sirolimus and Insulinoma

Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.

Topics: Antineoplastic Agents; Everolimus; Humans; Indoles; Insulinoma; Liver Neoplasms; Pancreatic Neoplasms; Pyrroles; Radiopharmaceuticals; Receptors, Somatostatin; Sirolimus; Somatostatin; Sunitinib

Topics: Everolimus; Humans; Hypoglycemia; Insulinoma; Pancreatic Neoplasms; Sirolimus

Topics: Everolimus; Humans; Hypoglycemia; Insulinoma; Pancreatic Neoplasms; Sirolimus

Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic β-cells against glucolipotoxicity via activation of the Akt pathway. The present study investigated the protective effects of the GLP-1 analog liraglutide against cholesterol-induced lipotoxicity and the mechanisms involved.. The mouse βTC-6 pancreatic β-cell line was preincubated for 30 min with 10 nmol/L liraglutide alone or in combination with the mammalian target of rapamycin (mTOR) inhibitor rapamycin (1 μmol/L) before being exposed to 5 mmol/L cholesterol for 6 h. 4',6'-Diamidino-2-phenylindole (DAPI) staining and Western blot analyses were used to assess the effects of liraglutide on cholesterol-induced apoptosis and the phosphorylation of Akt and mTOR.. Cholesterol significantly promoted cell apoptosis and attenuated the phosphorylation of Akt and mTOR, effects that were significantly reversed by liraglutide. Furthermore, rapamycin pretreatment alone significantly increased cholesterol-induced apoptosis compared with cholesterol-treated cells without any other pretreatment.. The data indicate that mTOR signaling is an essential mediator in the protection of pancreatic β-cells against cholesterol-induced apoptosis by a GLP-1 analog.

Topics: Animals; Apoptosis; Blotting, Western; Cholesterol; Electrophoresis, Polyacrylamide Gel; Glucagon-Like Peptide 1; Hypoglycemic Agents; Immunosuppressive Agents; Insulinoma; Liraglutide; Mice; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Hypoglycemia poses a significant management challenge in patients with unresectable metastatic insulinoma. A 57-year-old woman with pancreatic neuroendocrine tumor with multiple liver metastases was referred to our institution. During the clinical course of pancreatic neuroendocrine tumor, she had experienced palpitations, cold sweats and faintness between meals that indicated her tumors had attained the characteristics of an insulinoma, and her quality of life was impacted by frequent hypoglycemic episodes which could not be prevented by conventional therapies. Shortly after the approval of everolimus for pancreatic neuroendocrine tumor in Japan, we began oral administration at 10 mg per day, which produced a rapid and substantial improvement in glycemic control. The serum insulin level decreased dramatically despite the tumor size remaining stable on computed tomography evaluation. Despite a dose reduction of everolimus to 5 mg per day in response to the adverse reaction of interstitial pneumonitis and a subsequent moderate increase in the serum insulin level, the patient has maintained normoglycemia for a year. Everolimus might represent the treatment of choice for unresectable insulinoma in terms of not only tumor stabilization but also glycemic control.

Topics: Administration, Oral; Antineoplastic Agents; Blood Glucose; Drug Administration Schedule; Everolimus; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Japan; Liver Neoplasms; Middle Aged; Pancreatic Neoplasms; Quality of Life; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

Malignant insulinoma is an infrequent functional endocrine tumor of the pancreas. Adequate therapy is a demanding challenge for oncologists and endocrinologists.. To evaluate the results of multidisciplinary management of malignant insulinoma.. Retrospective review of patients with malignant insulinoma treated from 1995 to 2011.. Seven patients with malignant insulinoma were included: four males and three females; median age was 61.8 years (range 37-78). Six tumors were sporadic and one was diagnosed in a patient with a type 1 multiple endocrine neoplasia (MEN-1). Surgery was performed in six cases and one patient was considered unresectable. Hypoglycemias persisted in all cases and somatostatin analogs, glucocorticoids and diazoxide were used. Two patients received everolimus. Other techniques were chemoembolization and internal radiation therapy with yttrium-90. Successful liver transplant was done in the patient with MEN-1.. Hypoglycemia management is complex and requires multiple therapies. Further evaluations will be necessary to determine the best treatment.

Topics: Adult; Aged; Chemoembolization, Therapeutic; Diazoxide; Everolimus; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Radiotherapy; Retrospective Studies; Sirolimus; Treatment Outcome; Vasodilator Agents; Yttrium Radioisotopes

Topics: Antineoplastic Agents; Blood Glucose; Diazoxide; Everolimus; Humans; Hypoglycemia; Insulinoma; Octreotide; Pancreatic Neoplasms; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases

Topics: Everolimus; Humans; Hypoglycemia; Insulinoma; Male; Middle Aged; Sirolimus

Topics: Anti-Infective Agents; Brain Abscess; Everolimus; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Insulinoma; Middle Aged; Neoplasm Metastasis; Nocardia; Nocardia Infections; Pancreatic Neoplasms; Sirolimus; Trimethoprim, Sulfamethoxazole Drug Combination

Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option.. Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to the first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded.. Twelve patients with metastatic insulinoma and refractory hypoglycemia who were treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/day, except in one patient, 5 mg/day) was given after a median of four previous therapeutic lines. Medication aimed at normalizing blood glucose levels in 11 patients. After a median duration of 6.5 months (range 1-35+ months), median time to the first recurrence of symptomatic hypoglycemia was 6.5 months (range 0 to 35+ months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to two deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia.. Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.

Topics: Adult; Aged; Antineoplastic Agents; Everolimus; Female; Humans; Hypoglycemia; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Sirolimus; Treatment Outcome

This study demonstrated gemcitabine-induced cytotoxicity in the insulinoma cell line INS-1. Gemcitabine inhibited INS-1 cell proliferation and maintained consistent cell number for 24 h, and then caused apoptosis within 48 h of incubation. Since gemcitabine activates the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, which is involved in the resistance of pancreatic exocrine cancer to gemcitabine, we investigated the participation of this pathway in gemcitabine-induced cytotoxicity in INS-1 cells. LY294002 and wortmannin, two PI3-K inhibitors, significantly prevented gemcitabine-induced cytotoxicity in INS-1 cells, indicating that the PI3-K/Akt pathway is involved in gemcitabine-induced cytotoxicity. Gemcitabine-induced Akt phosphorylation in INS-1 cells was prevented by LY294002. Although gemcitabine induced cell cycle arrest at the G1 and early S phases, LY294002 did not inhibit the cell cycle. These data suggest that PI3-K activation does not influence gemcitabine-induced cell cycle arrest. In gemcitabine-treated cells, nuclear fragmentation and DNA ladder formation were observed. These findings suggest that gemcitabine induced apoptotic cell death in INS-1 cells through the activation of the PI3-K/Akt pathway.

Topics: Androstadienes; Animals; Antimetabolites, Antineoplastic; Apoptosis; Cell Death; Cell Line, Tumor; Chromones; Deoxycytidine; Gemcitabine; Insulinoma; Morpholines; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Wortmannin

Mammalian target of rapamycin inhibitor everolimus administered to four insulinoma patients rapidly controlled hypoglycemia (Kulke et al., N Engl J Med 2009;360:195-197). We wanted to identify the kinetics of everolimus effects on controlling hypoglycemia and understand underlying mechanisms.. Three consecutive patients with a metastasized symptomatic insulinoma were started on 100 μg of octreotide subcutaneously three times daily. Because of persisting hypoglycemias, treatment with daily 10 mg of oral everolimus was initiated. Serial plasma glucose levels and serum insulin levels were measured. Computer tomography (CT) scans were performed before and after 2 and 5 months of treatment. [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) scans, to visualize glucose metabolism, were made before and after 2 weeks, 5 weeks, and 5 months of treatment. The ¹⁸F-FDG uptake was quantified as the maximum standardized uptake value.. All patients achieved control of hypoglycemia on everolimus within 14 days. Insulin levels were 2.5- to 6.3-fold elevated before start of treatment and declined 14%-64% after 4 weeks of treatment. CT scans showed stable disease at 2 months in all patients, with progressive disease after 5 months in one. Before treatment, both the tumor lesions and the muscles and myocardium showed high ¹⁸F-FDG uptake. Everolimus reduced tumor and muscle ¹⁸F-FDG uptake after 2 weeks by 26% ± 14% and 19% ± 41%, and after 5 months by 31% ± 13% and 27% ± 41%.. Everolimus normalizes plasma glucose levels in metastatic insulinoma within 14 days, coinciding with a lower glucose uptake in tumor and muscles and declining (pro)insulin levels. This effect on tumor as well as normal tissues explains the rapid controlling of hypoglycemia.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Blood Glucose; Everolimus; Female; Fluorodeoxyglucose F18; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Positron-Emission Tomography; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases

HNF1A-maturity onset diabetes of the young (HNF1A-MODY) is caused by mutations in Hnf1a gene encoding the transcription factor hepatocyte nuclear factor 1alpha (HNF1A). An increased rate of apoptosis has been associated with the decrease in beta-cell mass that is a hallmark of HNF1A-MODY and other forms of diabetes. In a cellular model of HNF1A-MODY, we have recently shown that signalling through mammalian target of rapamycin (mTOR) is decreased by the overexpression of a dominant-negative mutant of HNF1A (DN-HNF1A). mTOR is a protein kinase which has important roles in cell metabolism and growth, but also in cell survival, where it has been shown to be both protective and detrimental. Here, we show that pharmacological inhibition of mTOR activity with rapamycin protected INS-1 cells against DN-HNF1A-induced apoptosis. Rapamycin also prevented DN-HNF1A-induced activation of AMP-activated protein kinase (AMPK), an intracellular energy sensor which we have previously shown to mediate DN-HNF1A-induced apoptosis. Conversely, activation of mTOR with leucine potentiated DN-HNF1A-induced apoptosis. Gene silencing of raptor (regulatory associated protein of mTOR), a subunit of mTOR complex 1 (mTORC1), also conferred protection on INS-1 cells against DN-HNF1A-induced apoptosis, confirming that mTORC1 mediates the protective effect. The potential relevance of this effect with regards to the clinical use of rapamycin as an immunosuppressant in diabetics post-transplantation is discussed.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Cell Survival; Diabetes Mellitus, Type 1; Gene Expression Regulation; Genes, Dominant; Hepatocyte Nuclear Factor 1-alpha; Insulin-Secreting Cells; Insulinoma; Leucine; Mutation; Pancreatic Neoplasms; Protein Processing, Post-Translational; Rats; Real-Time Polymerase Chain Reaction; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Hypoglycaemia poses a significant management challenge in patients with unresectable functional malignant insulinoma. Novel agents such as mammalian target of rapamycin (mTOR) inhibitors and radiolabelled peptides may be effective where there is failure of conventional therapy.. We present the cases of two men diagnosed with inoperable malignant insulinoma and hepatic metastases who developed severe symptomatic hypoglycaemia, and review potential therapies for glycaemic support.. Despite treatment with diazoxide, frequent oral carbohydrate, prednisolone and somatostatin analogue therapy, both men required hospital admission for treatment with continuous i.v. dextrose. Both were treated with Lutetium-177 octreotate. One man was also treated with everolimus, a mTOR inhibitor.. Use of Lutetium-177 octreotate, and in one case everolimus, successfully achieved normoglycaemia, facilitating safe discharge from hospital. Both men also had regression in the size and number of hepatic metastases.. Lutetium-177 octreotate and everolimus are options for managing hypoglycaemia due to unresectable malignant insulinoma when refractory to conventional supportive therapies.

Topics: Aged; Everolimus; Humans; Hypoglycemia; Insulinoma; Liver Neoplasms; Male; Middle Aged; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Radiopharmaceuticals; Sirolimus

To investigate the effect of immunosuppression agent Everolimus on the viability and function of insuloma cells (INS-1) and pancreatic islet cells cultured in vitro.. INS-1 cells and islets were treated with a series of concentrations of immunosuppression agents (Everolimus, Cyclosporin A, Sirolimus and Mycophenolate Mofetil). The viability of INS-1 cells and rat pancreatic islets were determined with MTT and the function of INS-1 cells and rat pancreatic islets was evaluated with Glucose-stimulated insulin secretion assay.. Above the clinical blood concentration, the inhibition rate of islet cell proliferation in the high concentration group of Everolimus and Sirolimus was significantly lower than that of Cyclosporin A and Mycophenolate Mofetil group (P < 0.05); Everolimus in the blood drug level, like other immunosuppressive agents, can inhibit the function of insulin secretion, and the stimulation index of each group was no significant difference.. Compared to Mycophenolate Mofetil and Cyclosporin A, Everilimus and Sirolimus demonstrate lower toxicity effect on INS-1 cells and rat pancreatic islets in vitro and Everolimus is expected as a new type of immunosuppressive agent used in clinical islet transplantation.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Cyclosporine; Everolimus; Immunosuppressive Agents; Insulin; Insulin Secretion; Insulinoma; Islets of Langerhans; Mycophenolic Acid; Pancreatic Neoplasms; Rats; Sirolimus

Topics: Adult; Aged; Blood Glucose; Everolimus; Female; Humans; Hypoglycemia; Immunosuppressive Agents; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Sirolimus; Young Adult

In pancreatic beta-cells, glucose causes a rapid increase in the rate of protein synthesis. However, the mechanism by which this occurs is poorly understood. In this report, we demonstrate, in the pancreatic beta-cell line MIN6, that glucose stimulates the recruitment of ribosomes onto the mRNA, indicative of an increase in the rate of the initiation step of protein synthesis. This increase in the rate of initiation is not mediated through an increase in the availability of the initiation complex eIF4F, because glucose is unable to stimulate eIF4F assembly or, in the absence of amino acids, modulate the phosphorylation status of 4E-BP1. Moreover, in MIN6 cells and isolated islets of Langerhans, rapamycin, an inhibitor of the mammalian target of rapamycin, only partially inhibited glucose-stimulated protein synthesis. However, we show that glucose stimulates the dephosphorylation of eIF2 alpha in MIN6 cells and the assembly of the translational ternary complex, eIF2-GTP.Met-tRNAi, in both MIN6 cells and islets of Langerhans. The changes in the phosphorylation of eIF2 alpha are not mediated by the PKR-like endoplasmic reticulum eIF2 alpha kinase (PERK), because PERK is not phosphorylated at low glucose concentrations and overexpression of a dominant negative form of PERK has no significant effect on either glucose-stimulated protein synthesis or the phosphorylation of eIF2 alpha. Taken together, these results indicate that glucose-stimulated protein synthesis in pancreatic beta-cells is regulated by a mechanism largely independent of the activity of mammalian target of rapamycin, but which is likely to be dependent on the availability of the translational ternary complex, regulated by the phosphorylation status of eIF2 alpha.

Topics: Activating Transcription Factor 4; Animals; Culture Media; eIF-2 Kinase; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4F; Gene Expression; Glucose; Guanosine Triphosphate; Insulinoma; Islets of Langerhans; Kinetics; Mice; Phosphorylation; Protein Biosynthesis; Protein Kinases; Recombinant Fusion Proteins; RNA, Transfer, Met; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors; Tumor Cells, Cultured