The role of proinsulin and insulin in the diagnosis of insulinoma: a critical evaluation of the Endocrine Society clinical practice guideline

Abstract

Context: An end of fast insulin ≥ 3 μIU/mL and a proinsulin concentration ≥ 5 pmol/L have been suggested as useful cutoffs for the diagnosis of insulinoma.

Objective: The main objective was to evaluate the diagnostic performance of an end of fast insulin concentration ≥ 3 μIU/mL and an end of fast proinsulin concentration ≥ 5 pmol/L.

Design: The design was a case-control series.

Setting: The setting was a tertiary-care center.

Patients: Fifty-six subjects with a positive 48-hour supervised fast had an insulinoma between June 2000 and April 2011. During this same time period, a diagnosis of insulinoma was excluded in 29 subjects who underwent a supervised fast.

Intervention: 48-hour supervised fast.

Main outcome measure: The main outcome measures were serum insulin concentration and plasma proinsulin concentration.

Results: Ninety-one percent of the patients with an insulinoma had a measured insulin concentration ≥5 μIU/mL at the end of fast. The sensitivity increased to 98% if the threshold to define inadequate insulin suppression was lowered to ≥3 μIU/mL. The median (interquartile range) end of fast proinsulin was 100 (53-270) pmol/L for cases and 6.8 (4.2-12.0) pmol/L for controls. An end of fast proinsulin value of ≥ 5 pmol/L could not distinguish cases from controls (59% false positive rate). All patients with an insulinoma (sensitivity 100%) and none of the control subject (specificity 100%) had end of fast proinsulin concentration ≥ 27 pmol/L.

Conclusions: Using a current insulin assay 9% of insulinoma cases end the supervised fast with an insulin concentration below 5 μIU/mL. Inadequate insulin suppression defined using a threshold of ≥ 3 μIU/mL increases the sensitivity of the test. The value of the proinsulin test lies in its unique ability to distinguish cases from controls. A proinsulin concentration of ≥22 pmol/L best discriminates cases from controls. Reliance on an end of fast proinsulin cutoff value of 5 pmol/L does not augment sensitivity but greatly reduces specificity of the test.

Figure 1.

End of fast proinsulin concentrations. The figure displays the distribution of the proinsulin concentration (log scale) observed at the end of a 48-hour supervised fast in 56 cases with insulin-producing tumors (Insulinoma) and 29 control subjects with no insulin-producing tumors (No Insulinoma) and their respective box-plots. (solid line) 5 pmol/L cutoff; (dotted line) 22 pmol/L cutoff.

Figure 2.

Start of fast proinsulin concentrations. The figure displays the distribution of the proinsulin concentrations (log scale) observed at the start of a 48-hour supervised fast in 56 cases with insulin-producing tumors (Insulinoma) and 29 control subjects with no insulin-producing tumors (No Insulinoma) and their respective box-plots.

Figure 3.

End of fast C-peptide concentrations. The figure displays the distribution of the C-peptide concentrations observed at the end of a 48-hour supervised fast in 56 cases with insulin-producing tumors (Insulinoma) and 29 control subjects with no insulin-producing tumors (No Insulinoma) and their respective box-plots. (solid line) Concentration of 0.6 ng/mL.

Figure 4.

Sensitivity of an end of fast insulin value of >5 μIU/mL and >3 μIU/mL for NIH cases before 1995 (RIA) and for current cases (newer “specific” insulin assay).

Figure 5.

Diagnostic performance of an end of fast proinsulin >22 pmol/L or equivalent across three nonoverlapping series of NIH patients evaluated with a supervised fast. These data represent 176 patients with insulin-producing tumors and 50 control subjects. (Proinsulin prior to 1995 was not directly measured; values obtained using the indirect proinsulin assay were converted to concentrations using a correlation analysis between the indirect and direct proinsulin assays.)