What is the purpose of C‑peptide in evaluating endogenous insulin production and pancreatic β‑cell function?

Purpose of C-Peptide Measurement

C-peptide serves as a direct biomarker of endogenous insulin production and pancreatic β-cell function because it is secreted in equimolar amounts to insulin but, unlike insulin, is not extracted by the liver, making it a more accurate reflection of β-cell secretory capacity. 1

Primary Clinical Applications

Diabetes Classification in Ambiguous Cases

• C-peptide measurement is most valuable when differentiating type 1 from type 2 diabetes in clinically ambiguous presentations, such as patients with a type 2 phenotype who present in ketoacidosis. 1
• C-peptide testing should only be performed in people receiving insulin treatment. 1
• A random C-peptide sample (with concurrent glucose) within 5 hours of eating can replace formal stimulation testing for classification purposes. 1

Interpretation Thresholds for Diabetes Classification

• C-peptide >600 pmol/L (>1.8 ng/mL) indicates preserved β-cell function, regardless of testing circumstances. 1
• C-peptide 200-600 pmol/L (0.6-1.8 ng/mL) is usually consistent with type 1 diabetes or MODY, but may occur in insulin-treated type 2 diabetes, particularly in patients with normal/low BMI or long disease duration. 1
• Very low levels (<80 pmol/L [<0.24 ng/mL]) indicate severe insulin deficiency and do not require repeat testing. 1
• If C-peptide is <600 pmol/L and concurrent glucose is <4 mmol/L (<70 mg/dL) or the person may have been fasting, repeat testing should be considered. 1

Critical Testing Considerations

• C-peptide must be measured prior to insulin discontinuation in insulin-treated patients to exclude severe insulin deficiency. 1
• Do not test C-peptide within 2 weeks of a hyperglycemic emergency. 1
• For insurance coverage of insulin pump therapy, measure fasting C-peptide when simultaneous fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L). 1

Investigation of Hypoglycemia

• C-peptide measurement is essential in investigating nondiabetic hypoglycemia to rule out surreptitious insulin administration. 1
• In islet cell tumor diagnosis, inappropriately elevated plasma insulin and C-peptide concentrations persist despite low glucose levels. 1
• An increased proinsulin-to-insulin ratio in the setting of hypoglycemia strongly suggests an islet cell tumor. 1

When NOT to Measure C-Peptide

• Routine C-peptide or insulin testing is not recommended in most people with diabetes, those at risk for diabetes, or those with cardiovascular disease, as these assays are primarily useful for research purposes. 1
• C-peptide measurement offers no advantage over clinical assessment (BMI, acanthosis nigricans) for evaluating insulin resistance in polycystic ovary syndrome and is not recommended. 1

Clinical Utility Beyond Classification

• C-peptide levels correlate with β-cell function and can predict clinical benefits including glycemic control and protection from severe hypoglycemia. 2
• C-peptide serves as a validated surrogate endpoint in clinical trials of disease-modifying therapies for type 1 diabetes. 2
• Postprandial C-peptide-to-glucose ratio may better reflect maximum β-cell secretory capacity compared with fasting measurements. 3

Common Pitfalls

• Clinical presentation and response to therapy usually provide sufficient information for diabetes classification; C-peptide measurement may not be clinically necessary even when differentiation is difficult. 1
• Misdiagnosis occurs in 40% of adults with new type 1 diabetes, often misclassified as type 2 diabetes, highlighting the importance of proper C-peptide interpretation when used. 1
• C-peptide levels can be confounded by insulin resistance in type 2 diabetes, limiting its utility in this population. 4