Test Catalog

Test ID: PINS    
Proinsulin, Plasma

Useful For Suggests clinical disorders or settings where the test may be helpful

As part of the diagnostic workup of suspected insulinoma


As part of the diagnostic workup of patients with suspected prohormone convertases1/3 deficiency


As part of the diagnostic workup of patients with suspected proinsulin variations

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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 non-suppressed 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.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

3.6-22 pmol/L

Interpretation Provides information to assist in interpretation of the test results

Normal individuals will have proinsulin concentrations below the upper limit of the normal fasting reference range (22 pmol/L) when hypoglycemic (blood glucose <60 mg/dL). Conversely, most (>80%) insulinoma patients will have proinsulin concentrations above the upper limit of the reference range. The sensitivity and specificity for a diagnosis of insulinoma during hypoglycemia are approximately 75% and near 100%, respectively, at the 22 pmol/L cutoff. A higher sensitivity (>95%) can be achieved using a 5 pmol/L cutoff, and this is the cutoff recommended by Mayo Clinic's highly experienced hypoglycemia team to avoid missing cases. However, the lower cutoff results in a reduced specificity (approximately 40%), emphasizing the need for a combination of different tests to assure accurate biochemical diagnosis.


Patients with PC1/3 deficiency have low, or sometimes undetectable, insulin levels and substantially elevated proinsulin levels, exceeding the upper limit of the reference range substantially in the fasting state and rising even higher after food intake. Many other hormonal abnormalities are also present, including cortisol deficiency (because of lack of processing of pro-opiomelanocortin to adrenocorticotropic hormone and other peptides), infertility, and, often, obesity.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

To avoid misdiagnoses, all proinsulin measurements used in the diagnostic workup of patients with hypoglycemia must be interpreted in the context of coexisting illnesses, blood glucose concentration at the time of sampling, and other tests, namely, insulin, C-peptide, beta-hydroxybutyrate measurements, and a sulfonylurea drug screen. Patients with chronic renal failure and type II diabetes mellitus can have increased proinsulin, C-peptide, and insulin values, but usually without suppressed (<45 mg/dL) blood glucose.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Murtha TD, Lupsa BC, Majumdar S, et al: A Systematic Review of Proinsulin-Secreting Pancreatic Neuroendocrine Tumors. J Gastrointest Surg 2017 Aug;21(8):1335-1341

2. Placzkowski KA, Vella A, Thompson GB, et al: Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab 2009 Apr;94(4):1069-1073

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

4. Service FJ: Hypoglycemic disorders. N Engl J Med 1995;322(17):1144-1152

5. Steiner DF: The proprotein convertases. Cur Opin Chem Biol 1998;2(1):31-39