Released Insulin appears initially in the plasma as a precursor proinsulin molecule. When insulin is cleaved from proinsulin, insulin-connecting peptide (C-peptide) is released in a 1:1 ratio with insulin. Measurement of the C-peptide level will indicate whether plasma insulin is of endogenous or exogenous origin.

Thus, in patients with sulphonylurea ingestion or insulinoma, C-peptide levels should parallel plasma insulin values. The characteristic pattern in hypoglycaemia due to insulin injection is a high level of plasma insulin and a low plasma level of C-peptide, because exogenous insulin, which does not contain C-peptide, suppresses endogenous insulin release in normal persons.

Antibodies to insulin are helpful if present because they usually indicate chronic insulin injection.

Sulphonylureas also elevate the concentrations of both C-peptide and insulin in plasma. Therefore, hypoglycaemia due to oral agents can only be diagnosed by a high index of suspicion coupled with assay of the drug in plasma or urine.

Plasma proinsulin is not elevated by the administration of exogenous insulin or sulphonylureas. In contrast, patients with insulinoma tend to have high concentrations of proinsulin in plasma (>20% of total insulin).

The features of insulinoma and the two types of factitious hypoglycaemia are shown in the table.

• * Total plasma insulin in patients with insulinoma is rarely above 1435 pmol/L (200U/mL) in the basal state and is often much lower. Values greater than 7175 pmol/L (1000 U/mL) are highly suggestive of exogenous insulin injection.
• † C-peptide level may be normal in absolute terms but low in relation to the increased insulin.
• ‡ Insulin antibodies may not be present if only a few injections have been given, especially with purified insulin.