The Role of Proinsulin and Insulin in the Diagnosis of Insulinoma: A Critical Evaluation of the Endocrine Society Clinical Practice Guideline

Context: An end of fast insulin >= 3 mu IU/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 mu IU/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 mu IU/mL at the end of fast. The sensitivity increased to 98% if the threshold to define inadequate insulin suppression was lowered to >= 3 mu IU/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 mu IU/mL. Inadequate insulin suppression defined using a threshold of >= 3 mu IU/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.