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

Elevated C-Peptide: Clinical Significance

An elevated C-peptide level indicates preserved or excessive endogenous insulin production, most commonly reflecting insulin resistance (as seen in type 2 diabetes and metabolic syndrome), but can also suggest insulinoma or factitious hypoglycemia from sulfonylurea use.

Primary Clinical Interpretations

Type 2 Diabetes and Insulin Resistance

• C-peptide values >600 pmol/L strongly suggest type 2 diabetes rather than type 1 diabetes 1
• Elevated fasting C-peptide in the presence of hyperglycemia indicates insulin resistance, where the pancreas overproduces insulin to compensate for decreased tissue sensitivity 2
• In non-obese Asian Indian patients with type 2 diabetes, higher fasting C-peptide levels correlate independently with intra-abdominal adipose tissue volume and liver span 3

Metabolic Syndrome and Cardiovascular Risk

• Elevated C-peptide serves as a clinically important marker of cardiovascular risk in metabolic syndrome 4
• Higher C-peptide levels correlate significantly with:
  • Elevated triglycerides (r=0.474, p=0.009) 4
  • Lower HDL-cholesterol (inverse correlation, r=-0.567, p=0.001) 4
  • Increased atherogenic index (r=0.599, p=0.0006) 4
  • Higher body mass index (r=0.519, p=0.004) 4
  • Elevated leptin levels (r=0.492, p=0.007) 4

Insulinoma

• Patients with insulinoma demonstrate elevated C-peptide levels during hypoglycemic episodes 5
• Diagnostic criteria include insulin level >3 mcIU/mL (usually >6 mcIU/mL) when blood glucose is <40-45 mg/dL, with insulin-to-glucose ratio ≥0.3, accompanied by elevated C-peptide 5
• Testing for urinary sulfonylurea is essential to exclude factitious hypoglycemia 5

Differential Diagnosis Algorithm

When C-peptide is >600 pmol/L:

1. First, assess for type 2 diabetes - check fasting glucose, HbA1c, and clinical phenotype 1
2. Evaluate for metabolic syndrome - measure lipid profile, blood pressure, waist circumference 4
3. If hypoglycemia is present, consider insulinoma and check urinary sulfonylurea 5

When C-peptide is 200-600 pmol/L:

• This intermediate range may indicate type 1 diabetes, MODY, or insulin-treated type 2 diabetes 1
• Further testing with islet autoantibodies or genetic testing may be needed 1

Important Clinical Caveats

Testing Considerations

• Do not measure C-peptide within 2 weeks of a hyperglycemic emergency, as results will be unreliable 1
• A random C-peptide sample within 5 hours of eating can replace formal stimulation testing for diabetes classification 1
• If concurrent glucose is <70 mg/dL when C-peptide is measured, consider repeating the test 1

Cancer Prognosis Context

• Patients with colorectal cancer in the highest quartile of C-peptide at diagnosis have higher risk of overall death compared to those with lower levels, suggesting that elevated C-peptide (reflecting hyperinsulinemia) may negatively impact cancer outcomes 5

Preserved Beta Cell Function

• In insulin-treated patients, elevated C-peptide indicates retained endogenous insulin production and suggests they may not have absolute insulin requirement 1
• This finding may allow for treatment modification away from insulin-only regimens 1

Clinical Utility for Risk Stratification

Use elevated fasting C-peptide as an effective tool for early detection of patients at particular risk for atherosclerotic cardiovascular disease who need aggressive preventive measures 4. The combination of C-peptide with fasting glucose (CpG coefficient) strengthens correlations with lipoprotein abnormalities and cardiovascular risk 4.