What are the typical insulin‑to‑C‑peptide molar ratios in insulinoma versus insulin‑autoimmune syndrome (Hirata disease), and how can this ratio be used to differentiate the two conditions?

Insulin-to-C-Peptide Molar Ratio in Insulinoma versus Hirata Disease

Direct Answer

In insulinoma, the insulin-to-C-peptide molar ratio is typically <1.0 (often 0.1–0.3), whereas in Hirata disease (insulin autoimmune syndrome), the ratio is usually >1.0 due to antibody interference with insulin clearance and assay measurements. 1, 2

Pathophysiology Underlying the Ratio Difference

Normal Physiology

• Insulin and C-peptide are secreted in equimolar (1:1) amounts from pancreatic beta cells during proinsulin cleavage. 1
• The liver extracts a large fraction of endogenous insulin on first pass, while C-peptide bypasses hepatic extraction and is cleared primarily by the kidneys with a longer half-life. 1
• Therefore, the peripheral venous insulin-to-C-peptide molar ratio (ICPR) should be <1.0 during both fasting and feeding states when only endogenous insulin is present. 1

Insulinoma Pattern

• Insulinomas produce endogenous insulin and C-peptide in the normal 1:1 ratio, resulting in a peripheral ICPR of <1.0 (typically 0.1–0.3) due to hepatic insulin extraction. 1, 2
• In a documented case, an 89-year-old woman with confirmed insulinoma had an insulin-to-C-peptide molar ratio of 0.14, with both insulin (21.1 µU/mL) and C-peptide (2.72 ng/mL) appropriately elevated during hypoglycemia. 2
• Both insulin and C-peptide are elevated simultaneously during hypoglycemic episodes in insulinoma. 3, 4

Hirata Disease (Insulin Autoimmune Syndrome) Pattern

• Anti-insulin antibodies bind endogenous insulin, creating a reservoir that prolongs insulin half-life, delays clearance, and causes the ICPR to exceed 1.0. 2, 5
• The antibodies interfere with insulin immunoassays, often producing falsely elevated total insulin measurements while C-peptide remains relatively normal or only modestly elevated. 5
• Free (unbound) C-peptide measurement after polyethylene glycol precipitation is the key diagnostic test to differentiate Hirata disease from insulinoma—free C-peptide will be normal or only mildly elevated in Hirata disease but significantly elevated in insulinoma. 5

Diagnostic Algorithm

Step 1: Confirm Endogenous Hyperinsulinemic Hypoglycemia

• Perform a supervised 48–72-hour fast with simultaneous measurement of glucose, insulin, C-peptide, and proinsulin when glucose drops below 55 mg/dL. 3, 4
• If both insulin and C-peptide are elevated together during documented hypoglycemia (glucose <55 mg/dL), endogenous hyperinsulinism is confirmed. 4, 6

Step 2: Calculate the Insulin-to-C-Peptide Molar Ratio

• An ICPR <1.0 strongly suggests insulinoma or other endogenous causes (sulfonylurea use). 1
• An ICPR >1.0 argues persuasively for either surreptitious exogenous insulin administration or insulin autoimmune syndrome (Hirata disease). 1

Step 3: Measure Anti-Insulin Antibodies

• If ICPR >1.0 and the patient denies exogenous insulin use, immediately measure serum anti-insulin antibodies. 2, 5
• Positive anti-insulin antibodies (>10–20 U/mL) confirm Hirata disease. 2
• HLA typing may reveal susceptibility alleles (HLA-DRB10407, HLA-DRB10406, HLA-DRB1*1405) commonly associated with Hirata disease. 2

Step 4: Measure Free C-Peptide if Antibodies Are Positive

• Perform polyethylene glycol precipitation to quantitate free (unbound) C-peptide levels. 5
• Elevated free C-peptide indicates insulinoma despite positive antibodies (rare coexistence), whereas normal free C-peptide confirms Hirata disease as the sole cause. 5

Step 5: Additional Confirmatory Tests

• An elevated proinsulin-to-insulin ratio during hypoglycemia is particularly suggestive of insulinoma. 6
• Screen urine for sulfonylureas to exclude factitious hypoglycemia from oral hypoglycemic agents. 4

Key Numerical Thresholds

Insulinoma

• Insulin-to-C-peptide molar ratio: 0.1–0.3 (always <1.0) 1, 2
• Both insulin and C-peptide are elevated during hypoglycemia 3
• Proinsulin-to-insulin ratio is often elevated 6

Hirata Disease

• Insulin-to-C-peptide molar ratio: >1.0 1
• Total insulin is markedly elevated (often >100 µU/mL) 5
• Free C-peptide (after precipitation) is normal or only mildly elevated 5
• Anti-insulin antibodies are positive (>10–20 U/mL) 2, 5

Critical Pitfalls to Avoid

• Do not rely solely on total insulin and C-peptide measurements in patients with suspected Hirata disease—antibody interference renders these assays unreliable. 5
• Always measure anti-insulin antibodies when the ICPR is >1.0 and exogenous insulin use is denied. 2, 5
• In rare cases, insulinoma can coexist with anti-insulin antibodies; free C-peptide measurement is essential to identify this scenario. 2, 5
• The presence of a monoclonal protein (as in the case report with IgG κ M-protein) can further interfere with immunoassays, making free C-peptide measurement even more critical. 5
• Do not perform C-peptide testing within 2 weeks of a hyperglycemic emergency, as results will be unreliable. 7