problendoПроблемы ЭндокринологииProblems of Endocrinology0375-96602308-1430Endocrinology Research Centre10.14341/probl2017635346-355problendo-8279Research ArticleОбзорыReviewsГипогликемический синдром (инсулинома): топическая, патоморфологическая и генетическая диагностика, лечение. Обзор литературы (часть 2)The hypoglicemic syndrome (insulinoma): topical, pathomorphological, and genetic diagnostics and treatment (review, part 2)https://orcid.org/0000-0002-8771-8300ЮкинаМарина ЮрьевнаYukinaMarina Yu.

к.м.н.

MD, PhD

kuronova@yandex.ruhttps://orcid.org/0000-0001-6876-3336НуралиеваНурана ФейзуллаевнаNuralievaNurana F.dr.nuralievanf@yandex.ruhttps://orcid.org/0000-0002-8520-8702ТрошинаЕкатерина АнатольевнаTroshinaEkaterina A.

д.м.н., профессор, член-корреспондент РАН

MD, PhD, Professor

troshina@inbox.ruhttps://orcid.org/0000-0002-9419-7013КузнецовНиколай СергеевичKuznetsovNikolay S.

д.м.н., профессор

MD, PhD

KuznetsovNikolayS@yandex.ruhttps://orcid.org/0000-0001-6388-1544ПлатоноваНадежда МихайловнаPlatonovaNadezhda M.

д.м.н.

MD, PhD

doc-platonova@inbox.ru<p>ФГБУ &laquo;Национальный медицинский исследовательский центр эндокринологии&raquo; Минздрава России</p>Россия<p>Endocrinology Research Centre</p>Russian Federation201711122017635346355Copyright &#x00A9; Юкина М.Ю., Нуралиева Н.Ф., Трошина Е.А., Кузнецов Н.С., Платонова Н.М., 20172017Юкина М.Ю., Нуралиева Н.Ф., Трошина Е.А., Кузнецов Н.С., Платонова Н.М.Yukina M.Y., Nuralieva N.F., Troshina E.A., Kuznetsov N.S., Platonova N.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.probl-endojournals.ru/jour/article/view/8279

Инсулинома — наиболее распространенная функционирующая опухоль поджелудочной железы, формирующаяся из β-клеток островков Лангерганса. В ткани опухоли происходят различные молекулярные нарушения, которые приводят к автономной гиперпродукции инсулина и дискоординации его секреции с формированием гипогликемического синдрома — крайне опасного для жизни состояния. В 10% случаев инсулинома бывает злокачественной и в 10% — мультифокальной. В обзоре рассматриваются новые возможности определения точной локализации инсулиномы, в том числе с учетом последних данных об экспрессии различных рецепторов в ткани опухоли. Отражены современные представления о молекулярных и генетических аспектах развития инсулиномы. В частности, освещены данные исследований, посвященных герминальным и соматическим мутациям, а также эпигенетическим нарушениям. Описаны новые биохимические маркеры инсулиномы, которые могут рассматриваться как предикторы рецидива и прогрессирования опухоли, а также применяться с целью дифференциальной диагностики, мониторинга лечения и прогнозирования заболевания. Обсуждается применение противоопухолевых препаратов и оптимальная медикаментозная коррекция гипогликемии при инсулиноме.

Insulinoma is the most common functioning tumor of the pancreas. It consists of β-cells of the Langerhans islets. Insulinoma is malignant in 10% of cases and multifocal in 10% of cases. This review discusses the new capabilities for identification of the exact location of insulinoma, in particular given the latest data on expression of different receptors in the tumor tissue. We discuss the modern concept of molecular and genetic aspects of insulinoma development. In particular, we analyze studies on germinal and somatic mutations and epigenetic abnormalities. We describe new biochemical markers of insulinoma, which may be used for differential diagnosis, timely detection of insulinoma recurrence and progression, individual prognosis, and monitoring of treatment. Also, we discuss application of antitumor medications and optimal drug correction of hypoglycemia in insulinoma patients.

инсулиномаподжелудочная железадиагностикарецепторные аномалиибиохимические маркерыгенетические нарушениялечениеinsulinomapancreasdiagnosisreceptor anomaliesbiochemical markersgenetic disorderstreatmentReferencesMcAuley G, Delaney H, Colville J, et al. Multimodality preoperative imaging of pancreatic insulinomas. Clin Radiol. 2005;60(10):1039-1050. doi: 10.1016/j.crad.2005.06.005McAuley G, Delaney H, Colville J, et al. Multimodality preoperative imaging of pancreatic insulinomas. Clin Radiol. 2005;60(10):1039-1050. doi: 10.1016/j.crad.2005.06.005Бельцевич Д.Г. Согласительные рекомендации ENETS (Европейское общество по нейроэндокринным опухолям) по ведению больных с нейроэндокринными опухолями ЖКТ: функционирующие нейроэндокринные опухоли поджелудочной железы // Эндокринная хирургия. — 2012. — Т. 6. — №3. — C. 8—40. [Beltsevich DG. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system. Endocrine Surgery. 2012;6(3):8-40. (In Russ.)]. doi: 10.14341/2306-3513-2012-3-8-40Бельцевич Д.Г. Согласительные рекомендации ENETS (Европейское общество по нейроэндокринным опухолям) по ведению больных с нейроэндокринными опухолями ЖКТ: функционирующие нейроэндокринные опухоли поджелудочной железы // Эндокринная хирургия. — 2012. — Т. 6. — №3. — C. 8—40. [Beltsevich DG. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system. Endocrine Surgery. 2012;6(3):8-40. (In Russ.)]. doi: 10.14341/2306-3513-2012-3-8-40Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009;94(3):709-728. doi: 10.1210/jc.2008-1410Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009;94(3):709-728. doi: 10.1210/jc.2008-1410An L, Li W, Yao KC, et al. Assessment of contrast-enhanced ultrasonography in diagnosis and preoperative localization of insulinoma. Eur J Radiol. 2011;80(3):675-680. doi: 10.1016/j.ejrad.2010.09.014An L, Li W, Yao KC, et al. Assessment of contrast-enhanced ultrasonography in diagnosis and preoperative localization of insulinoma. Eur J Radiol. 2011;80(3):675-680. doi: 10.1016/j.ejrad.2010.09.014Taieb D, Legmann P, Prat F, et al. Topographic diagnosis: respective roles of morphological and functional imaging. Ann Endocrinol (Paris). 2013;74(3):185-190. doi: 10.1016/j.ando.2013.05.008Taieb D, Legmann P, Prat F, et al. Topographic diagnosis: respective roles of morphological and functional imaging. Ann Endocrinol (Paris). 2013;74(3):185-190. doi: 10.1016/j.ando.2013.05.008D’Onofrio M, Mansueto G, Vasori S, et al. Contrast-enhanced ultrasonographic detection of small pancreatic insulinoma. J Ultrasound Med. 2003;22(4):413-417.D’Onofrio M, Mansueto G, Vasori S, et al. Contrast-enhanced ultrasonographic detection of small pancreatic insulinoma. J Ultrasound Med. 2003;22(4):413-417.Rebours V, Cordova J, Couvelard A, et al. Can pancreatic neuroendocrine tumour biopsy accurately determine pathological characteristics? Dig Liver Dis. 2015;47(11):973-977. doi: 10.1016/j.dld.2015.06.005Rebours V, Cordova J, Couvelard A, et al. Can pancreatic neuroendocrine tumour biopsy accurately determine pathological characteristics? Dig Liver Dis. 2015;47(11):973-977. doi: 10.1016/j.dld.2015.06.005Старков Ю.Г., Солодинина Е.Н., Егоров А.В. и др. Эндоскопическая ультрасонография в диагностике нейроэндокринных опухолей поджелудочной железы // Экспериментальная и клиническая гастроэнтерология. — 2010. — №10. — С. 37—45. [Starkov IG, Solodinina EN, Egorov AV, et al. Endoscopic ultrasonography in the diagnosis of neuroendocrine tumors of the pancreas.Eksperimental’naya i Klinicheskaya Gastroenterologiya. 2010;(10):37-45. (In Russ.).]Старков Ю.Г., Солодинина Е.Н., Егоров А.В. и др. Эндоскопическая ультрасонография в диагностике нейроэндокринных опухолей поджелудочной железы // Экспериментальная и клиническая гастроэнтерология. — 2010. — №10. — С. 37—45. [Starkov IG, Solodinina EN, Egorov AV, et al. Endoscopic ultrasonography in the diagnosis of neuroendocrine tumors of the pancreas.Eksperimental’naya i Klinicheskaya Gastroenterologiya. 2010;(10):37-45. (In Russ.).]Ishikawa T, Itoh A, Kawashima H, et al. Usefulness of EUS combined with contrast-enhancement in the differential diagnosis of malignant versus benign and preoperative localization of pancreatic endocrine tumors. Gastrointest Endosc. 2010;71(6):951-959. doi: 10.1016/j.gie.2009.12.023Ishikawa T, Itoh A, Kawashima H, et al. Usefulness of EUS combined with contrast-enhancement in the differential diagnosis of malignant versus benign and preoperative localization of pancreatic endocrine tumors. Gastrointest Endosc. 2010;71(6):951-959. doi: 10.1016/j.gie.2009.12.023Lin XZ, Wu ZY, Tao R, et al. Dual energy spectral CT imaging of insulinoma-Value in preoperative diagnosis compared with conventional multi-detector CT. Eur J Radiol. 2012;81(10):2487-2494. doi: 10.1016/j.ejrad.2011.10.028Lin XZ, Wu ZY, Tao R, et al. Dual energy spectral CT imaging of insulinoma-Value in preoperative diagnosis compared with conventional multi-detector CT. Eur J Radiol. 2012;81(10):2487-2494. doi: 10.1016/j.ejrad.2011.10.028Won JGS, Tseng H-S, Yang A-H, et al. Intra-arterial calcium stimulation test for detection of insulinomas: detection rate, responses of pancreatic peptides, and its relationship to differentiation of tumor cells. Metabolism. 2003;52(10):1320-1329. doi: 10.1016/s0026-0495(03)00200-2Won JGS, Tseng H-S, Yang A-H, et al. Intra-arterial calcium stimulation test for detection of insulinomas: detection rate, responses of pancreatic peptides, and its relationship to differentiation of tumor cells. Metabolism. 2003;52(10):1320-1329. doi: 10.1016/s0026-0495(03)00200-2Desimone ME, Weinstock RS. Non-Diabetic Hypoglycemia. [Updated 2016 Mar 25]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. 2000—2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK355894/Desimone ME, Weinstock RS. Non-Diabetic Hypoglycemia. [Updated 2016 Mar 25]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. 2000—2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK355894/Ambrosini V, Nanni C, Fanti S. The use of gallium-68 labeled somatostatin receptors in PET/CT imaging. PET Clinics. 2014;9(3):323-329. doi: 10.1016/j.cpet.2014.03.008Ambrosini V, Nanni C, Fanti S. The use of gallium-68 labeled somatostatin receptors in PET/CT imaging. PET Clinics. 2014;9(3):323-329. doi: 10.1016/j.cpet.2014.03.008Wild D, Christ E, Caplin ME, et al. Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J Nucl Med. 2011;52(7):1073-1078. doi: 10.2967/jnumed.110.085142Wild D, Christ E, Caplin ME, et al. Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J Nucl Med. 2011;52(7):1073-1078. doi: 10.2967/jnumed.110.085142Christ E, Wild D, Ederer S, et al. Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. Lancet Diabet Endocrinol. 2013;1(2):115-122. doi: 10.1016/s2213-8587(13)70049-4Christ E, Wild D, Ederer S, et al. Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. Lancet Diabet Endocrinol. 2013;1(2):115-122. doi: 10.1016/s2213-8587(13)70049-4Antwi K, Fani M, Heye T, et al. Localisation of insulinoma: comparison of glucagon-like peptide-1 receptor (GLP1-R) SPECT/CT, PET/CT and MRI. Preliminary results of a prospective clinical study. J Nucl Med. 2015;56(supplement 3):144-144.Antwi K, Fani M, Heye T, et al. Localisation of insulinoma: comparison of glucagon-like peptide-1 receptor (GLP1-R) SPECT/CT, PET/CT and MRI. Preliminary results of a prospective clinical study. J Nucl Med. 2015;56(supplement 3):144-144.Iglesias P, Lafuente C, Martín Almendra MÁ, et al. Insulinoma: a multicenter, retrospective analysis of three decades of experience (1983—2014). Endocrinología y Nutrición (English Edition). 2015;62(7):306-313. doi: 10.1016/j.endoen.2015.08.006Iglesias P, Lafuente C, Martín Almendra MÁ, et al. Insulinoma: a multicenter, retrospective analysis of three decades of experience (1983—2014). Endocrinología y Nutrición (English Edition). 2015;62(7):306-313. doi: 10.1016/j.endoen.2015.08.006Gama R. Best practice No 173: clinical and laboratory investigation of adult spontaneous hypoglycaemia. J Clin Pathol. 2003;56(9):641-646. doi: 10.1136/jcp.56.9.641Gama R. Best practice No 173: clinical and laboratory investigation of adult spontaneous hypoglycaemia. J Clin Pathol. 2003;56(9):641-646. doi: 10.1136/jcp.56.9.641Carrère N, Mathonnet M, Mirallié É, et al. Surgical treatment. Ann Endocrinol (Paris). 2013;74(3):191-195. doi: 10.1016/j.ando.2013.05.004Carrère N, Mathonnet M, Mirallié É, et al. Surgical treatment. Ann Endocrinol (Paris). 2013;74(3):191-195. doi: 10.1016/j.ando.2013.05.004Carneiro DM, Levi JU, Irvin GL, 3rd. Rapid insulin assay for intraoperative confirmation of complete resection of insulinomas. Surgery. 2002;132(6):937-942; discussion 942-933. doi: 10.1067/msy.2002.128481Carneiro DM, Levi JU, Irvin GL, 3rd. Rapid insulin assay for intraoperative confirmation of complete resection of insulinomas. Surgery. 2002;132(6):937-942; discussion 942-933. doi: 10.1067/msy.2002.128481Tabarin A, Goichot B, French Endocrine S. Treatment: symptomatic treatment of hypoglycaemia. Ann Endocrinol (Paris). 2013;74(3):196-199. doi: 10.1016/j.ando.2013.05.009Tabarin A, Goichot B, French Endocrine S. Treatment: symptomatic treatment of hypoglycaemia. Ann Endocrinol (Paris). 2013;74(3):196-199. doi: 10.1016/j.ando.2013.05.009Nakamura A, Mitsuhashi T, Takano Y, et al. Usefulness of the octreotide test in Japanese patients for predicting the presence/absence of somatostatin receptor 2 expression in insulinomas. Endocr J. 2016;63(2):135-142. doi: 10.1507/endocrj.EJ15-0371Nakamura A, Mitsuhashi T, Takano Y, et al. Usefulness of the octreotide test in Japanese patients for predicting the presence/absence of somatostatin receptor 2 expression in insulinomas. Endocr J. 2016;63(2):135-142. doi: 10.1507/endocrj.EJ15-0371Gullo D, Evans JL, Sortino G, et al. Insulin autoimmune syndrome (Hirata Disease) in European Caucasians taking alpha-lipoic acid. Clin Endocrinol (Oxf). 2014;81(2):204-209. doi: 10.1111/cen.12334Gullo D, Evans JL, Sortino G, et al. Insulin autoimmune syndrome (Hirata Disease) in European Caucasians taking alpha-lipoic acid. Clin Endocrinol (Oxf). 2014;81(2):204-209. doi: 10.1111/cen.12334Okabayashi T, Shima Y, Sumiyoshi T, et al. Diagnosis and management of insulinoma. World J Gastroenterol. 2013;19(6):829-837. doi: 10.3748/wjg.v19.i6.829Okabayashi T, Shima Y, Sumiyoshi T, et al. Diagnosis and management of insulinoma. World J Gastroenterol. 2013;19(6):829-837. doi: 10.3748/wjg.v19.i6.829Quinn TJ, Yuan Z, Adem A, et al. Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model. Surgery. 2012;152(6):1068-1077. doi: 10.1016/j.surg.2012.08.021Quinn TJ, Yuan Z, Adem A, et al. Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model. Surgery. 2012;152(6):1068-1077. doi: 10.1016/j.surg.2012.08.021Tirosh A, Stemmer SM, Solomonov E, et al. Pasireotide for malignant insulinoma. Hormones (Athens). 2016;15(2):271-276. doi: 10.14310/horm.2002.1639Tirosh A, Stemmer SM, Solomonov E, et al. Pasireotide for malignant insulinoma. Hormones (Athens). 2016;15(2):271-276. doi: 10.14310/horm.2002.1639Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005;54 Suppl 4:iv1-iv16. doi: 10.1136/gut.2004.053314Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005;54 Suppl 4:iv1-iv16. doi: 10.1136/gut.2004.053314Scoazec JY, Couvelard A, Leteurtre E, et al. Pathology. Ann Endocrinol (Paris). 2013;74(3):203-206. doi: 10.1016/j.ando.2013.05.005Scoazec JY, Couvelard A, Leteurtre E, et al. Pathology. Ann Endocrinol (Paris). 2013;74(3):203-206. doi: 10.1016/j.ando.2013.05.005Díaz Pérez JÁ, Currás Freixes M. Chromogranin A and neuroendocrine tumors. Endocrinología y Nutrición (English Edition). 2013;60(7):386-395. doi: 10.1016/j.endoen.2012.10.007Díaz Pérez JÁ, Currás Freixes M. Chromogranin A and neuroendocrine tumors. Endocrinología y Nutrición (English Edition). 2013;60(7):386-395. doi: 10.1016/j.endoen.2012.10.007Qiao X-W, Qiu L, Chen Y-J, et al. Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas. BMC Endocr Disord. 2014;14(1). doi: 10.1186/1472-6823-14-64Qiao X-W, Qiu L, Chen Y-J, et al. Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas. BMC Endocr Disord. 2014;14(1). doi: 10.1186/1472-6823-14-64Ramachandran R, Bech P, Murphy KG, et al. Comparison of the utility of cocaine- and amphetamine-regulated transcript (CART), chromogranin A, and chromogranin B in neuroendocrine tumor diagnosis and assessment of disease progression. J Clin Endocr Metab. 2015;100(4):1520-1528. doi: 10.1210/jc.2014-3640Ramachandran R, Bech P, Murphy KG, et al. Comparison of the utility of cocaine- and amphetamine-regulated transcript (CART), chromogranin A, and chromogranin B in neuroendocrine tumor diagnosis and assessment of disease progression. J Clin Endocr Metab. 2015;100(4):1520-1528. doi: 10.1210/jc.2014-3640Tomita T. PGP 9.5 immunocytochemical staining for pancreatic endocrine tumors. Islets. 2014;5(3):122-128. doi: 10.4161/isl.25351Tomita T. PGP 9.5 immunocytochemical staining for pancreatic endocrine tumors. Islets. 2014;5(3):122-128. doi: 10.4161/isl.25351Jakobsen AM, Ahlman H, Kölby L, et al. NESP55, a novel chromogranin-like peptide, is expressed in endocrine tumours of the pancreas and adrenal medulla but not in ileal carcinoids. Br J Cancer. 2003;88(11):1746-1754. doi: 10.1038/sj.bjc.6600924Jakobsen AM, Ahlman H, Kölby L, et al. NESP55, a novel chromogranin-like peptide, is expressed in endocrine tumours of the pancreas and adrenal medulla but not in ileal carcinoids. Br J Cancer. 2003;88(11):1746-1754. doi: 10.1038/sj.bjc.6600924Raffel A, Eisenberger CF, Cupisti K, et al. Increased EpCAM expression in malignant insulinoma: potential clinical implications. Eur J Endocrinol. 2010;162(2):391-398. doi: 10.1530/eje-08-0916Raffel A, Eisenberger CF, Cupisti K, et al. Increased EpCAM expression in malignant insulinoma: potential clinical implications. Eur J Endocrinol. 2010;162(2):391-398. doi: 10.1530/eje-08-0916Krug S, Kuhnemuth B, Griesmann H, et al. CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms. Endocrine Related Cancer. 2014;21(6):879-890. doi: 10.1530/erc-14-0152Krug S, Kuhnemuth B, Griesmann H, et al. CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms. Endocrine Related Cancer. 2014;21(6):879-890. doi: 10.1530/erc-14-0152Alkatout I, Friemel J, Sitek B, et al. Novel prognostic markers revealed by a proteomic approach separating benign from malignant insulinomas. Mod Pathol. 2014;28(1):69-79. doi: 10.1038/modpathol.2014.82Alkatout I, Friemel J, Sitek B, et al. Novel prognostic markers revealed by a proteomic approach separating benign from malignant insulinomas. Mod Pathol. 2014;28(1):69-79. doi: 10.1038/modpathol.2014.82Minnetti M, Grossman A. Somatic and germline mutations in NETs: Implications for their diagnosis and management. Best Pract Res Clin Endocrinol Metab. 2016;30(1):115-127. doi: 10.1016/j.beem.2015.09.007Minnetti M, Grossman A. Somatic and germline mutations in NETs: Implications for their diagnosis and management. Best Pract Res Clin Endocrinol Metab. 2016;30(1):115-127. doi: 10.1016/j.beem.2015.09.007Gillam MP, Nimbalkar D, Sun L, et al. MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2. Oncogene. 2015;34(7):932-938. doi: 10.1038/onc.2014.3Gillam MP, Nimbalkar D, Sun L, et al. MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2. Oncogene. 2015;34(7):932-938. doi: 10.1038/onc.2014.3Hamze Z, Vercherat C, Bernigaud-Lacheretz A, et al. Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma. Endocr Relat Cancer. 2013;20(6):833-848. doi: 10.1530/ERC-13-0164Hamze Z, Vercherat C, Bernigaud-Lacheretz A, et al. Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma. Endocr Relat Cancer. 2013;20(6):833-848. doi: 10.1530/ERC-13-0164Karpathakis A, Dibra H, Thirlwell C. Neuroendocrine tumours: cracking the epigenetic code. Endocr Relat Cancer. 2013;20(3):R65-R82. doi: 10.1530/ERC-12-0338Karpathakis A, Dibra H, Thirlwell C. Neuroendocrine tumours: cracking the epigenetic code. Endocr Relat Cancer. 2013;20(3):R65-R82. doi: 10.1530/ERC-12-0338Dejeux E, Olaso R, Dousset B, et al. Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression. Endocr Relat Cancer. 2009;16(3):939-952. doi: 10.1677/ERC-08-0331Dejeux E, Olaso R, Dousset B, et al. Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression. Endocr Relat Cancer. 2009;16(3):939-952. doi: 10.1677/ERC-08-0331Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab. 2007;21(1):1-14. doi: 10.1016/j.beem.2006.12.001Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab. 2007;21(1):1-14. doi: 10.1016/j.beem.2006.12.001Cromer MK, Choi M, Nelson-Williams C, et al. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. Proc Natl Acad Sci USA. 2015;112(13):4062-4067. doi: 10.1073/pnas.1503696112Cromer MK, Choi M, Nelson-Williams C, et al. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. Proc Natl Acad Sci USA. 2015;112(13):4062-4067. doi: 10.1073/pnas.1503696112Masjkur J, Arps-Forker C, Poser SW, et al. Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release. J Biol Chem. 2014;289(51):35503-35516. doi: 10.1074/jbc.M114.590687Masjkur J, Arps-Forker C, Poser SW, et al. Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release. J Biol Chem. 2014;289(51):35503-35516. doi: 10.1074/jbc.M114.590687Liu SH, Rao DD, Nemunaitis J, et al. PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform. PLoS One. 2012;7(8):e40452. doi: 10.1371/journal.pone.0040452Liu SH, Rao DD, Nemunaitis J, et al. PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform. PLoS One. 2012;7(8):e40452. doi: 10.1371/journal.pone.0040452Desai SS, Modali SD, Parekh VI, et al. GSK-3beta protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation. J Biol Chem. 2014;289(9):5386-5398. doi: 10.1074/jbc.M113.533612Desai SS, Modali SD, Parekh VI, et al. GSK-3beta protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation. J Biol Chem. 2014;289(9):5386-5398. doi: 10.1074/jbc.M113.533612Cheung SS, Ou D, Metzger DL, et al. B7-H4 expression in normal and diseased human islet beta cells. Pancreas. 2014;43(1):128-134. doi: 10.1097/MPA.0b013e31829695d2Cheung SS, Ou D, Metzger DL, et al. B7-H4 expression in normal and diseased human islet beta cells. Pancreas. 2014;43(1):128-134. doi: 10.1097/MPA.0b013e31829695d2Metukuri MR, Zhang P, Basantani MK, et al. ChREBP mediates glucose-stimulated pancreatic beta-cell proliferation. Diabetes. 2012;61(8):2004-2015. doi: 10.2337/db11-0802Metukuri MR, Zhang P, Basantani MK, et al. ChREBP mediates glucose-stimulated pancreatic beta-cell proliferation. Diabetes. 2012;61(8):2004-2015. doi: 10.2337/db11-0802Zhao F, Huang F, Tang M, et al. Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 beta-cells. Am J Physiol Endocrinol Metab. 2012;303(1):E132-E143. doi: 10.1152/ajpendo.00074.2012Zhao F, Huang F, Tang M, et al. Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 beta-cells. Am J Physiol Endocrinol Metab. 2012;303(1):E132-E143. doi: 10.1152/ajpendo.00074.2012Kim HS, Han TY, Yoo YM. Melatonin-Mediated Intracellular Insulin during 2-deoxy-d-glucose treatment is reduced through autophagy and EDC3 protein in insulinoma INS-1E cells. Oxid Med Cell Longev. 2016;2016:2594703. doi: 10.1155/2016/2594703Kim HS, Han TY, Yoo YM. Melatonin-Mediated Intracellular Insulin during 2-deoxy-d-glucose treatment is reduced through autophagy and EDC3 protein in insulinoma INS-1E cells. Oxid Med Cell Longev. 2016;2016:2594703. doi: 10.1155/2016/2594703Reubi JC, Waser B. Triple-peptide receptor targeting in vitro allows detection of all tested gut and bronchial NETs. J Nucl Med. 2015;56(4):613-615. doi: 10.2967/jnumed.114.153189Reubi JC, Waser B. Triple-peptide receptor targeting in vitro allows detection of all tested gut and bronchial NETs. J Nucl Med. 2015;56(4):613-615. doi: 10.2967/jnumed.114.153189Tomita T, Masuzaki H, Noguchi M, et al. GPR40 gene expression in human pancreas and insulinoma. Biochem Biophys Res Commun. 2005;338(4):1788-1790. doi: 10.1016/j.bbrc.2005.10.161Tomita T, Masuzaki H, Noguchi M, et al. GPR40 gene expression in human pancreas and insulinoma. Biochem Biophys Res Commun. 2005;338(4):1788-1790. doi: 10.1016/j.bbrc.2005.10.161Odori S, Hosoda K, Tomita T, et al. GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function. Metabolism. 2013;62(1):70-78. doi: 10.1016/j.metabol.2012.06.010Odori S, Hosoda K, Tomita T, et al. GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function. Metabolism. 2013;62(1):70-78. doi: 10.1016/j.metabol.2012.06.010Li C-J, Zhou H-L, Li J, et al. Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma. Hepatobiliary Pancreat Dis Int. 2011;10(1):88-94. doi: 10.1016/s1499-3872(11)60013-1Li C-J, Zhou H-L, Li J, et al. Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma. Hepatobiliary Pancreat Dis Int. 2011;10(1):88-94. doi: 10.1016/s1499-3872(11)60013-1

The authors declare that there are no conflicts of interest present.