What does an elevated C-peptide (Connecting Peptide) level with a normal insulin level indicate?

Interpreting Elevated C-peptide with Normal Insulin Level

Elevated C-peptide with normal insulin levels most likely indicates insulin resistance with compensatory insulin production, typically seen in early type 2 diabetes or insulin resistance syndromes. 1

Understanding C-peptide and Insulin Relationship

C-peptide is produced in equimolar amounts to insulin when proinsulin is cleaved in pancreatic beta cells. Unlike insulin, C-peptide:

• Is not extracted by the liver to any significant degree 2
• Has a longer half-life in circulation
• Provides a more stable measure of endogenous insulin production

Clinical Interpretation of Elevated C-peptide with Normal Insulin

Most Common Causes:

1. Early Type 2 Diabetes/Insulin Resistance

   • In type 2 diabetes, insulin secretion is initially increased to compensate for insulin resistance 3
   • C-peptide levels >600 pmol/L (>1.8 ng/mL) strongly suggest type 2 diabetes 1
   • Normal insulin with elevated C-peptide occurs because insulin has a shorter half-life and higher hepatic extraction

2. Hepatic Insulin Extraction Variation

   • The liver may be extracting insulin at a higher rate while C-peptide passes through unchanged 2
   • This creates a discrepancy between peripheral insulin and C-peptide levels

3. Obesity

   • Positive correlation exists between body weight/BMI and urinary C-peptide excretion 4
   • Obesity itself causes insulin resistance requiring increased insulin production 3

Less Common Causes:

• Monogenic Diabetes (MODY)

  • Some forms of MODY (particularly glucokinase mutations) can present with elevated C-peptide 3, 1
  • Genetic testing may be warranted in appropriate clinical contexts

• Early Recovery from Diabetic Ketoacidosis

  • Beta cell function may temporarily recover after resolution of glucotoxicity

Diagnostic Algorithm

1. Assess clinical context:

   • BMI (obesity strongly suggests insulin resistance)
   • Family history of diabetes
   • Age of onset (younger age may suggest monogenic diabetes)
   • Presence of acanthosis nigricans or other signs of insulin resistance

2. Additional testing to consider:

   • Fasting glucose and HbA1c to assess glycemic control
   • Oral glucose tolerance test with simultaneous insulin and C-peptide measurements
   • If diagnosis remains unclear, consider genetic testing for monogenic diabetes 1

3. Interpretation framework:

   • C-peptide <200 pmol/L (<0.6 ng/mL): Suggests type 1 diabetes 1
   • C-peptide 200-600 pmol/L (0.6-1.8 ng/mL): Indeterminate, may require additional testing 1
   • C-peptide >600 pmol/L (>1.8 ng/mL): Strongly suggests type 2 diabetes or insulin resistance 1

Clinical Implications and Management

• Insulin resistance: Consider lifestyle modifications and insulin-sensitizing medications
• Early type 2 diabetes: Implement appropriate diet, exercise, and possibly metformin
• Monogenic diabetes: May require specific treatment approaches based on genetic subtype

Important Caveats

• C-peptide measurement should not be performed within 2 weeks after a hyperglycemic emergency 1
• Concurrent glucose levels affect interpretation (low glucose can suppress C-peptide) 1
• The American Diabetes Association does not recommend routine insulin or C-peptide testing for diabetes diagnosis but acknowledges its utility in ambiguous cases 3
• C-peptide is most useful when measured after 3-5 years from diagnosis to help classify diabetes type 5