What is the treatment approach for a patient with elevated C-peptide (Connecting Peptide) and insulin levels?

Elevated C-Peptide and Insulin: Diagnostic Approach and Management

When both C-peptide and insulin are elevated together in the presence of hyperglycemia, this indicates endogenous insulin hypersecretion with insulin resistance, most commonly seen in type 2 diabetes or insulin resistance syndromes. 1, 2

Immediate Diagnostic Considerations

The key is determining whether hypoglycemia or hyperglycemia is present:

• If hyperglycemia is present with elevated C-peptide and insulin: This indicates type 2 diabetes with insulin resistance and compensatory hyperinsulinemia 1, 2
• If hypoglycemia is present with elevated C-peptide and insulin: This suggests endogenous hyperinsulinism (insulinoma, nesidioblastosis, or post-bariatric hypoglycemia) 3, 4

The fasting C-peptide/glucose ratio (CGR) is a practical tool to assess insulin secretory capacity and guide treatment decisions 2. A high CGR indicates insulin hypersecretion, while a low CGR (<0.2 nmol/L) suggests insulin deficiency consistent with type 1 diabetes 5, 6.

Management Based on Clinical Context

For Hyperglycemia with Elevated C-Peptide/Insulin (Type 2 Diabetes Pattern)

This represents insulin resistance with compensatory hyperinsulinemia requiring insulin-sensitizing therapy, not additional insulin:

• First-line therapy: Metformin up to 2000 mg daily (1000 mg twice daily) combined with comprehensive lifestyle modification 3

• Second-line additions based on comorbidities:

  • If cardiovascular disease, heart failure, or chronic kidney disease is present: Add GLP-1 receptor agonist (liraglutide 1.8 mg daily preferred) or SGLT2 inhibitor (empagliflozin 10 mg daily) 3
  • These agents address cardiovascular risk associated with hyperinsulinemia and provide A1C reduction of 1.0-1.5% 7, 3

• Avoid sulfonylureas or exogenous insulin initially as these worsen hyperinsulinemia and promote weight gain in insulin-resistant patients 3, 2

For Hypoglycemia with Elevated C-Peptide/Insulin (Endogenous Hyperinsulinism)

This requires differentiation between insulinoma and post-prandial hypoglycemia:

• Timing is critical: Late dumping syndrome occurs 1-3 hours postprandially, while insulinoma causes fasting hypoglycemia 3

• Diagnostic approach:

  • If fasting hypoglycemia: Consider 48-72 hour supervised fast to assess for inappropriately elevated insulin/C-peptide during hypoglycemia 3
  • Measure sulfonylurea levels to exclude surreptitious use 3
  • Key distinction: Exogenous insulin injection causes hyperinsulinemic hypoglycemia with inappropriately LOW C-peptide, while endogenous causes show elevated C-peptide 3

• Management of post-bariatric/post-gastric surgery hypoglycemia:

  • Dietary modification: Small frequent meals, eliminate rapidly absorbable carbohydrates, delay fluid intake 30 minutes after meals, high-fiber and protein-rich foods 3
  • Pharmacologic: Acarbose for late dumping symptoms 3
  • Somatostatin analogs for both early and late dumping if dietary measures fail 3

Critical Pitfalls to Avoid

• Do not assume all elevated C-peptide requires insulin therapy - this is only true when C-peptide is LOW (<0.2 nmol/L) indicating beta-cell failure 5, 6
• Do not measure C-peptide within 2 weeks of a hyperglycemic emergency as results will be unreliable 3
• Do not test C-peptide in patients not receiving insulin treatment unless specifically evaluating for endogenous hyperinsulinism 3
• In insulin-treated patients, C-peptide must be measured BEFORE insulin discontinuation to exclude severe insulin deficiency 3

Monitoring and Reassessment

• For type 2 diabetes with high CGR: Reassess medication regimen every 3-6 months, targeting insulin-sensitizing therapies rather than insulin secretagogues 3, 2
• For suspected endogenous hyperinsulinism: Refer to endocrinology for specialized testing including supervised fasting studies and imaging 3
• C-peptide levels correlate with microvascular and macrovascular complications and can predict future insulin requirements 5, 6