What is the diagnosis for a patient with elevated c-peptide (connecting peptide) levels and normal Hemoglobin A1C (HbA1C)?

Elevated C-Peptide with Normal A1C: Diagnostic Considerations

The most likely diagnosis in a patient with elevated C-peptide and normal A1C is insulinoma or insulin autoimmune syndrome (Hirata disease), though the specific clinical context—particularly whether hypoglycemia is present—is critical for distinguishing between these and other conditions.

Key Diagnostic Framework

The interpretation of elevated C-peptide with normal A1C requires understanding what each marker represents:

• C-peptide reflects endogenous insulin secretion and is produced in equimolar amounts with insulin 1
• A1C reflects average glucose levels over 2-3 months and serves as a marker of chronic glycemic control 2

Primary Diagnostic Considerations

If Hypoglycemia is Present

Insulinoma is the most critical diagnosis to consider when elevated C-peptide occurs with hypoglycemia 3:

• During hypoglycemia (plasma glucose ≤2.8 mmol/L), C-peptide ≥0.20 nmol/L confirms inappropriate insulin secretion 3
• Normal subjects suppress C-peptide to ≤0.10 nmol/L during hypoglycemia 3
• A1C remains normal because episodic hypoglycemia doesn't elevate average glucose sufficiently 2
• Diagnosis requires demonstrating Whipple's triad with concomitant elevated C-peptide during a supervised prolonged fast 3

Insulin Autoimmune Syndrome (Hirata Disease) presents similarly 4:

• Insulin-binding antibodies prolong insulin half-life causing hyperinsulinemic hypoglycemia 4
• C-peptide immunoassays may show artifactually elevated results due to cross-reactivity with proinsulin and des 31,32 proinsulin in immunocomplexes 4
• Polyethylene glycol precipitation can help identify antibody-bound C-peptide 4

If No Hypoglycemia is Present

Insulin resistance states (obesity, metabolic syndrome, early type 2 diabetes) show elevated C-peptide with normal or near-normal A1C 2:

• Compensatory hyperinsulinemia maintains euglycemia initially 2
• A1C of 5.7-6.4% indicates prediabetes, not frank diabetes 5
• These patients have intact beta cell function responding to insulin resistance 1

Early type 2 diabetes in the honeymoon phase may present this way 2:

• Beta cells are still producing adequate insulin (elevated C-peptide) 1
• Glycemic control hasn't deteriorated enough to elevate A1C above 6.5% 2
• This represents a transitional state before progressive beta cell failure 1

Important Caveats and Pitfalls

A1C Limitations to Consider

Several conditions can cause discordance between A1C and actual glycemic status 2:

• Hemoglobinopathies (sickle cell trait, thalassemia) interfere with A1C measurement 2
• Altered red cell turnover (hemolytic anemia, iron deficiency, recent blood loss, erythropoietin therapy) makes A1C unreliable 2
• Pregnancy (second and third trimesters) affects A1C accuracy 2
• In these situations, glucose-based criteria must be used exclusively 2

C-Peptide Interpretation Nuances

C-peptide levels vary significantly by clinical context 1:

• C-peptide <0.2 nmol/L typically indicates type 1 diabetes with beta cell failure 1
• Higher C-peptide levels are associated with type 2 diabetes and preserved beta cell function 1
• Assay interference from proinsulin can occur, particularly in insulin autoimmune syndrome 4

Recommended Diagnostic Approach

Step 1: Determine if hypoglycemia is present clinically or biochemically 3

Step 2: If hypoglycemia exists:

• Perform supervised prolonged fast (up to 72 hours) 3
• Measure simultaneous glucose, insulin, C-peptide, and screen for sulfonylureas 3
• C-peptide ≥0.20 nmol/L with glucose ≤2.8 mmol/L confirms endogenous hyperinsulinism 3
• Check for insulin antibodies to exclude insulin autoimmune syndrome 4

Step 3: If no hypoglycemia:

• Assess for insulin resistance (BMI, waist circumference, lipid profile, blood pressure) 2, 5
• Perform fasting glucose and/or oral glucose tolerance test to confirm prediabetes or early diabetes 2
• Consider that A1C may be falsely normal due to hemoglobinopathy or altered red cell turnover 2

Step 4: Verify A1C reliability:

• Check complete blood count to assess for anemia 2
• Consider hemoglobin electrophoresis if ethnicity suggests hemoglobinopathy risk 2
• Use glucose-based diagnostic criteria if A1C reliability is questionable 2

Clinical Significance

The combination of elevated C-peptide with normal A1C represents either:

1. Pathologic insulin hypersecretion (insulinoma, insulin autoimmune syndrome) requiring urgent evaluation if hypoglycemia is present 3, 4
2. Compensated insulin resistance (prediabetes, early type 2 diabetes) requiring lifestyle intervention and possibly metformin 5
3. Measurement discordance due to A1C assay limitations requiring alternative glucose testing 2

The presence or absence of hypoglycemia is the critical branch point that determines the urgency and direction of further evaluation 3.