-peptide Testing

• C-peptide testing should be reserved for insulin-treated patients where diabetes classification is unclear, not as a routine test for most people with diabetes 3
• C-peptide measurement is particularly valuable after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests type 2 or monogenic diabetes rather than type 1 4
• A random C-peptide sample within 5 hours of eating can replace formal stimulation tests for classification purposes 1, 2
• C-peptide testing should not be performed within 2 weeks of a hyperglycemic emergency as results may be unreliable 1, 2

Interpretation of C-peptide Results

• Values <200 pmol/L (<0.6 ng/mL) are consistent with type 1 diabetes 2
• Values between 200-600 pmol/L (0.6-1.8 ng/mL) usually indicate type 1 diabetes or maturity-onset diabetes of the young (MODY), but may occur in insulin-treated type 2 diabetes, particularly in people with normal/low BMI or after long disease duration 1
• Values >600 pmol/L (>1.8 ng/mL) suggest type 2 diabetes 1, 2
• Very low levels (<80 pmol/L or <0.24 ng/mL) do not need to be repeated and confirm absolute insulin deficiency 1

Practical Testing Considerations

• If C-peptide is <600 pmol/L and concurrent glucose is <4 mmol/L (<70 mg/dL) or the person may have been fasting, consider repeating the test 1
• For insulin-treated patients, C-peptide must be measured prior to insulin discontinuation to exclude severe insulin deficiency 1, 2
• When the result is >600 pmol/L (>1.8 ng/mL), the circumstances of testing (fasting vs. non-fasting) do not matter 1

Clinical Applications of C-peptide Testing

• Helps distinguish between type 1 and type 2 diabetes in ambiguous cases, such as individuals with type 2 phenotype presenting with ketoacidosis 2, 3
• Confirms absolute insulin requirement regardless of apparent etiology when C-peptide is absent 4
• Assists in identifying MODY, where persistence of C-peptide is an important clinical feature 5
• Can help identify LADA (Latent Autoimmune Diabetes in Adults), which presents clinically like type 2 diabetes but with positive pancreatic autoantibodies and lower C-peptide levels 5
• May be used for patient selection for islet cell transplantation and post-transplant monitoring 5

C-peptide as a Marker of Beta Cell Function

• C-peptide is produced in equal amounts to insulin but is not extracted by the liver, making it a more accurate reflection of endogenous insulin secretion than insulin itself 4, 6
• Postprandial C-peptide to glucose ratio may better reflect maximum beta cell secretory capacity compared to fasting measurements 6
• Beta cell dysfunction is a core deficit in both type 1 and type 2 diabetes, with residual beta cell function being a key factor in achieving optimal glycemic control 6

Common Pitfalls and Caveats

• C-peptide levels may be misleading if measured during or shortly after a hyperglycemic emergency (wait at least 2 weeks) 1, 2
• In type 2 diabetes, insulin resistance is a major confounder that limits the utility of C-peptide measurement 7
• Standardization issues between different laboratories may affect the comparability of C-peptide measurements 7
• Low C-peptide in a patient initially diagnosed with type 2 diabetes may indicate misdiagnosis and the need to reclassify as type 1 diabetes 5
• High uncorrected fasting C-peptide in the presence of hyperglycemia may suggest insulin resistance rather than good beta cell function 5