Correspondence

Glycemic Control in Patients with Insulinoma Treated with Everolimus

N Engl J Med 2009; 360:195-197January 8, 2009

Article

To the Editor:

Management of refractory hypoglycemia due to malignant insulinoma is challenging. Currently available treatments include dietary modification, diazoxide, and, in patients with resistant disease, the use of intravenous dextrose infusion or enteral feedings. Patients with advanced, unresectable insulinomas often have prolonged hospitalizations and may have fatal complications from this disease.

The mammalian target of rapamycin (mTOR) is a serine–threonine protein kinase that has been implicated in the cellular response to nutrients and growth factor signaling; mTOR functions downstream of phosphatidylinositol 3-kinase and AKT (also known as protein kinase B) and is abnormally activated in a number of cancers. Inhibitors of mTOR have been increasingly recognized as an important new class of agents for use in oncology. Everolimus, a rapamycin analogue, is a new oral mTOR inhibitor. In a recent study, everolimus was associated with regression of neuroendocrine tumors.1

Another observed effect of everolimus in various studies is the development of hyperglycemia. Given the effects of everolimus on both tumor growth and glycemic regulation, we evaluated the clinical responses of four consecutive patients with functioning insulinomas who were treated with everolimus at our institutions. Multiple therapies had failed in all four patients, and they all required aggressive management of hypoglycemia (Table 1Table 1Characteristics of the Patients, Previous Therapy, and Response to Everolimus.). After receiving everolimus, all four patients had substantial improvement in glycemic control.

Several mechanisms may account for the observed improvements. Two patients had radiologic evidence of tumor regression, suggesting that the clinical benefit may have resulted from an antitumor effect of the drug (Figure 1Figure 1Computed Tomographic Evidence of Tumor Response after Everolimus Therapy in Patient 1.).1 The clinical improvement of the two remaining patients who did not have tumor regression suggests that everolimus may have a direct effect on glycemic control. This hypothesis is supported by the observation that one patient who stopped taking everolimus after radiologic evidence of tumor progression had recurrent hypoglycemia 2 weeks later. The patient restarted therapy with an mTOR inhibitor and regained glycemic control.

Data suggest that functional insulin receptors are present on beta cells and mediate insulin-stimulated insulin production and release and that mTOR inhibition downstream of insulin receptors may decrease insulin production and release.2,3 Data from other studies have indicated that mTOR inhibition may either suppress or increase insulin output, depending on the dose and schedule.4 It is also possible that everolimus induces peripheral insulin resistance. In studies involving renal-transplant recipients, for example, long-term treatment with rapamycin has been observed to induce peripheral insulin resistance by impairing AKT activation and signaling through the insulin-receptor substrate pathway.5

In summary, the use of everolimus in four patients with insulinoma and refractory hypoglycemia was associated with improved glycemic control. The mechanisms underlying this observation would appear to warrant further investigation.

Matthew H. Kulke, M.D.
Dana–Farber Cancer Institute, Boston, MA 02115

Emily K. Bergsland, M.D.
University of California, San Francisco, San Francisco, CA 94115

James C. Yao, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
jyao@mdanderson.org

Supported in part by grants from Novartis.

Drs. Kulke and Yao report receiving lecture and consulting fees from Novartis; and Drs. Kulke, Bergsland, and Yao, receiving research support from Novartis through their respective institutions. No other potential conflict of interest relevant to this letter was reported.

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Citing Articles (15)

Citing Articles

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   Thomas Walter, Hedia Brixi-Benmansour, Catherine Lombard-Bohas, Guillaume Cadiot. (2012) New treatment strategies in advanced neuroendocrine tumours. Digestive and Liver Disease 44:2, 95-105
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   T. I. M. Korevaar, F. Ragazzoni, A. Weaver, N. Karavitaki, A. B. Grossman. (2011) IGF2-induced hypoglycemia unresponsive to everolimus. QJM
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   Wouter W. de Herder, Ellen van Schaik, Dik Kwekkeboom, Richard A. Feelders. (2011) New therapeutic options for metastatic malignant insulinomas. Clinical Endocrinology 75:3, 277-284
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   M. Pavel. (2011) Metastasierte neuroendokrine Neoplasien. Der Chirurg 82:7, 612-617
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5. 5

   (2011) Advances in Pancreatic Neuroendocrine Tumor Treatment. New England Journal of Medicine 364:19, 1871-1875
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   Juan C. Ferrer-García, Mercedes Tolosa-Torréns, Cristina Hernando-Meliá, Luis Arribas-Palomar, Carlos Sánchez-Juan. (2011) Everolimus Resolving Hypoglycemia, Producing Hyperglycemia, and Necessitating Insulin Use in a Patient with Diabetes and Nonresectable Malignant Insulinoma. Endocrine Practice 17:2, e17-e20
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   J. Capdevila, I. Diez Miranda, G. Obiols, J. Tabernero. (2011) Control of carcinoid syndrome with everolimus. Annals of Oncology 22:1, 237-239
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   Noormuhammad Oosman Abbasakoor, Marie Louise Healy, Donal O'Shea, Donal Maguire, Cian Muldoon, Kieran Sheahan, Dermot O'Toole. (2011) Metastatic Insulinoma in a Patient with Type 2 Diabetes Mellitus: Case Report and Review of the Literature. International Journal of Endocrinology 2011, 1-5
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   Matthew H Kulke, Johanna Bendell, Larry Kvols, Joel Picus, Rodney Pommier, James Yao. (2011) Evolving Diagnostic and Treatment Strategies for Pancreatic Neuroendocrine Tumors. Journal of Hematology & Oncology 4:1, 29
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    Kjell Öberg. (2010) Pancreatic Endocrine Tumors. Seminars in Oncology 37:6, 594-618
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    Maya B. Lodish, Constantine A. Stratakis. (2010) Rare and Unusual Endocrine Cancer Syndromes With Mutated Genes. Seminars in Oncology 37:6, 680-690
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    Prakash Chandra, Shadi Sadeghi Yarandi, Natasha Khazai, Sol Jacobs, Guillermo E. Umpierrez. (2010) Management of Intractable Hypoglycemia With Yttirum-90 Radioembolization in a Patient With Malignant Insulinoma. The American Journal of the Medical Sciences 340:5, 414-417
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    T. Walter, C. Lombard-Bohas. (2010) Apport des antiangiogéniques et des inhibiteurs de mTOR dans le traitement des tumeurs endocrines digestives. Oncologie 12:10, 636-640
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    Hiu-yan Chan, Ashley B. Grossman, Ronald M. Bukowski. (2010) Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors. Advances in Therapy 27:8, 495-511
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    Matthew H. Kulke, Lowell B. Anthony, David L. Bushnell, Wouter W. de Herder, Stanley J. Goldsmith, David S. Klimstra, Stephen J. Marx, Janice L. Pasieka, Rodney F. Pommier, James C. Yao, Robert T. Jensen. (2010) NANETS Treatment Guidelines. Pancreas 39:6, 735-752
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