Preview

Problems of Endocrinology

Advanced search

The hypoglicemic syndrome (insulinoma): topical, pathomorphological, and genetic diagnostics and treatment (review, part 2)

https://doi.org/10.14341/probl2017635346-355

Abstract

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.

About the Authors

Marina Yu. Yukina

Endocrinology Research Centre


Russian Federation

MD, PhD



Nurana F. Nuralieva

Endocrinology Research Centre


Russian Federation


Ekaterina A. Troshina

Endocrinology Research Centre


Russian Federation

MD, PhD, Professor



Nikolay S. Kuznetsov

Endocrinology Research Centre


Russian Federation

MD, PhD



Nadezhda M. Platonova

Endocrinology Research Centre


Russian Federation

MD, PhD



References

1. McAuley 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.2005.06.005

2. Бельцевич 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: 10.14341/2306-3513-2012-3-8-40

3. Cryer 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.2008-1410

4. An 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.2010.09.014

5. Taieb 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.2013.05.008

6. 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.

7. 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.2015.06.005

8. 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.).]

9. 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.2009.12.023

10. Lin 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.2011.10.028

11. Won 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)00200-2

12. 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/

13. 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.2014.03.008

14. Wild 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.110.085142

15. Christ 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)70049-4

16. 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.

17. 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.2015.08.006

18. Gama 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.56.9.641

19. Carrère N, Mathonnet M, Mirallié É, et al. Surgical treatment. Ann Endocrinol (Paris). 2013;74(3):191-195. doi: 10.1016/j.ando.2013.05.004

20. Carneiro 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.2002.128481

21. Tabarin A, Goichot B, French Endocrine S. Treatment: symptomatic treatment of hypoglycaemia. Ann Endocrinol (Paris). 2013;74(3):196-199. doi: 10.1016/j.ando.2013.05.009

22. Nakamura 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.EJ15-0371

23. Gullo 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.12334

24. Okabayashi 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.i6.829

25. Quinn 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.2012.08.021

26. Tirosh A, Stemmer SM, Solomonov E, et al. Pasireotide for malignant insulinoma. Hormones (Athens). 2016;15(2):271-276. doi: 10.14310/horm.2002.1639

27. Ramage 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.2004.053314

28. Scoazec JY, Couvelard A, Leteurtre E, et al. Pathology. Ann Endocrinol (Paris). 2013;74(3):203-206. doi: 10.1016/j.ando.2013.05.005

29. Díaz 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.2012.10.007

30. Qiao 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: 10.1186/1472-6823-14-64

31. Ramachandran 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.2014-3640

32. Tomita T. PGP 9.5 immunocytochemical staining for pancreatic endocrine tumors. Islets. 2014;5(3):122-128. doi: 10.4161/isl.25351

33. Jakobsen 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.6600924

34. Raffel 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-08-0916

35. Krug 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-14-0152

36. Alkatout 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.2014.82

37. Minnetti 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.2015.09.007

38. Gillam 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.2014.3

39. Hamze 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-13-0164

40. Karpathakis A, Dibra H, Thirlwell C. Neuroendocrine tumours: cracking the epigenetic code. Endocr Relat Cancer. 2013;20(3):R65-R82. doi: 10.1530/ERC-12-0338

41. Dejeux 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-08-0331

42. Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab. 2007;21(1):1-14. doi: 10.1016/j.beem.2006.12.001

43. Cromer 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.1503696112

44. Masjkur 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.M114.590687

45. Liu 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.0040452

46. Desai 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.M113.533612

47. Cheung 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.0b013e31829695d2

48. Metukuri MR, Zhang P, Basantani MK, et al. ChREBP mediates glucose-stimulated pancreatic beta-cell proliferation. Diabetes. 2012;61(8):2004-2015. doi: 10.2337/db11-0802

49. Zhao 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.00074.2012

50. Kim 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: 10.1155/2016/2594703

51. Reubi 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.114.153189

52. Tomita 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.2005.10.161

53. Odori 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.2012.06.010

54. Li 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


Review

For citations:


Yukina M.Yu., Nuralieva N.F., Troshina E.A., Kuznetsov N.S., Platonova N.M. The hypoglicemic syndrome (insulinoma): topical, pathomorphological, and genetic diagnostics and treatment (review, part 2). Problems of Endocrinology. 2017;63(5):346-355. https://doi.org/10.14341/probl2017635346-355

Views: 8549


ISSN 0375-9660 (Print)
ISSN 2308-1430 (Online)