OBJECTIVE: Neuroendocrine tumors of the pancreas (Pan-NETs) are rare, but among the most common neuroendocrine neoplasias. They are mostly slowly growing with a capacity to metastasize, but transition to a higher grade occurs, which lead to a more aggressive tumor phenotype. Very seldom, non-functional tumors can become hormonally active. Here we present four patients with originally non-functional Pan-NETs that subsequently started to produce insulin or its precursors, causing severe hypoglycemia. METHODS: We reviewed the medical files, biochemistry and radiological investigations. Pathology tissue samples were re-examined, and additional immunohistochemical analyses were performed. RESULTS: Four patients; three women and one man, aged 51, 61, 65 and 68 years at diagnosis developed malignant insulinomas 2, 5, 6 and 7 years respectively after initial diagnosis of non-secreting Pan-NETs. They had all metastatic disease at diagnosis. Ki-67 was initially 2, 5 and 6% and progressed to 25, 17 and 45%, respectively. In one patient the initial Ki-67 was 5% but was not reexamined. All four patients died due to their cancer disease within 12, 6, 19 and 29 months after treatment for hypoglycemia commenced. The clinical profile and/or review of the histopathology confirmed all original lesions as non-functional Pan-NETs with subsequent transformation into insulin-producing tumors. CONCLUSIONS: Non-functional, metastatic Pan-NETs may transform to insulin secreting lesions, with negative impact on prognosis. Therefore, if symptoms as hypoglycemia develops continuous follow-up of clinical parameters, biochemical profiles of pancreatic hormones and histopathological evaluation of proliferation is suggested to detect changes in characteristics of these malignant neoplasms.