A Case of Proinsulin-Secreting Malignant Insulinoma in an Elderly Patient with Cerebral Infarction

Kana Furushima, Atsuhito Tone*, Akihiro Katayama, Izumi Iseda, Chigusa Higuchi, Keiko Tsukamoto, Tomohiko Mannami, Haruhiro Yamashita, Tetsuya Ohta, Shuichi Nomura, Ichiro Yamadori, Jun Wada, Kenichi Shikata and Kazuyuki Hida 1Department of Diabetes and Metabolism, National Hospital Organization, Okayama Medical Center, Okayama, Japan 2Department of Gastroenterology, National Hospital Organization, Okayama Medical Center, Okayama, Japan 3Department of Surgery, National Hospital Organization, Okayama Medical Center, Okayama, Japan 4Department of Pathology, National Hospital Organization, Okayama Medical Center, Okayama, Japan 5Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan


Introduction
Insulinoma is an islet beta cell-derived tumor manifesting various clinical symptoms due to hypoglycemia. However, the diagnosis of insulinoma is sometimes challenging and overlooked in patients with higher cerebral dysfunction such as elderly patients with cerebrovascular diseases, since their complaint of hypoglycemia is often unclear. Recently, there have been an increasing number of cases with insulinoma secreting proinsulin without hyperinsulinemia.
Here we report a case of proinsulin-secreting malignant insulinoma in an elderly patient with aphasia due to cerebral infarction.

Case Report
A 72-year-old man with aphasia due to cerebral infarction lived in a nursing home. His hypoglycemia, plasma glucose 31 mg/dL, was incidentally found and repeated examination revealed his recurrent hypoglycemia without apparent symptoms. He was referred to our hospital for investigation and laboratory studies showed fasting plasma glucose, 50 mg/dl and fasting serum immunoreactive insulin (IRI), 14.7 U/ml and prominently elevated proinsulin concentration (2470 pmol/l, Human Proinsulin RIA kit, Linco Reasearch). The Fajans, Grunt and Turner indexes, diagnostic indicators of insulinoma, were all negative, and only the Taminato index was positive (585; insulinoma > 280) ( Table 1). Mild response of insulin secretion was observed in 75g oral glucose tolerance test (OGTT) and no response of insulin secretion in the glucagon stimulation tests (Figure 1a  After the surgery, recurrent hypoglycemia disappeared. Abnormal findings identified in 75g OGTT and the glucagon stimulation test revealed normal response (Figure 1a and b).

Discussion
There has been the reported cases of insulinoma without hyperinsulinemia and the importance of measurement of proinsulin is noted [I-3]. Tsuzuki and Ishii [4] reported that the levels of serum IRI were less than 20 U/ml in 46% of patients and 18% of those showed negative Fajans index in the review of 358 cases of insulinoma. In this case of proinsulin-secreting insulinoma, the Fajans, Grunt and Turner indexes were all negative and only the Taminato index was positive, although it revealed mild elevation of serum insulin levels.
An increasing number of case reports of insulinoma with elevated levels of proinsulin has been accumulated since the first case report by Melani et al. [3], Alsever et al. [1] also reported a case of hypoglycemia coexisting with low plasma IRI and high serum  proinsulin concentrations and they suggested that the difference in the methods of IRI measurement contributed to low plasma IRI levels in islet-cell tumor. Currently, fluorescent immunoassay, which has very low cross-reactivity to proinsulin, is commonly performed, resulting in the identification of an increasing number of the cases of insulinoma without apparent hyperinsulinemia. In current case, the levels of IRI were measured by fluorescent polarization immunoassay (FPIA) using monoclonal antibodies, which showed very low crossreactivity to proinsulin, i.e. 0.016%. Diagnostic criteria for insulinoma, such as the Tuner index, are not always applicable with IRI levels measured using monoclonal antibodies, since they were established when polyclonal antibodies were used. Given the situation where monoclonal antibodies are widely used, it is suggested that the Taminato index is more helpful for diagnosis than others.
In summary, we report a case of proinsulin-secreting malignant insulinoma in an elderly patient with cerebral infarction. In this case, there were no apparent symptoms of hypoglycemia. The diagnosis of hypoglycemia requires careful attention especially in elderly persons and patients with cerebrovascular diseases, since their complaint of hypoglycemia is often unclear. Measurement of proinsulin is recommended in the diagnosis of insulinoma without hyperinsulinemia.