Insulin to C-Peptide Molar Ratio in Peripheral Blood
Normal Physiological Ratio
In peripheral venous blood, the normal molar ratio of C-peptide to insulin is approximately 5:1 to 7:1, meaning insulin to C-peptide is approximately 1:5 to 1:7 (or 0.14 to 0.20). 1, 2
Physiological Basis
Insulin and C-peptide are secreted from pancreatic beta cells in equimolar (1:1) concentrations into the portal circulation. 1, 2
The peripheral ratio differs dramatically from the portal ratio because the liver extracts 50-80% of insulin during first-pass metabolism, while C-peptide passes through the liver with essentially no hepatic extraction. 3, 4
C-peptide has a longer plasma half-life and lower metabolic clearance rate than insulin, being cleared primarily by the kidneys rather than the liver. 3, 4
The fasting molar ratio of C-peptide to insulin is approximately 7:1, which decreases to approximately 5:1 during glucose-stimulated conditions due to the relative increase in insulin secretion. 1
Clinical Application: Detecting Exogenous Insulin
An insulin-to-C-peptide molar ratio greater than 1.0 in a hypoglycemic patient strongly indicates surreptitious or inadvertent exogenous insulin administration rather than endogenous hyperinsulinism (such as insulinoma). 3
This diagnostic principle works because exogenous insulin enters the systemic circulation directly, bypassing hepatic extraction, while suppressing endogenous C-peptide production through negative feedback. 3
In contrast, insulinoma produces both insulin and C-peptide in equimolar amounts, so after hepatic extraction the peripheral ratio remains less than 1.0 (i.e., C-peptide exceeds insulin). 3
Important Clinical Caveats
The marked difference in plasma half-lives between insulin (3-5 minutes) and C-peptide (30-35 minutes) complicates interpretation of their ratio during dynamic conditions or rapid changes in secretion. 4
Portal vein insulin and C-peptide levels do not reliably correlate with simultaneously drawn peripheral samples after acute stimulation, though significant correlation exists at steady state. 2
Using the peripheral C-peptide-to-insulin ratio as a precise reflection of hepatic insulin extraction has not been experimentally validated and should be interpreted cautiously. 4