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

Elevated C-peptide: Clinical Significance and Interpretation

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

What is C-peptide?

C-peptide (connecting peptide) is a polypeptide produced during the cleavage of proinsulin into insulin in pancreatic beta cells. It is:

• Secreted in equimolar amounts with insulin into the portal circulation
• Minimally extracted by the liver (unlike insulin)
• Primarily eliminated by the kidneys
• More stable in circulation than insulin, making it a reliable marker of endogenous insulin secretion 2

Clinical Significance of Elevated C-peptide

Elevated C-peptide levels can indicate several conditions:

1. Insulin Resistance:

   • Common in type 2 diabetes, especially early stages
   • High uncorrected fasting C-peptide in the presence of hyperglycemia suggests insulin resistance 3
   • Often seen in obesity, metabolic syndrome, and polycystic ovary syndrome

2. Insulinoma or Endogenous Hyperinsulinism:

   • In patients with hypoglycemia, elevated C-peptide (≥0.20 nmol/L) with glucose ≤2.8 mmol/L strongly suggests insulinoma 4
   • 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 5

3. Type 2 Diabetes (Early Stage):

   • Beta cells initially overproduce insulin to compensate for insulin resistance
   • C-peptide values >1.8 ng/mL (>600 pmol/L) typically indicate a type 2 diabetes pattern 1

4. Renal Impairment:

   • C-peptide is primarily cleared by the kidneys, so renal failure can lead to elevated levels

Diagnostic Value in Diabetes Classification

C-peptide measurement helps distinguish between diabetes types:

• Type 1 vs Type 2 Diabetes:

  • C-peptide <0.6 ng/mL (<200 pmol/L): Type 1 diabetes pattern
  • C-peptide 0.6-1.8 ng/mL (200-600 pmol/L): Indeterminate status
  • C-peptide >1.8 ng/mL (>600 pmol/L): Type 2 diabetes pattern 1

• Identifying LADA (Latent Autoimmune Diabetes in Adults):

  • Patients have lower C-peptide levels than typical type 2 diabetes
  • Represents approximately 5-10% of adults initially diagnosed with type 2 diabetes 1

Clinical Applications

1. Differentiating between endogenous and exogenous hyperinsulinism:

   • Elevated C-peptide with hypoglycemia suggests endogenous insulin production (insulinoma)
   • Low C-peptide with elevated insulin suggests exogenous insulin administration 1, 2

2. Ambiguous diabetes cases:

   • Particularly useful in individuals who have a type 2 phenotype but present with ketoacidosis 5
   • Helps identify MODY (Maturity Onset Diabetes of the Young) where C-peptide persistence is common 3

3. Treatment guidance:

   • Higher C-peptide levels (>1.9 ng/mL) suggest potential effectiveness of non-insulin therapies
   • Low levels suggest need for insulin therapy 1

Important Caveats

• Proton pump inhibitor use: Can cause spuriously elevated chromogranin A levels (often measured alongside C-peptide in suspected insulinoma) 5
• Timing of measurement: For accurate assessment, C-peptide should be measured when fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L) 5
• Not recommended for routine screening: C-peptide testing is not recommended for routine screening for diabetes or cardiovascular disease risk 5
• Renal function: Interpret with caution in patients with renal impairment as C-peptide clearance may be reduced

When to Measure C-peptide

C-peptide measurement is most valuable in:

• Differentiating diabetes types in ambiguous cases
• Evaluating hypoglycemia to determine if it's due to endogenous insulin production
• Assessing residual beta cell function in patients with established diabetes
• Determining the need for insulin therapy in patients already on insulin

C-peptide testing is not recommended for routine screening or assessment of insulin resistance in the general population or in conditions like polycystic ovary syndrome 5.