Clinical Information

Proinsulin is the precursor of insulin and C-peptide (connecting peptide). Following synthesis, proinsulin is packaged into secretory granules, where it is processed to C-peptide and insulin by prohormone convertases (PC1/3 and PC2) and carboxypeptidase E. Only 1% to 3% of proinsulin is secreted intact. However, because proinsulin has a longer half-life than insulin, circulating proinsulin concentrations are in the range of 5% to 30% of circulating insulin concentrations on a molar basis, with the higher relative proportions seen after meals and in patients with insulin resistance or early type 2 diabetes. Proinsulin can bind to the insulin receptor and exhibits 5% to 10% of the metabolic activity of insulin.

Proinsulin levels might be elevated in patients with insulin-producing islet cell tumors (insulinomas). These patients suffer from hypoglycemic attacks due to inappropriate secretion of insulin by the tumors. The biochemical diagnosis rests primarily on demonstrating nonsuppressed insulin levels in the presence of hypoglycemia (blood glucose <45 mg/dL). The diagnosis can be difficult, as tumors might be small or secrete insulin only episodically. Insulin injections or hypoglycemic drugs can also mimic insulinoma. Evaluation of these patients frequently requires a prolonged fast (72 hours) as well as supplementary tests in addition to insulin and glucose measurements, including a sulfonylurea screen and measurement of C-peptide, proinsulin, and beta-hydroxybutyrate. The inappropriate oversecretion of insulin by insulinomas causes the release of an increased numbers of secretory granules with incompletely processed insulin, resulting in elevated serum/plasma proinsulin concentrations. This oversecretion of proinsulin in insulinomas is accentuated during fasting, when proinsulin normally does not account for more than 5% of the insulin concentrations.

Proinsulin is strikingly elevated in PC1/3 deficiency. These patients have defects in the processing of multiple peptide hormones and suffer from diabetes, adrenal insufficiency, infertility, and obesity. Affected individuals typically have red hair regardless of racial background. Variants in the proinsulin molecule have been reported that affect PC cleavage efficiency or subsequent proinsulin metabolism. These variants can also lead to markedly elevated proinsulin levels but are usually not accompanied by diabetes or any other hormonal abnormalities.