What is C-peptide (Connecting peptide)?

What is C-peptide?

C-peptide (connecting peptide) is a protein fragment produced in equal amounts to insulin when the pancreas cleaves proinsulin into insulin and C-peptide, serving as the most reliable marker of endogenous insulin production and pancreatic beta cell function. 1, 2

Biochemistry and Physiology

• C-peptide joins insulin's alpha and beta chains in the proinsulin molecule before being cleaved off during insulin synthesis in pancreatic beta cells 3
• It is secreted in equimolar concentrations with insulin into the portal circulation, meaning one molecule of C-peptide is released for every molecule of insulin 4, 3
• Unlike insulin, C-peptide experiences minimal first-pass hepatic clearance (extraction by the liver), making it a more stable and accurate reflection of insulin production than measuring insulin itself 4, 3
• The kidney primarily removes C-peptide from circulation, with a small constant proportion excreted in urine 4
• C-peptide levels are not affected by exogenous insulin administration, which is crucial for distinguishing endogenous from exogenous insulin 3, 5

Clinical Measurement and Testing

Measurement Methods

• C-peptide can be measured in serum (blood) or urine using radioimmunoassay techniques 4
• Modern assays have made C-peptide measurement both more reliable and inexpensive 2
• A random C-peptide sample within 5 hours of eating can replace formal C-peptide stimulation tests for diabetes classification 5
• Glucagon stimulation C-peptide testing offers the best balance of sensitivity and practicality when stimulation testing is needed 1

Testing Considerations and Timing

• Do not measure C-peptide within 2 weeks of a hyperglycemic emergency, as results will be unreliable 5, 6
• For fasting C-peptide measurement (when required by insurance for insulin pump coverage), measure only when simultaneous fasting plasma glucose is ≤220 mg/dL 5
• If concurrent glucose is <4 mmol/L (<70 mg/dL) when C-peptide is measured, consider repeating the test 5
• Very low C-peptide levels (e.g., <80 pmol/L) do not need to be repeated 5
• In insulin-treated patients, C-peptide must be measured prior to insulin discontinuation to exclude severe insulin deficiency 5

Clinical Applications

Diabetes Classification and Diagnosis

• C-peptide measurement is essential for distinguishing between diabetes types when presentation is ambiguous, such as individuals with type 2 phenotype presenting with ketoacidosis 5
• The American Diabetes Association recommends measuring islet autoantibodies first in patients with ambiguous presentation, and if antibody-negative, proceed to C-peptide testing 5
• For antibody-negative patients under 35 years with suspected type 1 diabetes but no clinical features of type 2 or monogenic diabetes, C-peptide testing helps distinguish between type 1 and type 2 diabetes 5
• After at least 3 years of diabetes duration in antibody-negative patients, C-peptide testing can help confirm classification 5

Interpretation of C-peptide Values

Low C-peptide (<200 pmol/L or <0.2 nmol/L):

• Values <200 pmol/L are consistent with type 1 diabetes 5, 1
• Very low levels (<80 pmol/L or <0.24 ng/mL) strongly suggest type 1 diabetes and indicate absolute insulin deficiency, requiring insulin therapy for survival 5
• Absent C-peptide at any time confirms absolute insulin requirement and the appropriateness of type 1 diabetes management strategies regardless of apparent etiology 2

Intermediate C-peptide (200-600 pmol/L or 0.6-1.8 ng/mL):

• May indicate type 1 diabetes, MODY (maturity-onset diabetes of the young), or insulin-treated type 2 diabetes with long duration 5
• Further testing with autoantibodies or genetic testing may be needed for definitive diagnosis 5

High C-peptide (>600 pmol/L):

• Values >600 pmol/L strongly suggest type 2 diabetes rather than type 1 diabetes 5, 6
• In insulin-treated patients, elevated C-peptide indicates retained endogenous insulin production and suggests they may not have absolute insulin requirement, potentially allowing for treatment modification 5, 6
• Persistence of substantial C-peptide after 3-5 years from diagnosis suggests type 2 or monogenic diabetes 2

Hypoglycemia Investigation

• C-peptide is essential in investigating nondiabetic hypoglycemia to rule out surreptitious insulin administration 5, 7
• Patients with insulinoma demonstrate elevated C-peptide levels during hypoglycemic episodes, with diagnostic criteria including insulin level >3 mcIU/mL when blood glucose is <40-45 mg/dL, accompanied by elevated C-peptide 6
• With exogenous insulin administration, C-peptide would be low or suppressed, helping differentiate from endogenous hyperinsulinism 7

Additional Clinical Uses

• C-peptide can assist in patient selection for islet cell transplantation and post-transplant monitoring 8
• C-peptide level may be a good predictor of clinical partial remission during the first year of type 1 diabetes 8
• C-peptide levels may correlate with microvascular and macrovascular complications and future use of insulin therapy 1

Important Clinical Caveats

• The primary value of C-peptide in routine practice is to assist classification and management of insulin-treated patients, with greatest utility after 3-5 years from diagnosis 2
• Normal C-peptide levels indicate that the pancreas is producing adequate amounts of insulin, reflecting preserved pancreatic beta cell function and excluding absolute insulin deficiency states like type 1 diabetes 5
• High uncorrected fasting C-peptide in the presence of hyperglycemia may suggest insulin resistance 8
• Latent autoimmune diabetes in adults (LADA) shows positivity for pancreatic autoantibodies with lower C-peptide levels than typical type 2 diabetes, and C-peptide will decrease with time similar to classical type 1 diabetes 8