Insulinoma pathophysiology: Difference between revisions
Jump to navigation
Jump to search
| Line 5: | Line 5: | ||
==Overview== | ==Overview== | ||
Insulinoma arises from β [[Islets of Langerhans|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]]. Inhibitors of mTOR ([[rapamycin]]) or dual [[PI3K]]/mTOR (NVP-BEZ2235) thus 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 inheritance|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 have a gray to red-brown appearance, encapsulated. On microscopic [[histopathological]] analysis, patterns like [[Trabecular meshwork|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 [[ | Insulinoma arises from β [[Islets of Langerhans|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]]. Inhibitors of mTOR ([[rapamycin]]) or dual [[PI3K]]/mTOR (NVP-BEZ2235) thus 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 inheritance|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 have a gray to red-brown appearance, encapsulated. On microscopic [[histopathological]] analysis, patterns like [[Trabecular meshwork|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 [[Beta cells|β cells]] with [[Trabecular meshwork|trabecular]] arrangement and group B as scarce well-granulated typical [[B cells|β cells]] and a [[medullary]] arrangement. | ||
==Pathophysiology== | ==Pathophysiology== | ||
| Line 11: | Line 11: | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
*Insulinoma is a rare benign [[pancreatic neuroendocrine tumor]] that arises from [[Islet cell|β islet cells]], which are cells that are normally involved in the production of [[insulin]]. Few insulinomas can also produce other hormones such as [[Serotonin]], [[gastrin]], [[ACTH]], [[glucagon]], and [[somatostatin]] <ref name="AlJadir2015">{{cite journal|last1=AlJadir|first1=Saadi|title=Insulinoma: Literature’s Review (Part 1)|journal=Endocrinology&Metabolism International Journal|volume=2|issue=3|year=2015|issn=24730815|doi=10.15406/emij.2015.02.00025}}</ref> | *Insulinoma is a rare benign [[pancreatic neuroendocrine tumor]] that arises from [[Islet cell|β islet cells]], which are cells that are normally involved in the production of [[insulin]]. Few insulinomas can also produce other hormones such as [[Serotonin]], [[gastrin]], [[ACTH]], [[glucagon]], and [[somatostatin]]. <ref name="AlJadir2015">{{cite journal|last1=AlJadir|first1=Saadi|title=Insulinoma: Literature’s Review (Part 1)|journal=Endocrinology&Metabolism International Journal|volume=2|issue=3|year=2015|issn=24730815|doi=10.15406/emij.2015.02.00025}}</ref> | ||
* They are usually small (90%), sporadic (90%), [[solitary]] (90%) and [[benign]] (90%) tumors. | * They are usually small (90%), sporadic (90%), [[solitary]] (90%) and [[benign]] (90%) tumors. | ||
* It usually occurs sporadically but 10% are found to be associated with [[MEN 1 syndrome]].<ref name="pmid18672144">{{cite journal| author=Callender GG, Rich TA, Perrier ND| title=Multiple endocrine neoplasia syndromes. | journal=Surg Clin North Am | year= 2008 | volume= 88 | issue= 4 | pages= 863-95, viii | pmid=18672144 | doi=10.1016/j.suc.2008.05.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18672144 }} </ref> Those associated with the [[MEN1 syndrome]] are usually [[malignant]] and higher recurrence rate (21% at 10 and 20 years) than in those without [[MEN 1]] (5% at 10 and 7% at 20 years).<ref name="pmid1677058">{{cite journal| author=Service FJ, McMahon MM, O'Brien PC, Ballard DJ| title=Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study. | journal=Mayo Clin Proc | year= 1991 | volume= 66 | issue= 7 | pages= 711-9 | pmid=1677058 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1677058 }} </ref> | * It usually occurs sporadically but 10% are found to be associated with [[MEN 1 syndrome]].<ref name="pmid18672144">{{cite journal| author=Callender GG, Rich TA, Perrier ND| title=Multiple endocrine neoplasia syndromes. | journal=Surg Clin North Am | year= 2008 | volume= 88 | issue= 4 | pages= 863-95, viii | pmid=18672144 | doi=10.1016/j.suc.2008.05.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18672144 }} </ref> Those associated with the [[MEN1 syndrome]] are usually [[malignant]] and higher recurrence rate (21% at 10 and 20 years) than in those without [[MEN 1]] (5% at 10 and 7% at 20 years). <ref name="pmid1677058">{{cite journal| author=Service FJ, McMahon MM, O'Brien PC, Ballard DJ| title=Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study. | journal=Mayo Clin Proc | year= 1991 | volume= 66 | issue= 7 | pages= 711-9 | pmid=1677058 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1677058 }} </ref> | ||
*It is thought that insulinoma is mediated by mTOR/P70S6K signaling pathway. Inhibitors of mTOR ([[rapamycin]]) or dual [[PI3K]]/mTOR (NVP-BEZ2235) thus have become new drugs for treating insulinoma. | *It is thought that insulinoma is mediated by mTOR/P70S6K [[signaling pathway]]. Inhibitors of mTOR ([[rapamycin]]) or dual [[PI3K]]/mTOR (NVP-BEZ2235) thus have become new drugs for treating insulinoma. | ||
*An oral mTOR inhibitor, [[Everolimus]], make better [[Glycemic control|glycemic contro]]<nowiki/>l in people having an insulinoma.<ref name="pmid19129539">{{cite journal| author=Kulke MH, Bergsland EK, Yao JC| title=Glycemic control in patients with insulinoma treated with everolimus. | journal=N Engl J Med | year= 2009 | volume= 360 | issue= 2 | pages= 195-7 | pmid=19129539 | doi=10.1056/NEJMc0806740 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19129539 }} </ref> The pathway will give more possibilities for medical treatment.<ref name="pmid22711648">{{cite journal| author=Zhan HX, Cong L, Zhao YP, Zhang TP, Chen G, Zhou L et al.| title=Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis. | journal=J Surg Oncol | year= 2012 | volume= 106 | issue= 8 | pages= 972-80 | pmid=22711648 | doi=10.1002/jso.23176 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22711648 }} </ref> | *An oral mTOR inhibitor, [[Everolimus]], make better [[Glycemic control|glycemic contro]]<nowiki/>l in people having an insulinoma.<ref name="pmid19129539">{{cite journal| author=Kulke MH, Bergsland EK, Yao JC| title=Glycemic control in patients with insulinoma treated with everolimus. | journal=N Engl J Med | year= 2009 | volume= 360 | issue= 2 | pages= 195-7 | pmid=19129539 | doi=10.1056/NEJMc0806740 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19129539 }} </ref> The pathway will give more possibilities for medical treatment. <ref name="pmid22711648">{{cite journal| author=Zhan HX, Cong L, Zhao YP, Zhang TP, Chen G, Zhou L et al.| title=Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis. | journal=J Surg Oncol | year= 2012 | volume= 106 | issue= 8 | pages= 972-80 | pmid=22711648 | doi=10.1002/jso.23176 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22711648 }} </ref> | ||
*[[Mitochondria]] play a key role in [[glucose]] and [[insulin]] coupling to assure [[insulin]] [[secretion]] after [[glucose]] stimulation in pancreatic β cells. Coupling is impaired due to abnormal [[mitochondrial]] function in β cells causes the death of the cell.<ref name="pmid22766318">{{cite journal| author=Supale S, Li N, Brun T, Maechler P| title=Mitochondrial dysfunction in pancreatic β cells. | journal=Trends Endocrinol Metab | year= 2012 | volume= 23 | issue= 9 | pages= 477-87 | pmid=22766318 | doi=10.1016/j.tem.2012.06.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22766318 }} </ref> [[YY1]] regulates this [[mitochondrial]] function.<ref name="pmid18046414">{{cite journal| author=Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P| title=mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. | journal=Nature | year= 2007 | volume= 450 | issue= 7170 | pages= 736-40 | pmid=18046414 | doi=10.1038/nature06322 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18046414 }} </ref> T372R mutation increases the [[transcription]] of YY1.<ref name="CaoGao2013">{{cite journal|last1=Cao|first1=Yanan|last2=Gao|first2=Zhibo|last3=Li|first3=Lin|last4=Jiang|first4=Xiuli|last5=Shan|first5=Aijing|last6=Cai|first6=Jie|last7=Peng|first7=Ying|last8=Li|first8=Yanli|last9=Jiang|first9=Xiaohua|last10=Huang|first10=Xuanlin|last11=Wang|first11=Jiaqian|last12=Wei|first12=Qing|last13=Qin|first13=Guijun|last14=Zhao|first14=Jiajun|last15=Jin|first15=Xiaolong|last16=Liu|first16=Li|last17=Li|first17=Yingrui|last18=Wang|first18=Weiqing|last19=Wang|first19=Jun|last20=Ning|first20=Guang|title=Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1|journal=Nature Communications|volume=4|year=2013|issn=2041-1723|doi=10.1038/ncomms3810}}</ref> | *[[Mitochondria]] play a key role in [[glucose]] and [[insulin]] coupling to assure [[insulin]] [[secretion]] after [[glucose]] stimulation in pancreatic β cells. Coupling is impaired due to abnormal [[mitochondrial]] function in β cells causes the death of the cell.<ref name="pmid22766318">{{cite journal| author=Supale S, Li N, Brun T, Maechler P| title=Mitochondrial dysfunction in pancreatic β cells. | journal=Trends Endocrinol Metab | year= 2012 | volume= 23 | issue= 9 | pages= 477-87 | pmid=22766318 | doi=10.1016/j.tem.2012.06.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22766318 }} </ref> [[YY1]] regulates this [[mitochondrial]] function.<ref name="pmid18046414">{{cite journal| author=Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P| title=mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. | journal=Nature | year= 2007 | volume= 450 | issue= 7170 | pages= 736-40 | pmid=18046414 | doi=10.1038/nature06322 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18046414 }} </ref> T372R mutation increases the [[transcription]] of YY1.<ref name="CaoGao2013">{{cite journal|last1=Cao|first1=Yanan|last2=Gao|first2=Zhibo|last3=Li|first3=Lin|last4=Jiang|first4=Xiuli|last5=Shan|first5=Aijing|last6=Cai|first6=Jie|last7=Peng|first7=Ying|last8=Li|first8=Yanli|last9=Jiang|first9=Xiaohua|last10=Huang|first10=Xuanlin|last11=Wang|first11=Jiaqian|last12=Wei|first12=Qing|last13=Qin|first13=Guijun|last14=Zhao|first14=Jiajun|last15=Jin|first15=Xiaolong|last16=Liu|first16=Li|last17=Li|first17=Yingrui|last18=Wang|first18=Weiqing|last19=Wang|first19=Jun|last20=Ning|first20=Guang|title=Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1|journal=Nature Communications|volume=4|year=2013|issn=2041-1723|doi=10.1038/ncomms3810}}</ref> | ||
Revision as of 13:31, 22 September 2017
|
Insulinoma Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Insulinoma pathophysiology On the Web |
|
American Roentgen Ray Society Images of Insulinoma pathophysiology |
|
Risk calculators and risk factors for Insulinoma pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]
Overview
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. Inhibitors of mTOR (rapamycin) or dual PI3K/mTOR (NVP-BEZ2235) thus 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 have a gray to red-brown appearance, encapsulated. 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 trabecular arrangement and group B as scarce well-granulated typical β cells and a medullary arrangement.
Pathophysiology
Pathogenesis
- Insulinoma is a rare benign pancreatic neuroendocrine tumor that arises from β islet cells, which are cells that are normally involved in the production of insulin. Few insulinomas can also produce other hormones such as Serotonin, gastrin, ACTH, glucagon, and somatostatin. [1]
- They are usually small (90%), sporadic (90%), solitary (90%) and benign (90%) tumors.
- It usually occurs sporadically but 10% are found to be associated with MEN 1 syndrome.[2] Those associated with the MEN1 syndrome are usually malignant and higher recurrence rate (21% at 10 and 20 years) than in those without MEN 1 (5% at 10 and 7% at 20 years). [3]
- It is thought that insulinoma is mediated by mTOR/P70S6K signaling pathway. Inhibitors of mTOR (rapamycin) or dual PI3K/mTOR (NVP-BEZ2235) thus have become new drugs for treating insulinoma.
- An oral mTOR inhibitor, Everolimus, make better glycemic control in people having an insulinoma.[4] The pathway will give more possibilities for medical treatment. [5]
- Mitochondria play a key role in glucose and insulin coupling to assure insulin secretion after glucose stimulation in pancreatic β cells. Coupling is impaired due to abnormal mitochondrial function in β cells causes the death of the cell.[6] YY1 regulates this mitochondrial function.[7] T372R mutation increases the transcription of YY1.[8]
- The understanding of role and functions of YY1 in β cells in near future might prove to be therapeutic potentials.
- 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.[9]
- The neuroglycopenic symptoms appear eventually due to decreased blood glucose. Hypoglycemia stimulates catecholamine release which produces adrenergic symptoms.[10]
Genetics
- Insulinoma is transmitted in an autosomal dominant pattern when it is associated with MEN 1 syndrome.
- Genes involved in the pathogenesis of insulinoma include MEN1gene. Loss of heterozygosity of MEN1 gene takes place on chromosome 11q13. [11]
Associated Conditions
- Other pancreatic neuroendocrine tumors like gastrinoma, glucagonoma, VIPoma, somatostatinoma
- MEN 1 [3]
- von Hippel-Lindau
- Neurofibromatosis type 1
Gross Pathology
- On gross pathology insulinomas have a gray to red brown appearance, encapsulated [12]and are usually small and solitary tumors. Although there is a case report of a large (9cm), pedunculated and weighing more than 100g.[13]
- Almost all insulinomas are present throughout the pancreas and extrapancreatic ones causing hypoglycemia are rare (<2%)[14]
- Various other findings are noted on gross pathology like[15]
- Size of the tumor
- Metastasis to lymph nodes
- Extrapancreatic involvement
- Distant metastasis
Microscopic Pathology
- On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures particularly with amyloid in fibrovascular stroma are characteristic findings of insulinoma.[16]
- 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.[15]
- The structure of tumor cells observed under electron microscopy as: Group A characterised by abundant well-granulated typical B cells with trabecular arrangement and Group B as scarce well-granulated typical B cells and a medullary arrangement.[17]
-
![Histopathology of pancreatic endocrine tumor (insulinoma)[18]](/images/2/2f/Pancreatic_insulinoma_histology_2.JPG)
Histopathology of pancreatic endocrine tumor (insulinoma)[18] -
![Histopathology of pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain[18]](/images/a/a3/Pancreatic_insulinoma_histopathology_3.JPG)
Histopathology of pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain[18] -
![Histopathology of pancreatic endocrine tumor (insulinoma). Insulin immunostain[18]](/images/d/d5/Pancreatic_insulinoma_histology_4.JPG)
Histopathology of pancreatic endocrine tumor (insulinoma). Insulin immunostain[18]
![Histopathology of pancreatic endocrine tumor (insulinoma)[18]](/index.php/File:Pancreatic_insulinoma_histology_2.JPG)
![Histopathology of pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain[18]](/index.php/File:Pancreatic_insulinoma_histopathology_3.JPG)
![Histopathology of pancreatic endocrine tumor (insulinoma). Insulin immunostain[18]](/index.php/File:Pancreatic_insulinoma_histology_4.JPG)
References
- ↑ AlJadir, Saadi (2015). "Insulinoma: Literature's Review (Part 1)". Endocrinology&Metabolism International Journal. 2 (3). doi:10.15406/emij.2015.02.00025. ISSN 2473-0815.
- ↑ Callender GG, Rich TA, Perrier ND (2008). "Multiple endocrine neoplasia syndromes". Surg Clin North Am. 88 (4): 863–95, viii. doi:10.1016/j.suc.2008.05.001. PMID 18672144.
- ↑ 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.
- ↑ Kulke MH, Bergsland EK, Yao JC (2009). "Glycemic control in patients with insulinoma treated with everolimus". N Engl J Med. 360 (2): 195–7. doi:10.1056/NEJMc0806740. PMID 19129539.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Abe T (1992). "[Letter from Alabama--Medicaid and Medicare]". Kango. 44 (2): 135–40. PMID 1305178.
- ↑ 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.
- ↑ Lloyd, Ricardo (2010). Endocrine pathology : differential diagnosis and molecular advances. New York London: Springer. ISBN 978-1441910684.
- ↑ 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.
- ↑ 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.
- ↑ 15.0 15.1 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.
- ↑ Lloyd, Ricardo (2010). Endocrine pathology : differential diagnosis and molecular advances. New York London: Springer. ISBN 978-1441910684.
- ↑ 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.
- ↑ 18.0 18.1 18.2 Neuroendocrine tumour of the pancreas. Libre Pathology. http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_pancreas