Insulinoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]


Insulinoma arises from β islet cells, which are endocrine cells that are normally involved in the production of insulin. It is thought that insulinoma is mediated by mTOR/P70S6K signaling pathway. Thus, inhibitors of mTOR (rapamycin) or dual PI3K/mTOR (NVP-BEZ2235) have become new drugs for treating insulinoma. YY1 gene is mutated by T372R mutation that causes a defect in mitochondrial function for glucose-stimulated insulin action which is thought to be involved in mTOR pathway. The progression to hypoglycemia is actually because of decreased glucose synthesis rather than increased use due to the direct effect of insulin on the liver. Insulinoma is transmitted in an autosomal dominant pattern when it is associated with MEN 1 syndrome. They are usually small (90%), sporadic (90%), solitary (90%) and benign (90%) tumors. On gross pathology insulinomas are encapsulated and have a gray to red-brown appearance. On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with amyloid in the fibrovascular stroma, are characteristic findings of insulinoma. It is also evaluated for the mitotic index (mitosis per 10 high power field) and immunohistochemistry staining by Chromogranin A, synaptophysin, and Ki-67 index. The structure of tumor cells observed under electron microscopy as group A characterized by abundant well-granulated typical β cells with a trabecular arrangement and group B as scarce well-granulated typical β cells and a medullary arrangement.




Associated Conditions

The following conditions are associated with insulinomas:

Gross Pathology

  • On gross pathology insulinoma is encapsulated and have a gray to red brown appearance.[12]
  • They are usually small and solitary tumors, although there is a case report of a large (9 cm), pedunculated insulinoma and weighing more than 100 grams.[13]
Insulinoma- Red brown appearance. By Edward Alabraba et al. [14]
  • Almost all insulinomas are present throughout the pancreas and extrapancreatic ones causing hypoglycemia are rare (<2%)[15]

Microscopic Pathology


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  3. 3.0 3.1 Service FJ, McMahon MM, O'Brien PC, Ballard DJ (1991). "Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study". Mayo Clin Proc. 66 (7): 711–9. PMID 1677058.
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  5. Zhan HX, Cong L, Zhao YP, Zhang TP, Chen G, Zhou L; et al. (2012). "Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis". J Surg Oncol. 106 (8): 972–80. doi:10.1002/jso.23176. PMID 22711648.
  6. Supale S, Li N, Brun T, Maechler P (2012). "Mitochondrial dysfunction in pancreatic β cells". Trends Endocrinol Metab. 23 (9): 477–87. doi:10.1016/j.tem.2012.06.002. PMID 22766318.
  7. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007). "mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex". Nature. 450 (7170): 736–40. doi:10.1038/nature06322. PMID 18046414.
  8. Cao, Yanan; Gao, Zhibo; Li, Lin; Jiang, Xiuli; Shan, Aijing; Cai, Jie; Peng, Ying; Li, Yanli; Jiang, Xiaohua; Huang, Xuanlin; Wang, Jiaqian; Wei, Qing; Qin, Guijun; Zhao, Jiajun; Jin, Xiaolong; Liu, Li; Li, Yingrui; Wang, Weiqing; Wang, Jun; Ning, Guang (2013). "Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1". Nature Communications. 4. doi:10.1038/ncomms3810. ISSN 2041-1723.
  9. Rizza, R. A.; Haymond, M. W.; Verdonk, C. A.; Mandarino, L. J.; Miles, J. M.; Service, F. J.; Gerich, J. E. (1981). "Pathogenesis of Hypoglycemia in Insulinoma Patients: Suppression of Hepatic Glucose Production by Insulin". Diabetes. 30 (5): 377–381. doi:10.2337/diab.30.5.377. ISSN 0012-1797.
  10. Abe T (1992). "[Letter from Alabama--Medicaid and Medicare]". Kango. 44 (2): 135–40. PMID 1305178.
  11. Shin JJ, Gorden P, Libutti SK (2010). "Insulinoma: pathophysiology, localization and management". Future Oncol. 6 (2): 229–37. doi:10.2217/fon.09.165. PMC 3498768. PMID 20146582.
  12. Lloyd, Ricardo (2010). Endocrine pathology : differential diagnosis and molecular advances. New York London: Springer. ISBN 978-1441910684.
  13. Mittendorf EA, Liu YC, McHenry CR (2005). "Giant insulinoma: case report and review of the literature". J Clin Endocrinol Metab. 90 (1): 575–80. doi:10.1210/jc.2004-0825. PMID 15522939.
  14. Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1. World Journal of Surgical Oncology 2009, 7:18doi:10.1186/1477-7819-7-18, CC BY 2.0, Source:
  15. Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y, Kobayashi M, Hanazaki K (2013). "Diagnosis and management of insulinoma". World J. Gastroenterol. 19 (6): 829–37. doi:10.3748/wjg.v19.i6.829. PMC 3574879. PMID 23430217.
  16. 16.0 16.1 de Herder, Wouter W.; Niederle, Bruno; Scoazec, Jean-Yves; Pauwels, Stanislas; Klöppel, Günter; Falconi, Massimo; Kwekkeboom, Dik J.; Öberg, Kjel; Eriksson, Barbro; Wiedenmann, Bertram; Rindi, Guido; O’Toole, Dermot; Ferone, Diego (2007). "Well-Differentiated Pancreatic Tumor/Carcinoma: Insulinoma". Neuroendocrinology. 84 (3): 183–188. doi:10.1159/000098010. ISSN 0028-3835.
  17. Lloyd, Ricardo (2010). Endocrine pathology : differential diagnosis and molecular advances. New York London: Springer. ISBN 978-1441910684.
  18. Berger M, Bordi C, Cüppers HJ, Berchtold P, Gries FA, Münterfering H; et al. (1983). "Functional and morphologic characterization of human insulinomas". Diabetes. 32 (10): 921–31. PMID 6311653.
  19. 19.0 19.1 19.2 Neuroendocrine tumor of the pancreas. Libre Pathology.