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 .
 we report a rare case of severe hypoglycemia after sunitinib treatment for pancreatic neuroendocrine carcinoma . 
 we describe the initial clinical presentation , laboratory results , pathologic findings , and managment in a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases who developed life threatening hypoglycemia after 2 months of sunitinib therapy . a 46-year - old woman presented to the emergency department with loss of consciousness from hypoglycemia . 
 serum c - peptide and insulin levels at fasting state revealed that the hypoglycemia resulted from endogenous hyperinsulinemia . 
 she had been diagnosed with nonfunctioning pancreatic neuroendocrine carcinoma based on a biopsy of metastatic cervical lymph node and was being treated with sunitinib , a small molecule tyrosine kinase inhibitor . 
 immunohistochemical stain of the metastatic liver mass demonstrated that the initially nonfunctioning neuroendocrine carcinoma cells had changed into insulin - producing cells after sunitinib therapy . 
 transarterial chemoembolization of the liver masses and systemic chemotherapy with streptozotocin / adriamycin relieved the hypoglycemia . 
 a nonfunctioning pancreatic neuroendocrine carcinoma was transformed into an insulin - producing tumor after treatment with sunitinib , causing endogenous hyperinsulinemia and severe hypoglycemia . 
INTRODUCTION
CASE REPORT
DISCUSSION