sunitinib is a small molecule multitargeted tyrosine kinase inhibitor currently used for the treatment of cancer . this class of drugs has also been reported to have antidiabetic effects [ 1 - 3 ] , but the mechanism has not been elucidated . here we describe a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastasis , who developed life - threatening hypoglycemia after treatment with sunitinib . histological examination of the metastatic mass in the liver suggested that the nonfunctioning neuroendocrine cells were converted into insulin - producing cells , causing hyperinsulinemia and severe hypoglycemia . a 46-year - old woman was carried to the emergency room with sudden loss of consciousness before breakfast . during transfer in the ambulance , 1a ) , with metastases to retroperitoneal lymph nodes , left supraclavicular lymph nodes and liver ( fig . the patient had received this diagnosis 4 months prior , after presenting with right flank pain . needle biopsy and immunohistochemical ( ihc ) staining of the supraclavicular lymph node had been positive for cd56 , chromogranin , and synaptophysin , and negative for glucagon and insulin . one month later , she started taking sunitinib 37.5 mg per day because the disease progressed and the right flank pain increased . after 2 months of sunitinib treatment she felt severe fatigue from which she was diagnosed with hypothyroidism , a common adverse event of sunitinib . she began levothyroxine , but even after normalization of thyroid hormone levels , she experienced intermittent weakness , dizziness , and hunger . to relieve fatigue and hunger , she increased oral intake and experienced weight gain of 10 kg over a month . she reported having no personal or family history of thyroid disease or diabetes mellitus . on physical examination her vital signs were within the normal range , height 156.5 cm and body weight 53 kg . there were two palpable , hard , and nontender lymph nodes of less than 1 cm each in the left supraclavicular area . she had tenderness in the right flank on percussion , but hepatosplenomegaly was not noted . grade 1 hand - foot syndrome ( mild erythema ) , a skin - related side effect of sunitinib was observed . the blood cell count , urinalysis , and serum chemistry and electrolytes were within normal range . an electrocardiogram revealed a normal sinus rhythm and chest x - ray showed no abnormality . computed tomography of the abdomen demonstrated an increase in the size of the liver mass from 1.8 to 2.8 cm . overnight fasting plasma glucose was 16 mg / dl with c - peptide and insulin levels of 6.1 ng / ml and 27.2 iu / ml , respectively . these inappropriately elevated fasting insulin and c - peptide levels compared to the glucose level confirmed that the patient 's hypoglycemia resulted from endogenous hyperinsulinemia . differential diagnosis of endogenous hyperinsulinemia was based on negative titers for insulin antibody and insulin receptor antibody . we performed a liver biopsy to obtain metastatic tissue , and the histologic examination revealed diffuse infiltration of the cancer cells in the liver . in addition , the metastatic lesion in the liver which had been negative at the initial diagnosis ( fig . we concluded that the nonfunctional neuroendocrine carcinoma that metastasized to the liver changed into an insulin - producing tumor after 2 months of administration of sunitinib . however , even with frequent dietary intake , the patient required more than 500 g of glucose per day via the central vein to prevent hypoglycemia . high - dose glucocorticoid and glucagon administration were not effective in relieving the severe hypoglycemia . eighteen days after discontinuation of sunitinib , severe hypoglycemia persisted and she underwent transarterial chemoembolization ( tace ) for the metastatic lesions in the left lobe of her liver . intravenous glucose infusion was slowly tapered to 200 g per day during the 2 weeks after tace . then a -cell toxin , streptozotocin ( 500 mg / m ) , and adriamycin ( 50 mg / m ) were administrated intravenously the patient underwent another round of tace for the right lobe of the liver and intravenous streptozotocin / adriamycin , and she was successfully discharged . one month after the final treatment , her fasting blood glucose was 101 mg / dl . local control of metastatic carcinoma and systemic administration of -cell toxin had reversed her severe hypoglycemia . generally , tumorous conditions that induce endogenous hyperinsulinism such as insulinoma and nesidioblastosis cause clinical hypoglycemia even for small tumors . therefore , it is unlikely that the slight increase in tumor burden in the liver in the current case had caused conversion of " preclinical " insulinoma into clinical insulinoma . the patient 's liver metastases did not impair liver function , so liver function did not contribute to the hypoglycemia . she developed severe hypoglycemia from endogenous hyperinsulinemia after treatment with sunitinib without initial evidence of insulinoma or impaired liver function . ihc staining for insulin in tumor specimens before and after sunitinib treatment suggests that neuroendocrine carcinoma cells were transformed from nonfunctioning to insulin - producing cells after treatment with sunitinib . this hypothesis is further supported by the fact that she recovered from severe hypoglycemia after controlling metastatic tumors with tace and streptozotocin . however , we should note that her supraclavicular lymph node was biopsied at initial diagnosis of pancreatic neuroendocrine carcinoma because it was easily accessible . in contrast , liver tissue was obtained after use of sunitinib due to significant progression of liver metastases . our findings suggested that the metastatic liver mass turned to producing insulin upon sunitinib treatment , but we could not rule out production of insulin by the same liver metastatic tissue before sunitinib treatment because pretreatment liver metastatic tissue was not available . we previously published a case of sunitinib - induced hypoglycemia occurring in nonfunctioning pancreatic neuroendocrine carcinoma with liver metastasis . in that case , we identified endogenous hyperinsulinism but did not attempt to examine insulin production by tumor cells because the hypoglycemia resolved after treatment with a small dose of prednisolone . recently reported a similar rare case of transformation from nonfunctioning neuroendocrine tumor into insulin - producing tumor , where the patient had liver metastases . however , hypoglycemia was not ascribed to sunitinib treatment as various chemotherapeutic regimens had been used . in our case , the patient developed severe hypoglycemia after treatment with only sunitinib , with the exception of thyroid hormone which has no previous report of causing hypoglycemia . the similar characteristics of nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases in all these cases suggest that a common mechanism might exist , such as the milieu of liver tissue in which the neuroendocrine carcinoma is embedded . the molecular mechanism of the glucose - lowering effect of sunitinib has not been elucidated . several in vitro and in vivo experiments have suggested that imatinib , another kind of small molecule tyrosine kinase inhibitor , is involved in the autoimmune process , -cell protection , and insulin sensitivity [ 6 - 10 ] . the platelet - derived growth factor signaling pathway , through which sunitinib works , was recently shown to control age - dependent -cell proliferation in mouse and human pancreatic islets . further studies are warranted to understand the molecular mechanism of neuroendocrine cell fate to produce insulin by sunitinib . in conclusion , this case and a review of the literature suggest that the use of sunitinib in a patient with pancreatic neuroendocrine carcinoma with liver metastases can bring about hypoglycemia , which could be lethal . considering the possibility of such a serious adverse effect , we recommend that oncologists carefully monitor hypoglycemic symptoms and blood glucose levels of patients treated with sunitinib . the possibility of transformation of neuroendocrine cells into insulin - producing cells by sunitinib would provide a novel way of manipulating -cell fate .