Insulin levels measured with an insulin-specific assay in patients with fasting hypoglycaemia related to endogenous hyperinsulinism

Abstract

Objective: The finding of insulin levels above a minimum threshold at the time of symptomatic hypoglycaemia is crucial in the diagnosis of endogenous hyperinsulinism. The aim of this study was to evaluate insulin levels at the time of hypoglycaemia with an insulin-specific assay in such patients. Design and methods: We measured insulin levels in 15 patients with fasting hypoglycaemia related to endogenous hyperinsulinism using an insulin-specific immunoradiometric assay (IRMA) without any significant cross-reaction with intact proinsulin. Results: Insulin levels were below 6 mIU/l in all the samples taken at the time of symptomatic hypoglycaemia in 6/15 patients, and in some of the samples in three patients; insulin levels were below 3 mIU/l in samples from 5 patients. C-peptide levels were above 0.6 ng/ml in all these samples. The lowest proinsulin level was 35 pmol/l. Insulin levels were measured with a less specific RIA (40% cross-reaction with proinsulin) in 8/15 patients and were above 6 mIU/l in all samples in seven patients, and all but one sample in the 8th patient. Mean concomitant C-peptide and insulinoma size were lower in those patients with insulin-IRMA levels below 6 mIU/l. Conclusion: Symptomatic hypoglycaemia below 0.45 g/l can result from insulin levels below 6 or even 3 mIU/l; lower insulin levels and secretion could be observed preferentially in small insulinomas. If an insulin assay devoid of any significant cross-reaction with intact proinsulin is employed, measuring C-peptide (and/or proinsulin) levels at the time of symptomatic hypoglycaemia is mandatory to make the diagnosis of endogenous hyperinsulinism.

Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycaemia related to endogenous hyperinsulinism

“…Using two insulin-specific assays, both devoid of any significant cross-reaction with intact proinsulin, 35% of the patients with endogenous hyperinsulinism had an insulin-IRMA level below 21 pmol/l and 11% of them had an insulin-ICL level below 21 pmol/l. Thus, at the time of symptomatic hypoglycaemia below 2.5 mmol/l, an insulin level below 21 pmol/l cannot rule out the diagnosis of endogenous hyperinsulinism (4)(5)(6).…”

“…With the insulin and C-peptide-specific assays devoid of significant cross-reaction with proinsulin which are now in use, a lower insulin threshold of 3 mIU/l (21 pmol/l) was recommended by Service et al (3), but already there are reports of insulinoma patients with insulin levels below 3 mIU/l (21 pmol/l) at the time of symptomatic hypoglycaemia (4)(5)(6). Finally, the availability of proinsulin assays led to the use of serum proinsulin thresholds as diagnostic tools; a 5 pmol/l proinsulin cut-off level at the time of hypoglycaemia below 0.45 g/l was recommended by Service et al as a diagnostic criterion (1), but others selected a higher threshold (22 pmol/l (7), 20 pmol/l (8)), for the diagnosis of insulinomas.…”

Diagnosis and Treatment of Insulinomas in the Adults

“…The insulin assays that are now in use have negligible crossreaction with proinsulin. Though the 3 mIU/L threshold (which replaces a 6 mIU/l threshold previously established with less specific insulin assays) was established for insulin-specific assays, it is known now that the finding of low insulin levels with such assays cannot rule out the diagnosis of insulinoma (Vezzosi et al 2003). 11-35% patients with insulinoma were found to have insulin levels below the recommended diagnostic threshold (3 mIU/L) at the time of hypoglycemia when insulin was measured with insulinspecific assays, the percentage of values below 3 mIU/L depending on the assay employed (Vezzosi et al 2007).…”

“…One must remind that some insulinoma patients do not have elevated insulin levels when insulin is measured with insulin-specific assays (Vezzosi et al 2003). When an insulinoma is not found by imaging techniques, two very different diagnoses must be suspected: factitious hypoglycemia related to sulfonylurea or glinide, or nesidioblastosis, which is rare in adult patients.…”

Diagnosis and localisation of insulinoma: the value of modern magnetic resonance imaging in conjunction with calcium stimulation catheterisation

“…The original suggested diagnostic criterion for an insulinoma was an insulin level O6 mU/l in the presence of hypoglycaemia, measured by a double-antibody RIA with a lower limit of detection of 5 mU/l (4,5). With the introduction of new highly specific insulin assays, lower levels of insulin have been detected in patients with insulinomas, and thus, new lower diagnostic criteria have been proposed by some groups (1,(6)(7)(8). A recent consensus set of guidelines for the diagnosis of inappropriate hyperinsulinemia in the presence of documented hypoglycaemia have proposed a diagnostic threshold of plasma insulin of 3 mU/l (9).…”