Proinsulin

Insulin is a peptide hormone secreted by beta cells that are located in the islets of Langerhans of the pancreas. Insulin regulates uptake and metabolism glucose. Proinsulin is the precursor of insulin. Following translation, proinsulin is cleaved to C-peptide and insulin. Only 1 to 3% of proinsulin is secreted into the circulation. Proinsulin has a longer circulating half-life than insulin and can bind to insulin receptors. It has 5 to 10% of the metabolic activity of insulin.

Insulinoma is a rare tumor that produces excess insulin and causes hypoglycemia. Eighty percent of patients have a single benign tumor, usually <2-cm in diameter, that is located about equally in the head, body or tail of the pancreas. About 10% of patients have multiple tumors associated with multiple endocrine neoplasia type 1. The remaining 10% of patients have metastatic malignant insulinoma.  

Proinsulin measurement is a useful adjunct for the diagnosis of insulinoma.  Proinsulin is normally converted to insulin and C-peptide in the beta cells. Hypersecretion of proinsulin by a tumor overwhelms this proteolytic pathway, resulting in the release of proinsulin into the circulation. Proinsulin levels are typically greater than 20 pmol/L.  

Laboratory tests play an important role in the initial diagnosis of an insulinoma. The diagnosis depends on demonstrating elevated serum proinsulin, insulin, and C-peptide levels when the patient has symptoms of hypoglycemia and plasma glucose concentration is low. 

Diagnostic criteria for insulinoma include: hypoglycemia and elevated plasma levles of insulin, C-peptide, and proinsulin. Altogether, these findings indicate that hypoglycemia is mediated by hyperinsulinemia. 

Patients with chronic renal failure and Type 2 diabetes may have increased proinsulin values but do not have concomitant hypoglycemia.  

Proinsulin is measured by an enzyme immunoassay. Reference range for a fasting specimen is 3-20 pmol/L.  

Specimen requirement is one lavender top (EDTA) tube of blood collected from a fasting patient and immediately placed in ice. The tube should be immediately centrifuged and the plasma separated and frozen in a plastic vial.

References

Zhuo F, Menon G, and Anastasopoulou C. Insulinoma, 2025. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544299/.

Murtha TD, et al, systematic review of proinsulin-secreting pancreatic neuroendocrine tumors. J Gastrointest Surg. 2017;21(8):1335-1341.

Vezzosi D, et al, Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycemia related to endogenous hyperinsulinism. Eur J Endocrinol. 2007;157(1):75-83.

Morales J, Schneider D, Hypoglycemia, American J Med.2014;127(10):S17-S24.

Diabetes Canada Clinical Practice Guidelines Expert Working Group, Hypoglycemia in Adults, Canad J Med.2023;47(7):548-559.