What does an elevated C-peptide (connecting peptide) level indicate?

Elevated C-peptide: Clinical Significance and Diagnostic Implications

Elevated C-peptide levels indicate excessive endogenous insulin production, which can be seen in insulin resistance, insulinomas, or early type 2 diabetes. 1, 2, 3

What is C-peptide?

• C-peptide (connecting peptide) is produced in equimolar amounts to insulin during the cleavage of proinsulin in pancreatic β-cells
• Unlike insulin, C-peptide is not extracted by the liver, making it a more reliable marker of endogenous insulin secretion
• C-peptide has a longer half-life than insulin, providing a more stable measurement of β-cell function 3, 4

Clinical Significance of Elevated C-peptide

Common causes of elevated C-peptide:

1. Insulin Resistance

   • High uncorrected fasting C-peptide in the presence of hyperglycemia suggests insulin resistance 3
   • Seen in:
     • Type 2 diabetes (especially early stages)
     • Obesity
     • Metabolic syndrome
     • Polycystic ovary syndrome

2. Insulinoma

   • Elevated C-peptide levels with hypoglycemia strongly suggest insulinoma
   • An insulin level >3 mcIU/mL (usually >6 mcIU/mL) when blood glucose is <40-45 mg/dL, with an insulin-to-glucose ratio ≥0.3 indicates inappropriate insulin secretion 1
   • Patients with insulinoma have elevated C-peptide levels during hypoglycemic episodes, confirming endogenous hyperinsulinism

3. Renal Impairment

   • C-peptide is primarily cleared by the kidneys
   • Reduced renal clearance in kidney disease can lead to elevated C-peptide levels without necessarily indicating increased insulin production

4. Early Type 2 Diabetes

   • In early stages, pancreatic β-cells hypersecrete insulin to compensate for insulin resistance
   • This results in elevated C-peptide levels before eventual β-cell failure 5

Diagnostic Value in Different Types of Diabetes

Type 1 vs. Type 2 Diabetes

• C-peptide helps differentiate between diabetes types:
  • Type 1 diabetes: Low or undetectable C-peptide (<0.6 ng/mL or <200 pmol/L) 2
  • Type 2 diabetes: Normal or elevated C-peptide (>1.8 ng/mL or >600 pmol/L) 2, 3

LADA (Latent Autoimmune Diabetes in Adults)

• LADA patients typically have lower C-peptide levels than type 2 diabetes patients
• C-peptide levels in LADA decrease over time, similar to type 1 diabetes 2, 3

MODY (Maturity Onset Diabetes of the Young)

• Persistence of C-peptide is an important clinical feature of MODY
• Helps identify patients who may be misdiagnosed as type 1 diabetes and unnecessarily treated with insulin 3

Clinical Applications of C-peptide Measurement

1. Differential Diagnosis

   • Distinguishing between type 1 and type 2 diabetes
   • Identifying LADA and MODY
   • Diagnosing insulinoma (elevated C-peptide with hypoglycemia) 1, 3

2. Treatment Guidance

   • Predicting insulin requirement
   • Guiding appropriate therapy selection
   • Monitoring β-cell function over time 2, 4

3. Monitoring Disease Progression

   • Tracking β-cell function decline in diabetes
   • Assessing partial remission in type 1 diabetes 3, 6

4. Evaluating Suspected Factitious Hypoglycemia

   • Low C-peptide with elevated insulin suggests exogenous insulin administration
   • Normal/high C-peptide with hypoglycemia suggests endogenous hyperinsulinism or sulfonylurea use 1

Interpretation Pitfalls and Considerations

• C-peptide should be interpreted in the context of concurrent glucose levels
• Postprandial C-peptide to glucose ratio may better reflect maximum β-cell secretory capacity than fasting measurements 5
• Renal function must be considered when interpreting C-peptide levels
• Medications (especially insulin secretagogues) can affect C-peptide levels

When to Consider Further Evaluation for Elevated C-peptide

• Persistent hyperglycemia with elevated C-peptide: Consider insulin resistance and type 2 diabetes
• Hypoglycemia with elevated C-peptide: Evaluate for insulinoma or other causes of endogenous hyperinsulinism 1
• Elevated C-peptide without diabetes: Consider early insulin resistance, renal impairment, or other causes

In summary, elevated C-peptide indicates increased endogenous insulin production, most commonly due to insulin resistance, insulinoma, or early type 2 diabetes. The clinical context and concurrent glucose levels are essential for proper interpretation and management decisions.