Keywords
hypoglycemia
insulinoma
nesidioblastosis
insulinomatosis
pancreatic neuroendocrine
insulinoma
nesidioblastosis
insulinomatosis
pancreatic neuroendocrine
How to Cite
Jaramillo Chacón, H., González Devia, D., López Panqueva, R. P., Cañon Solano, D., Aguirre Matallana, D., Rey Rubiano, A. M., Segovia Gómez, J. M., & Dussan Flórez, R. F. (2020). Insulinomatosis: a very rare cause of pancreatic neuroendocrine tumor. Revista Colombiana De Endocrinología, Diabetes &Amp; Metabolismo, 7(2), 76–85. https://doi.org/10.53853/encr.7.2.607
Abstract
Pancreatic neuroendocrine tumors represent 2-10 % of all tumors of the pancreas and approximately 7 % of all neuroendocrine tumors. They are classified as functioning or non-functioning depending on the presence or absence of clinical syndromes associated with hormonal hypersecretion. Insulinomas are the most frequent functioning pancreatic neuroendocrine tumors (45 % of cases), and the most frequent cause of persistent hyperinsulinemic hypoglycemia in adults. Furthermore, 10 % of pancreatic neuroendocrine tumors are associated with multiple endocrine neoplasia type 1 (MEN-1). Insulinomatosis is a distinct clinical entity in which there are multiple insulinomas.
Objectives: Present the cases reported to the date of insulinomatosis and describe the genetic causes, clinical characteristics, treatment and prognosis of insulinomatosis.
Methods: A search about insulinomatosis and the factors that govern beta cells proliferation was conducted in the databases of PubMed, Medline and Google Scholar until July 2020.
Results: 108 cases of patients with insulinomatosis have been reported to date, is recurrent and rarely malignant; multiple protooncogenes and tumor suppressors control locally and systemically the growth of beta cells; however, few have been studied in the tumoral landscape, and MafA mutation in p.Ser64Phe has been involved.
Conclusion: Insulinomatosis is characterized by the synchronous and metachronous occurrence of insulinomas; it has a histological, clinical and genetic phenotype different from other pancreatic neuroendocrine tumors. MEN-1 genetic testing is negative, can be sporadic or hereditary, and MafA could be a driver mutation.
References
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3. Harris S. Hyperinsulinism and dysinsulinism. JAMA. 1924;83(10):729- 733.
4. Parker JT, Finley CS. Some results obtained by the treatment of nervous phenomena with glucose. Proc Soc Exper Biol Med. 1924;21(8):517-9.
5. Wolf A, Hare CC, and Riggs HW. Neurological Manifestations in Two Patients with Spontaneous Hypoglycemia; with Necropsy Report of a Case of Pancreatic Island Adenomata. Bull Neurol Inst. 1933;3:232.
6. Harris S. Hyperinsulinism, a Definite Disease Entity. JAMA. 1933;101(25):1958-65.
7. Harris S. Epilepsy and Narcolepsy Associated with Hyperinsulinism. JAMA. 1933;100(5):321-328.
8. Harris S. The Diagnosis of Surgical Hyperinsulinism. Southern Surgeon. 1934;3:199.
9. Harris S Nomenclature of the Disorders of Insulin Secretion; Diabetes Mellitus, Hyperinsulinism and Dysinsulinism. Ann Int Med.1934;7:1084-100.
10. Wilder RM. Hyperinsulinism (Colver Lecture). Internat Clin. 1933;2:1-18.
11. Wauchope GM. Critical Review. Hypoglycemia. Qt J Med. 1933;2:117.
12. Restrepo K, Garavito G, Rojas L, et al. Nesidioblastosis del adulto coexistente con insulinoma: Reporte de caso. Rev Colomb Cancerol. 2009;13(1):49-60.
13. Leong AS, Slavotinek AH, Higgins BA. Nesidioblastosis, islet cell hyperplasia, and adenomatosis in a case of metastasizing insulinoma: contribution to the genesis of the islets of Langerhans. Diabetes Care. 1980;3(4):537- 42.
14. Bettini V, Martini C, Ferrata M, et al. Hypoglycemic Syndrome Recurrence after Surgical Removal of a Pancreatic Neuroendocrine Adenoma. Abstract #958. 11th Annual ENETS Conference; 2014.
15. González-Devia D, Gómez-Escobar G, López-Panqueva R, et al. Recurrent Hypoglycemia Related By Sporadic Malignant Insulinomatosis: Case Report. Abstract # O09, 16th Annual ENETS Conference 2019 [Internet]. Enets.org. 2020 [citado el 14 de agosto de 2020]. Disponible en:
https://www.enets.org/16th_annual_enets_conference.html
16. Iacovazzo D, Flanagan SE, Walker E, et al. MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. Proceedings of the National Academy of Sciences. 2018;115(5):1027-32.
17. Schmitt J, Boullu-Sanchis S, Moreau F, et al. Association of malignant insulinoma and type 2 diabetes mellitus: a case report. Ann Endocrinol. 2008;69(1):69-72.
18. Sakurai A, Aizawa T, Katakura M, et al. Insulinoma in a patient with Non-Insulin-dependent Diabetes Mellitus. Endocrine Journal. 1997,44(4):473-7.
19. Anlauf M, Bauersfeld J, Raffel A, Koch CA, Henopp T, Alkatout I, et al. Insulinomatosis: multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia. Am J Surg Pathol. 2009;33(3):339-46.
20. Rothmund M, Angelini L, Brunt LM, et al. Surgery for benign insulinoma: an international review. World J Surg. 1990;14(3):393-8.
21. Nikfarjam M, Warshaw AL, Axelrod L, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg. 2008;247(1):165-72.
22. Zhao YP, Zhan HX, Cong L, Zhang TP, Liao Q, Dai MH, et al. Risk factors for postoperative pancreatic fistula in patients with insulinomas: analysis of 292 consecutive cases. Hepatobiliary Pancreat Dis Int 2012;11(1):102- 106.
23. Crippa S, Zerbi A, Boninsegna L, Capitanio V, Partelli S, Balzano G, et al. Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Arch Surg. 2012;147(3):261-6.
24. Akca A, Wirowski D, Starke AAR, Goretzki PE. Follow-Up in Adult Patients with Pancreatogenic Hypoglycemia Caused by Sporadic Micro- or MacroInsulinomatosis: 16 Years of Experience in One Center. J Diabetes Treat. 2018;JDBT-144.
25. Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40(1):1-18, vii.
26. Mckenna LR, Edil BH. Update on pancreatic neuroendocrine tumors. 2014;3(4):258-75.
27. Guzmán YF, López RP, Vera A, et al. Herramientas para el abordaje diagnóstico de los tumores neuroendocrinos de páncreas. Rev Colomb Cir. 2018,33(1):79-99.
28. Vanderveen K, Grant C. Insulinoma. Cancer Treat Res. 2010;153:235-52.
29. Guettier JM, Gorden P. Insulin secretion and insulin-producing tumors. Expert Rev Endocrinol Metab. 2010;5(2):217-27.
30. De Herder WW, Niederle B, Scoazec JY, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology. 2006;84(3):183-8.
31. Vinik A, Perry RR, Casellini C, Hughes MS, Feliberti E. Pathophysiology and treatment of pancreatic neuroendocrine tumors (PNETs): new developments. InEndotext [Internet] 2018 Jun 12. MDText. com, Inc.
32. Dadan J, Wojskowicz P, Wojskowicz A. Neuroendocrine tumors of the pancreas. Wiad Lek. 2008;61(1-3):43-7
33. Rich TA, Perrier ND. Multiple endocrine neoplasia syndromes. Surg Clin North Am. 2008;88(4):863-95.
34. Demeure MJ, Klonoff DC, Karam JH, et al. Insulinomas associated with multiple endocrine neoplasia type I: the need for a different surgical approach. Surgery. 1991;110:998-1005.
35. O’Riordain DS, Brien T, van Heerden JA, et al. Surgical management of insulinoma associated with multiple endocrine neoplasia type I. World J Surg. 1994;18:488-94.
36. Wills B, López R, González-Devia, et al. Papel de la ultrasonografía intraoperatoria en sujetos con tumores neuroendocrinos de páncreas con sospecha de NEM 1. Rev. Colomb. Radiol. 2014;25(4):4090-5.
37. Le Bodic MF, Heymann MF, Lecomte M, et al. Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. Am J Surg Pathol. 1996;20(11):1378-84.
38. Herxheimer, G. Ueber Pankreascirrhose (bei Diabetes). Arch f path Anat u Phys. 1906:183:228.
39. Tragl KH, Mayr WR. Familial islet-cell adenomatosis. Lancet. 1977;2:426- 8.
40. Hellman P, Goretzki P, Simon D, Dotzenrath C, Röher HD. Therapeutic experience of 65 cases with organic hyperinsulinism. Langenbecks Arch Surg. 2000;385(5):329-36.
41. Rosman J, Bravo-Vera R, Sheikh A, Gouller A. Metastatic insulinoma in an adult patient with underlying nesidioblastosis. J Endocrinol Invest. 2007;30(6):521-4.
42. Sheikh A, Zuberi L, Haque N. Rare among the rarities--recurrent insulinoma. J Coll Physicians Surg Pak. 2007;17(6):364-6.
43. Ishigaki S, Yoshihara A, Ohwada R, Hizuka N, Hatori T, Furukawa T, et al. Insulinoma with six islet cell tumors associated with severe hypoglycemia. Intern Med. 2009;48(12):1041-6.
44. Menassa-Moussa L, Halaby G, Braidy C. Multiple pancreatic insulinomas: multislice CT. Abdom Imaging. 2010;35(6):690-3.
45. Chen PY, Wu TJ, Ou HY, et al. Applying intraoperative insulin level monitoring for tumor removal in a patient with recurrent pancreatic multiple insulinomas. J Formos Med Assoc. 2011;110(6):410-4.
46. Guoqing Y, Dou-Jingtao D, Li Z, Yiming MA. Special Form of Pancreatic Hyperinsulinemic Hypoglycemia -Insulinomatosis: A Case Report. Endocrine Reviews. 2014;35(3): SUN-0288.
47. Babic B, Keutgen X, Nockel P, Miettinen M, Millo C, Herscovitch P, et al. Insulinoma Due to Multiple Pancreatic Microadenoma Localized by Multimodal Imaging. J Clin Endocrinol Metab. 2016;101(10):3559-63.
48. Snaith J y Chipps D. Will this ever end? Recurrent hypoglycaemia due to insulinomatosis. Poster Presentation #271. The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017. Clin Endocrinol. 2018;89:86.
49. Akiko K, Tomoko N, Nobuyuki O, Ja-Mun C. Insulinomatosis: A case repart [Internet]. Jglobal.jst.go.jp. 2020 [citado el 20 de agosto de 2020]. Disponible en:
https://jglobal.jst.go.jp/en/detail?JGLOBAL_ID=201802250401216649
50. Kawabata S, Minamiguchi S, Kataoka TR, Umakoshi H, Haga H, Moriyoshi K. Insulinomatosis, Two cases of pancreatic insulinomatosis [Internet]. Sasappa.co.jp. 2020 [citadado el 20 de agosto de 2020]. Disponible en:
http://www.sasappa.co.jp/online/abstract/jjdp/1/035/html/0910350207.html
51. Alencar N, Nunes M, Segatelli V, Castanheira T, Seraphim C, Pereira M. Insulinomatosis: A Rare Cause of Recurrent Hyperinsulinemic Hypoglycemia. Presentation Number SUN-320 Journal of the Endocrine Society. 2019;3(suppl 1):SU-320.
52. Parsons JA, Brelje TC, Sorenson RL. Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology. 1992;130:1459-66.
53. Rieck S, White P, Schug J, et al. he transcriptional response of the islet to pregnancy in mice. Mol Endocrinol. 2009;23:1702-12.
54. Alonso LC, Yokoe T, Zhang P, et al. Glucose infusion in mice: a new model to induce beta-cell replication. Diabetes. 2007;56(7):1792-801.
55. Cano DA, Rulifson IC, Heiser PW, et al. Regulated ?-cell regeneration in the adult mouse pancreas. Diabetes. 2008;57(4):958-66.
56. Brüning JC, Winnay J, Bonner-Weir S, et al. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997;88(4):561-72.
57. Terauchi, Y, Takamoto I, Kubota N, et al. Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. J Clin Invest. 2007;117:246-57.
58. Porat S, Weinberg-Corem N, Tornovsky-Babaey S, et al. Control of pancreatic ? cell regeneration by glucose metabolism. Cell metabolism. 2011;13(4):440-9.
59. Bernard C, Thibault C, Berthault MF, et al. Pancreatic beta-cell regeneration after 48-h glucose infusion in mildly diabetic rats is not correlated with functional improvement. Diabetes. 1998;47(7):1058-65.
60. Drucker DJ. The biology of incretin hormones. Cell metabolism. 2006;3(3):153-65.
61. Flier SN, Kulkarni RN, Kahn CR. Evidence for a circulating islet cell growth factor in insulin-resistant states. Proceedings of the National Academy of Sciences. 2001;98(13):7475-80.
62. Yuchi Y, Cai Y, Legein B, De Groef S, Leuckx G, Coppens V, et al. Estrogen Receptor ? Regulates ?-Cell Formation During Pancreas Development and Following Injury. Diabetes. 2015;64(9):3218-28.
63. Diana ZY, Tai MH, Linning KD, et al. MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic beta-cells. Diabetes. 2006;55(3):742-50.
64. Ye DZ, Tai MH, Linning KD, et al. MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic beta-cells. Diabetes. 2006;55(3):742-50.
65. Matsuoka TA, Kaneto H, Miyatsuka T, et al. Regulation of MafA expression in pancreatic betacells in db/db mice with diabetes. Diabetes. 2010;59(7):1709-20.
66. Zhang C, Moriguchi T, Kajihara M, et al. MafA is a key regulator of glucosestimulated insulin secretion. Mol Cell Biol. 2005;25(12):4969-76.
67. Kaneto H, Matsuoka TA, Katakami N, Matsuhisa M. Combination of MafA, PDX-1 and NeuroD is a useful tool to efficiently induce insulin-producing surrogate beta-cells. Curr Med Chem. 2009;16(24):3144-51.
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2. Whipple AO, Frautz VK. Adenomas of islet cells with hyperinsulinism: a review. Ann Surg. 1935;101(6):1299-335.
3. Harris S. Hyperinsulinism and dysinsulinism. JAMA. 1924;83(10):729- 733.
4. Parker JT, Finley CS. Some results obtained by the treatment of nervous phenomena with glucose. Proc Soc Exper Biol Med. 1924;21(8):517-9.
5. Wolf A, Hare CC, and Riggs HW. Neurological Manifestations in Two Patients with Spontaneous Hypoglycemia; with Necropsy Report of a Case of Pancreatic Island Adenomata. Bull Neurol Inst. 1933;3:232.
6. Harris S. Hyperinsulinism, a Definite Disease Entity. JAMA. 1933;101(25):1958-65.
7. Harris S. Epilepsy and Narcolepsy Associated with Hyperinsulinism. JAMA. 1933;100(5):321-328.
8. Harris S. The Diagnosis of Surgical Hyperinsulinism. Southern Surgeon. 1934;3:199.
9. Harris S Nomenclature of the Disorders of Insulin Secretion; Diabetes Mellitus, Hyperinsulinism and Dysinsulinism. Ann Int Med.1934;7:1084-100.
10. Wilder RM. Hyperinsulinism (Colver Lecture). Internat Clin. 1933;2:1-18.
11. Wauchope GM. Critical Review. Hypoglycemia. Qt J Med. 1933;2:117.
12. Restrepo K, Garavito G, Rojas L, et al. Nesidioblastosis del adulto coexistente con insulinoma: Reporte de caso. Rev Colomb Cancerol. 2009;13(1):49-60.
13. Leong AS, Slavotinek AH, Higgins BA. Nesidioblastosis, islet cell hyperplasia, and adenomatosis in a case of metastasizing insulinoma: contribution to the genesis of the islets of Langerhans. Diabetes Care. 1980;3(4):537- 42.
14. Bettini V, Martini C, Ferrata M, et al. Hypoglycemic Syndrome Recurrence after Surgical Removal of a Pancreatic Neuroendocrine Adenoma. Abstract #958. 11th Annual ENETS Conference; 2014.
15. González-Devia D, Gómez-Escobar G, López-Panqueva R, et al. Recurrent Hypoglycemia Related By Sporadic Malignant Insulinomatosis: Case Report. Abstract # O09, 16th Annual ENETS Conference 2019 [Internet]. Enets.org. 2020 [citado el 14 de agosto de 2020]. Disponible en:
https://www.enets.org/16th_annual_enets_conference.html
16. Iacovazzo D, Flanagan SE, Walker E, et al. MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. Proceedings of the National Academy of Sciences. 2018;115(5):1027-32.
17. Schmitt J, Boullu-Sanchis S, Moreau F, et al. Association of malignant insulinoma and type 2 diabetes mellitus: a case report. Ann Endocrinol. 2008;69(1):69-72.
18. Sakurai A, Aizawa T, Katakura M, et al. Insulinoma in a patient with Non-Insulin-dependent Diabetes Mellitus. Endocrine Journal. 1997,44(4):473-7.
19. Anlauf M, Bauersfeld J, Raffel A, Koch CA, Henopp T, Alkatout I, et al. Insulinomatosis: multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia. Am J Surg Pathol. 2009;33(3):339-46.
20. Rothmund M, Angelini L, Brunt LM, et al. Surgery for benign insulinoma: an international review. World J Surg. 1990;14(3):393-8.
21. Nikfarjam M, Warshaw AL, Axelrod L, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg. 2008;247(1):165-72.
22. Zhao YP, Zhan HX, Cong L, Zhang TP, Liao Q, Dai MH, et al. Risk factors for postoperative pancreatic fistula in patients with insulinomas: analysis of 292 consecutive cases. Hepatobiliary Pancreat Dis Int 2012;11(1):102- 106.
23. Crippa S, Zerbi A, Boninsegna L, Capitanio V, Partelli S, Balzano G, et al. Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Arch Surg. 2012;147(3):261-6.
24. Akca A, Wirowski D, Starke AAR, Goretzki PE. Follow-Up in Adult Patients with Pancreatogenic Hypoglycemia Caused by Sporadic Micro- or MacroInsulinomatosis: 16 Years of Experience in One Center. J Diabetes Treat. 2018;JDBT-144.
25. Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40(1):1-18, vii.
26. Mckenna LR, Edil BH. Update on pancreatic neuroendocrine tumors. 2014;3(4):258-75.
27. Guzmán YF, López RP, Vera A, et al. Herramientas para el abordaje diagnóstico de los tumores neuroendocrinos de páncreas. Rev Colomb Cir. 2018,33(1):79-99.
28. Vanderveen K, Grant C. Insulinoma. Cancer Treat Res. 2010;153:235-52.
29. Guettier JM, Gorden P. Insulin secretion and insulin-producing tumors. Expert Rev Endocrinol Metab. 2010;5(2):217-27.
30. De Herder WW, Niederle B, Scoazec JY, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology. 2006;84(3):183-8.
31. Vinik A, Perry RR, Casellini C, Hughes MS, Feliberti E. Pathophysiology and treatment of pancreatic neuroendocrine tumors (PNETs): new developments. InEndotext [Internet] 2018 Jun 12. MDText. com, Inc.
32. Dadan J, Wojskowicz P, Wojskowicz A. Neuroendocrine tumors of the pancreas. Wiad Lek. 2008;61(1-3):43-7
33. Rich TA, Perrier ND. Multiple endocrine neoplasia syndromes. Surg Clin North Am. 2008;88(4):863-95.
34. Demeure MJ, Klonoff DC, Karam JH, et al. Insulinomas associated with multiple endocrine neoplasia type I: the need for a different surgical approach. Surgery. 1991;110:998-1005.
35. O’Riordain DS, Brien T, van Heerden JA, et al. Surgical management of insulinoma associated with multiple endocrine neoplasia type I. World J Surg. 1994;18:488-94.
36. Wills B, López R, González-Devia, et al. Papel de la ultrasonografía intraoperatoria en sujetos con tumores neuroendocrinos de páncreas con sospecha de NEM 1. Rev. Colomb. Radiol. 2014;25(4):4090-5.
37. Le Bodic MF, Heymann MF, Lecomte M, et al. Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. Am J Surg Pathol. 1996;20(11):1378-84.
38. Herxheimer, G. Ueber Pankreascirrhose (bei Diabetes). Arch f path Anat u Phys. 1906:183:228.
39. Tragl KH, Mayr WR. Familial islet-cell adenomatosis. Lancet. 1977;2:426- 8.
40. Hellman P, Goretzki P, Simon D, Dotzenrath C, Röher HD. Therapeutic experience of 65 cases with organic hyperinsulinism. Langenbecks Arch Surg. 2000;385(5):329-36.
41. Rosman J, Bravo-Vera R, Sheikh A, Gouller A. Metastatic insulinoma in an adult patient with underlying nesidioblastosis. J Endocrinol Invest. 2007;30(6):521-4.
42. Sheikh A, Zuberi L, Haque N. Rare among the rarities--recurrent insulinoma. J Coll Physicians Surg Pak. 2007;17(6):364-6.
43. Ishigaki S, Yoshihara A, Ohwada R, Hizuka N, Hatori T, Furukawa T, et al. Insulinoma with six islet cell tumors associated with severe hypoglycemia. Intern Med. 2009;48(12):1041-6.
44. Menassa-Moussa L, Halaby G, Braidy C. Multiple pancreatic insulinomas: multislice CT. Abdom Imaging. 2010;35(6):690-3.
45. Chen PY, Wu TJ, Ou HY, et al. Applying intraoperative insulin level monitoring for tumor removal in a patient with recurrent pancreatic multiple insulinomas. J Formos Med Assoc. 2011;110(6):410-4.
46. Guoqing Y, Dou-Jingtao D, Li Z, Yiming MA. Special Form of Pancreatic Hyperinsulinemic Hypoglycemia -Insulinomatosis: A Case Report. Endocrine Reviews. 2014;35(3): SUN-0288.
47. Babic B, Keutgen X, Nockel P, Miettinen M, Millo C, Herscovitch P, et al. Insulinoma Due to Multiple Pancreatic Microadenoma Localized by Multimodal Imaging. J Clin Endocrinol Metab. 2016;101(10):3559-63.
48. Snaith J y Chipps D. Will this ever end? Recurrent hypoglycaemia due to insulinomatosis. Poster Presentation #271. The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017. Clin Endocrinol. 2018;89:86.
49. Akiko K, Tomoko N, Nobuyuki O, Ja-Mun C. Insulinomatosis: A case repart [Internet]. Jglobal.jst.go.jp. 2020 [citado el 20 de agosto de 2020]. Disponible en:
https://jglobal.jst.go.jp/en/detail?JGLOBAL_ID=201802250401216649
50. Kawabata S, Minamiguchi S, Kataoka TR, Umakoshi H, Haga H, Moriyoshi K. Insulinomatosis, Two cases of pancreatic insulinomatosis [Internet]. Sasappa.co.jp. 2020 [citadado el 20 de agosto de 2020]. Disponible en:
http://www.sasappa.co.jp/online/abstract/jjdp/1/035/html/0910350207.html
51. Alencar N, Nunes M, Segatelli V, Castanheira T, Seraphim C, Pereira M. Insulinomatosis: A Rare Cause of Recurrent Hyperinsulinemic Hypoglycemia. Presentation Number SUN-320 Journal of the Endocrine Society. 2019;3(suppl 1):SU-320.
52. Parsons JA, Brelje TC, Sorenson RL. Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology. 1992;130:1459-66.
53. Rieck S, White P, Schug J, et al. he transcriptional response of the islet to pregnancy in mice. Mol Endocrinol. 2009;23:1702-12.
54. Alonso LC, Yokoe T, Zhang P, et al. Glucose infusion in mice: a new model to induce beta-cell replication. Diabetes. 2007;56(7):1792-801.
55. Cano DA, Rulifson IC, Heiser PW, et al. Regulated ?-cell regeneration in the adult mouse pancreas. Diabetes. 2008;57(4):958-66.
56. Brüning JC, Winnay J, Bonner-Weir S, et al. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997;88(4):561-72.
57. Terauchi, Y, Takamoto I, Kubota N, et al. Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. J Clin Invest. 2007;117:246-57.
58. Porat S, Weinberg-Corem N, Tornovsky-Babaey S, et al. Control of pancreatic ? cell regeneration by glucose metabolism. Cell metabolism. 2011;13(4):440-9.
59. Bernard C, Thibault C, Berthault MF, et al. Pancreatic beta-cell regeneration after 48-h glucose infusion in mildly diabetic rats is not correlated with functional improvement. Diabetes. 1998;47(7):1058-65.
60. Drucker DJ. The biology of incretin hormones. Cell metabolism. 2006;3(3):153-65.
61. Flier SN, Kulkarni RN, Kahn CR. Evidence for a circulating islet cell growth factor in insulin-resistant states. Proceedings of the National Academy of Sciences. 2001;98(13):7475-80.
62. Yuchi Y, Cai Y, Legein B, De Groef S, Leuckx G, Coppens V, et al. Estrogen Receptor ? Regulates ?-Cell Formation During Pancreas Development and Following Injury. Diabetes. 2015;64(9):3218-28.
63. Diana ZY, Tai MH, Linning KD, et al. MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic beta-cells. Diabetes. 2006;55(3):742-50.
64. Ye DZ, Tai MH, Linning KD, et al. MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic beta-cells. Diabetes. 2006;55(3):742-50.
65. Matsuoka TA, Kaneto H, Miyatsuka T, et al. Regulation of MafA expression in pancreatic betacells in db/db mice with diabetes. Diabetes. 2010;59(7):1709-20.
66. Zhang C, Moriguchi T, Kajihara M, et al. MafA is a key regulator of glucosestimulated insulin secretion. Mol Cell Biol. 2005;25(12):4969-76.
67. Kaneto H, Matsuoka TA, Katakami N, Matsuhisa M. Combination of MafA, PDX-1 and NeuroD is a useful tool to efficiently induce insulin-producing surrogate beta-cells. Curr Med Chem. 2009;16(24):3144-51.
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