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

Elevated C-Peptide: Clinical Significance and Diagnostic Implications

An elevated C-peptide level primarily indicates increased endogenous insulin production, which can be seen in insulin resistance conditions like type 2 diabetes, insulinoma, or early stages of autoimmune diabetes before significant beta cell destruction occurs. 1, 2

Understanding C-Peptide

C-peptide (connecting peptide) is produced in equimolar amounts to endogenous insulin when proinsulin is cleaved in pancreatic beta cells. Unlike insulin, which has variable hepatic clearance, C-peptide:

• Is cleared primarily by the kidneys
• Has a longer half-life than insulin
• Provides a more stable reflection of endogenous insulin secretion

Clinical Interpretation of C-Peptide Levels

Normal and Abnormal Values

• Normal range: Typically 0.6-1.8 ng/mL (200-600 pmol/L)
• Low C-peptide (<0.6 ng/mL): Indicates type 1 diabetes pattern with minimal beta cell function
• Elevated C-peptide (>1.8 ng/mL): Indicates preserved or increased beta cell function 2

Common Causes of Elevated C-Peptide

1. Insulin Resistance Conditions:

   • Type 2 diabetes (most common)
   • Obesity
   • Metabolic syndrome
   • Polycystic ovary syndrome

2. Insulinoma:

   • Characterized by inappropriate insulin and C-peptide secretion during hypoglycemia
   • C-peptide ≥0.20 nmol/L during hypoglycemia (glucose ≤2.8 mmol/L) strongly suggests insulinoma 3, 1

3. Early Stages of Autoimmune Diabetes:

   • Before significant beta cell destruction occurs
   • May have transiently normal or elevated C-peptide

4. Renal Impairment:

   • Reduced clearance of C-peptide can lead to elevated levels

Diagnostic Value in Specific Conditions

Differentiating Diabetes Types

• Helps distinguish between type 1 and type 2 diabetes in ambiguous cases 1
• Particularly useful in:
  • Adults presenting with ketoacidosis
  • Patients with atypical presentations
  • Determining if residual beta cell function exists

Insulinoma Diagnosis

• Elevated C-peptide during hypoglycemia is diagnostic
• Patients with insulinoma have C-peptide values ≥0.20 nmol/L when glucose is ≤2.8 mmol/L 3, 1
• Testing for urinary sulfonylurea helps rule out factitious hypoglycemia 1

Factitious Hypoglycemia

• In surreptitious insulin administration, C-peptide levels are suppressed while insulin levels are elevated
• Helps distinguish from insulinoma, where both insulin and C-peptide are elevated 1, 3

Clinical Pitfalls and Considerations

1. Assay Variability:

   • Different laboratories may use different assays with varying reference ranges
   • Important to interpret results in context of the specific laboratory's reference range

2. Renal Function:

   • C-peptide is primarily cleared by the kidneys
   • Levels may be falsely elevated in patients with renal impairment

3. Timing of Measurement:

   • Fasting vs. stimulated (post-meal or after glucagon) values provide different information
   • Stimulated values may be more informative in some clinical scenarios

4. Diabetes Duration:

   • C-peptide levels decline over time in type 1 diabetes
   • May remain elevated in long-standing type 2 diabetes with significant insulin resistance

Prognostic Implications

• Elevated C-peptide in non-diabetic individuals may predict future development of type 2 diabetes 4
• In established diabetes, C-peptide levels may help predict:
  • Response to specific therapies
  • Risk of complications
  • Need for insulin therapy

By understanding the clinical significance of elevated C-peptide levels, clinicians can better diagnose and manage conditions associated with abnormal insulin secretion and resistance.