What is the role of C-peptide (Connecting peptide) levels in diabetes management?

Role of C-peptide Levels in Diabetes Management

C-peptide testing is primarily valuable for differentiating between diabetes types, assessing residual beta cell function, and guiding appropriate treatment selection, but is not recommended for routine screening or monitoring in most diabetes cases. 1

Clinical Utility of C-peptide Testing

Diagnostic Applications

• C-peptide is secreted in equimolar amounts to insulin but reflects endogenous insulin secretion more accurately as it is not extracted by the liver 2
• Interpretation of C-peptide levels 1:
  • <0.6 ng/mL (<200 pmol/L): Type 1 diabetes pattern
  • 0.6-1.8 ng/mL (200-600 pmol/L): Indeterminate status

  • 1.8 ng/mL (>600 pmol/L): Type 2 diabetes pattern

Indications for C-peptide Testing

• Only indicated in people already receiving insulin treatment 1
• Particularly useful in:
  • Differentiating between type 1 and type 2 diabetes in ambiguous cases 1
  • Evaluating patients with suspected monogenic diabetes (MODY) 3
  • Assessing insulin secretory capacity in long-standing diabetes 3
  • Investigating hypoglycemia with suspected insulinoma (elevated C-peptide) 1
  • Evaluating checkpoint inhibitor-associated diabetes (low C-peptide <0.4 nmol/L) 1

Best Practices for C-peptide Testing

Testing Methodology

• Random C-peptide sample (with concurrent glucose) within 5 hours of eating can replace formal stimulation tests 1
• For accurate assessment, C-peptide should be measured when fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L) 1
• Glucagon stimulation test provides good balance between sensitivity and practicality 4

Important Considerations

• Do not perform testing within 2 weeks of a hyperglycemic emergency (results may be misleading) 1
• In overweight adolescents, C-peptide measurement may help differentiate type 1 from type 2 diabetes 5
• Postprandial C-peptide to glucose ratio may better reflect maximum beta cell secretory capacity compared to fasting measurements 2

Clinical Applications in Different Diabetes Types

Type 1 Diabetes

• Very low C-peptide levels (<0.24 ng/mL or <80 pmol/L) indicate severe insulin deficiency 1
• C-peptide level may predict clinical partial remission during the first year of type 1 diabetes 6
• Absent C-peptide confirms absolute insulin requirement regardless of apparent etiology 3

Type 2 Diabetes

• Higher C-peptide levels (>1.8 ng/mL) suggest preserved beta cell function 1
• Residual beta cell function is key for achieving optimal glycemic control 2
• Initial therapy for patients with C-peptide level of 1.9 ng/mL can focus on non-insulin approaches 1

Latent Autoimmune Diabetes in Adults (LADA)

• Clinically similar to type 2 diabetes but with positive pancreatic autoantibodies and lower C-peptide levels 6
• C-peptide levels decrease over time similar to type 1 diabetes 6
• Early insulin therapy recommended to preserve beta cell function 1

Common Pitfalls and Limitations

• C-peptide interpretation can be challenging in the indeterminate range (0.6-1.8 ng/mL) 1
• Not recommended for routine screening for diabetes or cardiovascular disease risk 1
• Not recommended for routine assessment of insulin resistance in general population 1
• Results may be affected by kidney function (as C-peptide is primarily cleared by kidneys) 7
• High uncorrected fasting C-peptide with hyperglycemia may suggest insulin resistance rather than healthy beta cell function 6

Practical Recommendations

• Use C-peptide testing after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests Type 2 or monogenic diabetes 3
• For patients with low C-peptide levels (<0.6 ng/mL), intensive insulin therapy and vigilant monitoring for complications are essential 1
• For patients with preserved C-peptide (>1.8 ng/mL), non-insulin therapies including lifestyle modifications, oral agents, and newer medications like GLP-1 receptor agonists may be appropriate 1
• Consider periodic reassessment of C-peptide levels to track disease progression in cases where diabetes classification remains uncertain 1