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[[File:Insulin mechanism 1.gif|500px|center|thumb: Insulin cellular effect, source: Wikipedia]]
[[File:Insulin mechanism 1.gif|500px|center|thumb: Insulin cellular effect, source: Wikipedia]]
<br clear="left" />The actions of [[insulin]] on the human metabolism include:<ref name="pmid24783939">{{cite journal| author=Ahmad K| title=Insulin sources and types: a review of insulin in terms of its mode on diabetes mellitus. | journal=J Tradit Chin Med | year= 2014 | volume= 34 | issue= 2 | pages= 234-7 | pmid=24783939 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24783939  }}</ref>
<br clear="left" />The actions of [[insulin]] on the human metabolism include:<ref name="pmid24783939">{{cite journal| author=Ahmad K| title=Insulin sources and types: a review of insulin in terms of its mode on diabetes mellitus. | journal=J Tradit Chin Med | year= 2014 | volume= 34 | issue= 2 | pages= 234-7 | pmid=24783939 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24783939  }}</ref>
* [[Insulin]] decreases [[Blood sugar|blood glucose]] concentration by inducing the cell to intake the [[glucose]]. This function is as a result of increase [[GLUT4]] transporter insertion in cell membrane of [[Muscle|muscles]] and [[Adipose tissue|fat tissues]] which allow glucose to enter the cell.
* [[Insulin]] decreases [[Blood sugar|blood glucose]] concentration by inducing uptake of the [[glucose]] by peripheral cells. This function is as a result of increase [[GLUT4]] transporter insertion in the [[cell membrane]] of [[Muscle|muscles]] and [[Adipose tissue|fat tissues]] which allow [[glucose]] to enter the cell.
* Increase of [[DNA replication]] and [[protein synthesis]] via control of [[Amino acid|amino acids]] uptake.
* The increase of [[DNA replication]] and [[protein synthesis]] via control of [[Amino acid|amino acids]] uptake.
* Induction of [[glycogen]] synthesis when [[glucose]] levels are high.
* Induction of [[glycogen]] synthesis when [[glucose]] levels are high.
* Increase of cellular [[potassium]] uptake.
* The increase of cellular [[potassium]] uptake.
* Decreased [[gluconeogenesis]] and [[glycogenolysis]]: Decreased production of [[glucose]] from noncarbohydrate substrates, primarily in the [[liver]] (the vast majority of endogenous [[insulin]] arriving into the [[liver]] never leaves the [[Liver|liver)]].
* Decreased [[gluconeogenesis]] and [[glycogenolysis]]: Decreased production of [[glucose]] from noncarbohydrate substrates, primarily in the [[liver]] (the vast majority of endogenous [[insulin]] arriving into the [[liver]] never leaves the [[Liver|liver)]].
* Increase of [[lipid]] synthesis: [[insulin]] forces [[fat cells]] to take in [[blood glucose]], which is converted into [[triglycerides]]; a decrease of [[insulin]] causes the reverse.
* The increase of [[lipid]] synthesis: [[insulin]] forces [[fat cells]] to take in [[blood glucose]], which is converted into [[triglycerides]]; a decrease of [[insulin]] causes the reverse.
* Decrease of [[lipolysis]]: [[insulin]] forces reduction in conversion of [[Lipid|fat cell lipid]] stores into [[blood]] [[fatty acids]] and [[glycerol]]; a decrease of [[insulin]] causes the reverse.
* The decrease of [[lipolysis]]: [[insulin]] forces reduction in conversion of [[Lipid|fat cell lipid]] stores into [[blood]] [[fatty acids]] and [[glycerol]]; a decrease of [[insulin]] causes the reverse.
* Decrease of [[proteolysis]]: Insulin decreases the breakdown of [[protein]].
* The decrease of [[proteolysis]]: [[insulin]] decreases the breakdown of [[protein]].
* Decrease of renal [[sodium]] excretion.
* The decrease of renal [[sodium]] excretion.


=== Pathogenesis of hypoglycemia in diabetics ===
=== Pathogenesis of hypoglycemia in diabetics ===
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Hypoglycemia stimulates secretion of [[glucagon]]. This happens when blood glucose level falls between 65–70 mmHg. Failure to secrete glucagon may be the result of [[Beta cell|beta-cell]] failure and high [[insulin]] level that inhibits [[glucagon]] secretion.<ref name="pmid157348532">{{cite journal| author=Raju B, Cryer PE| title=Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans. | journal=Diabetes | year= 2005 | volume= 54 | issue= 3 | pages= 757-64 | pmid=15734853 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15734853  }}</ref>
Hypoglycemia stimulates secretion of [[glucagon]]. This happens when blood glucose level falls between 65–70 mmHg. Failure to secrete glucagon may be the result of [[Beta cell|beta-cell]] failure and high [[insulin]] level that inhibits [[glucagon]] secretion.<ref name="pmid157348532">{{cite journal| author=Raju B, Cryer PE| title=Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans. | journal=Diabetes | year= 2005 | volume= 54 | issue= 3 | pages= 757-64 | pmid=15734853 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15734853  }}</ref>
* '''[[Epinephrine]]'''
* '''[[Epinephrine]]'''
[[Epinephrine]] response to hypoglycemia becomes suppressed in many patients.<ref name="pmid8450063">{{cite journal| author=Dagogo-Jack SE, Craft S, Cryer PE| title=Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. | journal=J Clin Invest | year= 1993 | volume= 91 | issue= 3 | pages= 819-28 | pmid=8450063 | doi=10.1172/JCI116302 | pmc=288033 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8450063  }}</ref> This happens when [[blood glucose]] level falls between 65–70mmHg. A suppressed [[epinephrine]] response causes defective glucose counter-regulation and hypoglycemia unawareness occurs.<ref name="pmid18387080">{{cite journal| author=Geddes J, Schopman JE, Zammitt NN, Frier BM| title=Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. | journal=Diabet Med | year= 2008 | volume= 25 | issue= 4 | pages= 501-4 | pmid=18387080 | doi=10.1111/j.1464-5491.2008.02413.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18387080  }}</ref> This may be due to shifting the [[glycemic]] threshold for the sympathoadrenal response to a lower [[plasma glucose]] concentration. [[Brain|The brain]] is the first organ to be affected by decreased blood glucose level. Impairment of judgment and [[Seizure]]s may occur resulting in [[coma]].
[[Epinephrine]] response to hypoglycemia becomes suppressed in many patients.<ref name="pmid8450063">{{cite journal| author=Dagogo-Jack SE, Craft S, Cryer PE| title=Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. | journal=J Clin Invest | year= 1993 | volume= 91 | issue= 3 | pages= 819-28 | pmid=8450063 | doi=10.1172/JCI116302 | pmc=288033 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8450063  }}</ref> This happens when [[blood glucose]] level falls between 65–70mmHg. A suppressed [[epinephrine]] response causes defective [[glucose]] counter-regulation and hypoglycemia unawareness occurs.<ref name="pmid18387080">{{cite journal| author=Geddes J, Schopman JE, Zammitt NN, Frier BM| title=Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. | journal=Diabet Med | year= 2008 | volume= 25 | issue= 4 | pages= 501-4 | pmid=18387080 | doi=10.1111/j.1464-5491.2008.02413.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18387080  }}</ref> This may be due to shifting the [[glycemic]] threshold for the [[Adrenal|sympathoadrenal]] response to a lower [[plasma glucose]] concentration. [[Brain|The brain]] is the first organ to be affected by decreased [[blood glucose]] level. Impairment of judgment and [[Seizure]]s may occur resulting in [[coma]].


=== Pathogenesis of hypoglycemia in [[insulinoma]]: ===
=== Pathogenesis of hypoglycemia in [[insulinoma]]: ===
* [[Insulinoma]] is a rare benign [[pancreatic neuroendocrine tumor]] that arises from [[Islet cell|β islet cells]].<sup>[[Insulinoma pathophysiology#cite note-AlJadir2015-1|[1]]]</sup>
* [[Insulinoma]] is a rare benign [[pancreatic neuroendocrine tumor]] that arises from [[Islet cell|β islet cells]].<sup>[[Insulinoma pathophysiology#cite note-AlJadir2015-1|[1]]]</sup>
* It usually occurs sporadically but 10% are found to be associated with [[MEN 1]] syndrome.<sup>[[Insulinoma pathophysiology#cite note-pmid18672144-2|[2]]]</sup>
* It usually occurs sporadically but 10% are found to be associated with [[MEN 1]] syndrome.<sup>[[Insulinoma pathophysiology#cite note-pmid18672144-2|[2]]]</sup>
* It is thought that [[insulinoma]] is mediated by mutation in mTOR/P70S6K signaling pathway. An oral mTOR inhibitor ([[Everolimus]]) may make better [[Glycemic control|glycemic control]]<nowiki/> in people having [[insulinoma]].<sup>[[Insulinoma pathophysiology#cite note-pmid19129539-4|[4]]]</sup>
* It is thought that [[insulinoma]] is mediated by a mutation in mTOR/P70S6K signaling pathway. An oral mTOR inhibitor ([[Everolimus]]) may make better [[Glycemic control|glycemic control]]<nowiki/> in people having an [[insulinoma]].<sup>[[Insulinoma pathophysiology#cite note-pmid19129539-4|[4]]]</sup>
* [[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.<sup>[[Insulinoma pathophysiology#cite note-pmid22766318-6|[6]]]</sup>
* [[Mitochondria]] play a key role in [[glucose]] and [[insulin]] coupling to assure insulin secretion after [[glucose]] stimulation in [[pancreatic]] [[Beta cells|β cells]]. Coupling is impaired due to abnormal [[mitochondrial]] function in [[Beta cells|β cells]] causes the death of the cell.<sup>[[Insulinoma pathophysiology#cite note-pmid22766318-6|[6]]]</sup>
* [[YY1]] regulates this [[mitochondria]]<nowiki/>l function.<sup>[[Insulinoma pathophysiology#cite note-pmid18046414-7|[7]]]</sup> T372R mutation increase the [[transcription]] of YY1.<sup>[[Insulinoma pathophysiology#cite note-CaoGao2013-8|[8]]]</sup> The understanding of role and functions of [[YY1]] in β cells in near future might prove to be therapeutic potentials.
* [[YY1]] regulates this [[mitochondria]]<nowiki/>l function.<sup>[[Insulinoma pathophysiology#cite note-pmid18046414-7|[7]]]</sup> T372R mutation increases the [[transcription]] of YY1.<sup>[[Insulinoma pathophysiology#cite note-CaoGao2013-8|[8]]]</sup> The understanding of role and functions of [[YY1]] in [[Beta cells|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]].<sup>[[Insulinoma pathophysiology#cite note-RizzaHaymond1981-9|[9]]]</sup>
* 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]].<sup>[[Insulinoma pathophysiology#cite note-RizzaHaymond1981-9|[9]]]</sup>
* The neuroglycopenic symptoms appear eventually due to decreased [[blood glucose]]. [[Hypoglycemia]] stimulates [[catecholamine]] release which produces [[adrenergic]] symptoms.<sup>[[Insulinoma pathophysiology#cite note-pmid1305178-10|[10]]]</sup>
* The neuroglycopenic symptoms appear eventually due to decreased [[blood glucose]]. [[Hypoglycemia]] stimulates [[catecholamine]] release which produces [[adrenergic]] symptoms.<sup>[[Insulinoma pathophysiology#cite note-pmid1305178-10|[10]]]</sup>


=== Pathogenesis of hypoglycemia in non-islet-cell tumors hypoglycemia(NICTH): ===
=== Pathogenesis of hypoglycemia in non-islet-cell tumors hypoglycemia(NICTH): ===
* Non-islet-cell tumors are large tumors of [[mesenchymal]] or [[Epithelial cells|epithelial cell]] types originate from the [[Pancreas|pancreas.]]
* Non-islet-cell [[tumors]] are large tumors of [[mesenchymal]] or [[Epithelial cells|epithelial cell]] types originate from the [[Pancreas|pancreas.]]
* NICTH appears to be increased [[glucose]] utilization and inhibition of glucose release from the [[liver]].
* NICTH appears to be increased [[glucose]] utilization and inhibition of glucose release from the [[liver]].
* This happens as a result of tumor production of incompletely processed [[IGF2|IGF-2]].<ref name="pmid19088155">{{cite journal| author=Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER et al.| title=Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2009 | volume= 94 | issue= 3 | pages= 709-28 | pmid=19088155 | doi=10.1210/jc.2008-1410 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19088155  }}</ref>
* This happens as a result of tumor production of incompletely processed [[IGF2|IGF-2]].<ref name="pmid19088155">{{cite journal| author=Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER et al.| title=Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2009 | volume= 94 | issue= 3 | pages= 709-28 | pmid=19088155 | doi=10.1210/jc.2008-1410 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19088155  }}</ref>
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== Gross pathology ==
== Gross pathology ==
On gross pathology insulinomas have a gray to red brown appearance, encapsulated and are usually small and solitary tumors. Although there is a case report of a large(9cm), pedunculated and weighing more than 100g.<ref name="pmid15522939">{{cite journal| author=Mittendorf EA, Liu YC, McHenry CR| title=Giant insulinoma: case report and review of the literature. | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 1 | pages= 575-80 | pmid=15522939 | doi=10.1210/jc.2004-0825 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15522939  }} </ref>
On gross pathology insulinomas have a gray to red-brown appearance, encapsulated and are usually small and solitary tumors. Although there is a case report of a large(9cm), pedunculated and weighing more than 100g.<ref name="pmid15522939">{{cite journal| author=Mittendorf EA, Liu YC, McHenry CR| title=Giant insulinoma: case report and review of the literature. | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 1 | pages= 575-80 | pmid=15522939 | doi=10.1210/jc.2004-0825 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15522939  }} </ref>
* Almost all [[Insulinoma|insulinomas]] are present throughout the [[pancreas]] and extrapancreatic ones causing hypoglycemia are rare(<2%).<ref name="pmid23430217">{{cite journal| author=Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y et al.| title=Diagnosis and management of insulinoma. | journal=World J Gastroenterol | year= 2013 | volume= 19 | issue= 6 | pages= 829-37 | pmid=23430217 | doi=10.3748/wjg.v19.i6.829 | pmc=3574879 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23430217  }}</ref>
* Almost all [[Insulinoma|insulinomas]] are present throughout the [[pancreas]] and extrapancreatic ones causing hypoglycemia are rare(<2%).<ref name="pmid23430217">{{cite journal| author=Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y et al.| title=Diagnosis and management of insulinoma. | journal=World J Gastroenterol | year= 2013 | volume= 19 | issue= 6 | pages= 829-37 | pmid=23430217 | doi=10.3748/wjg.v19.i6.829 | pmc=3574879 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23430217  }}</ref>
* Various other findings are noted on gross pathology such as:<ref name="pmid17312378">{{cite journal| author=de Herder WW, Niederle B, Scoazec JY, Pauwels S, Kloppel G, Falconi M et al.| title=Well-differentiated pancreatic tumor/carcinoma: insulinoma. | journal=Neuroendocrinology | year= 2006 | volume= 84 | issue= 3 | pages= 183-8 | pmid=17312378 | doi=10.1159/000098010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17312378  }}</ref>
* Various other findings are noted on [[gross pathology]] such as:<ref name="pmid17312378">{{cite journal| author=de Herder WW, Niederle B, Scoazec JY, Pauwels S, Kloppel G, Falconi M et al.| title=Well-differentiated pancreatic tumor/carcinoma: insulinoma. | journal=Neuroendocrinology | year= 2006 | volume= 84 | issue= 3 | pages= 183-8 | pmid=17312378 | doi=10.1159/000098010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17312378  }}</ref>


* Size of the tumor
* Size of the [[tumor]]
* [[Metastasis]] to lymph nodes
* [[Metastasis]] to lymph nodes
* Extrapancreatic involvement
* Extra[[pancreatic]] involvement
* Distant [[metastasis]]
* Distant [[metastasis]]
[[File:Insulinoma.jpg|center|300px|thumb|Gross pathology of insulinoma, source: By Edward Alabraba et al. - 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, https://commons.wikimedia.org/w/index.php?curid=6686376]]
[[File:Insulinoma.jpg|center|300px|thumb|Gross pathology of insulinoma, source: By Edward Alabraba et al. - 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, https://commons.wikimedia.org/w/index.php?curid=6686376]]
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== Microscopic pathology ==
== Microscopic pathology ==
* On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with [[amyloid]] in a fibrovascular [[stroma]], are characteristic findings of [[Insulinoma|insulinoma.]]<ref>{{cite book | last = Lloyd | first = Ricardo | title = Endocrine pathology : differential diagnosis and molecular advances | publisher = Springer | location = New York London | year = 2010 | isbn = 978-1441910684 }}</ref>
* On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with [[amyloid]] in a fibrovascular [[stroma]], are characteristic findings of [[Insulinoma|insulinoma.]]<ref>{{cite book | last = Lloyd | first = Ricardo | title = Endocrine pathology : differential diagnosis and molecular advances | publisher = Springer | location = New York London | year = 2010 | isbn = 978-1441910684 }}</ref>
* 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.<ref name="de HerderNiederle2007">{{cite journal|last1=de Herder|first1=Wouter W.|last2=Niederle|first2=Bruno|last3=Scoazec|first3=Jean-Yves|last4=Pauwels|first4=Stanislas|last5=Klöppel|first5=Günter|last6=Falconi|first6=Massimo|last7=Kwekkeboom|first7=Dik J.|last8=Öberg|first8=Kjel|last9=Eriksson|first9=Barbro|last10=Wiedenmann|first10=Bertram|last11=Rindi|first11=Guido|last12=O’Toole|first12=Dermot|last13=Ferone|first13=Diego|title=Well-Differentiated Pancreatic Tumor/Carcinoma: Insulinoma|journal=Neuroendocrinology|volume=84|issue=3|year=2007|pages=183–188|issn=0028-3835|doi=10.1159/000098010}}</ref>
* 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.<ref name="de HerderNiederle2007">{{cite journal|last1=de Herder|first1=Wouter W.|last2=Niederle|first2=Bruno|last3=Scoazec|first3=Jean-Yves|last4=Pauwels|first4=Stanislas|last5=Klöppel|first5=Günter|last6=Falconi|first6=Massimo|last7=Kwekkeboom|first7=Dik J.|last8=Öberg|first8=Kjel|last9=Eriksson|first9=Barbro|last10=Wiedenmann|first10=Bertram|last11=Rindi|first11=Guido|last12=O’Toole|first12=Dermot|last13=Ferone|first13=Diego|title=Well-Differentiated Pancreatic Tumor/Carcinoma: Insulinoma|journal=Neuroendocrinology|volume=84|issue=3|year=2007|pages=183–188|issn=0028-3835|doi=10.1159/000098010}}</ref>
* The structure of tumor cells observed under [[Electron microscope|electron microscopy]] as Group A characterized by abundant well-granulated typical B cells with the [[Trabeculae|trabecula]]<nowiki/>r arrangement and Group B as scarce well-granulated typical B cells and a medullary arrangement.
* The structure of [[Tumor cell|tumor cells]] observed under [[Electron microscope|electron microscopy]] as Group A characterized by abundant well-granulated typical B cells with the [[Trabeculae|trabecula]]<nowiki/>r arrangement and Group B as scarce well-granulated typical B cells and a medullary arrangement.
[[File:Pancreatic insulinoma histology 2.JPG|300px|thumb|left|Pancreatic insulinoma histopathology, source: CCBY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=507384]]
[[File:Pancreatic insulinoma histology 2.JPG|300px|thumb|left|Pancreatic insulinoma histopathology, source: CCBY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=507384]]


Revision as of 21:31, 19 September 2017

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

Overview

The pathophysiology of hypoglycemia depends on the failure of physiological defense mechanisms and hormones such as insulin, glucagon and epinephrine to correct hypoglycemia. Most of these defense mechanisms are hormones that control glycogenolysis and gluconeogenesis.

Pathogenesis

Physiological effect of insulin

  1. Insulin binds to its receptor which starts many protein activation cascades.
  2. The insulin signal transduction pathway begins when insulin binds to the insulin receptor proteins.
  3. Once the transduction pathway is completed, the GLUT-4 storage vesicles fuse with the cellular membrane.
  4. As a result, the GLUT-4 protein channels become embedded into the membrane, allowing glucose to be transported into the cell.[1]
thumb: Insulin cellular effect, source: Wikipedia
thumb: Insulin cellular effect, source: Wikipedia


The actions of insulin on the human metabolism include:[2]

Pathogenesis of hypoglycemia in diabetics

The pathophysiology of hypoglycemia mainly relies on the failure of physiological defense mechanisms and hormones such as insulin, glucagon and epinephrine to correct hypoglycemia. Most of these hormones control glycogenolysis and gluconeogenesis, including:

The most important and the first mechanism to counter-regulate hypoglycemia is the ability to suppress insulin release. This happens early when blood glucose level is between 80–85 mmHg. This cannot occur in patients with absolute beta-cell failure, type 1 diabetes mellitus, and long-standing type 2 diabetes.[3] High insulin levels inhibit hepatic glycogenolysis causing more hypoglycemia.

Hypoglycemia stimulates secretion of glucagon. This happens when blood glucose level falls between 65–70 mmHg. Failure to secrete glucagon may be the result of beta-cell failure and high insulin level that inhibits glucagon secretion.[4]

Epinephrine response to hypoglycemia becomes suppressed in many patients.[5] This happens when blood glucose level falls between 65–70mmHg. A suppressed epinephrine response causes defective glucose counter-regulation and hypoglycemia unawareness occurs.[6] This may be due to shifting the glycemic threshold for the sympathoadrenal response to a lower plasma glucose concentration. The brain is the first organ to be affected by decreased blood glucose level. Impairment of judgment and Seizures may occur resulting in coma.

Pathogenesis of hypoglycemia in insulinoma:

Pathogenesis of hypoglycemia in non-islet-cell tumors hypoglycemia(NICTH):

Genetics

Genes associated with diabetes include the following:[9]

Genetics associated with syndrome:[10]

Genes associated with autoimmune hypoglycemia include the following:[11]

  • Serological HLA typing demonstrated the patient had HLA-DR4.
  • DNA typing showed she had HLA-DRB1*0401 and HLA-DRB1*0406 is strikingly associated with patients with insulin autoimmune syndrome who have polyclonal insulin autoantibodies.

Gross pathology

On gross pathology insulinomas have a gray to red-brown appearance, encapsulated and are usually small and solitary tumors. Although there is a case report of a large(9cm), pedunculated and weighing more than 100g.[12]

Gross pathology of insulinoma, source: By Edward Alabraba et al. - 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, https://commons.wikimedia.org/w/index.php?curid=6686376

Microscopic pathology

Pancreatic insulinoma histopathology, source: CCBY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=507384
Pancreatic insulinoma histopathology, source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=507387
Pancreatic insulinoma histopathology, source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=507388


References

  1. ↑ Kuznetsova LA, Plesneva SA, Sharova TS, Pertseva MN, Shpakov AO (2013). "[Regulation of adenylyl cyclase signaling system by insulin, biogenic amines, and glucagon at their separate and combined action in the muscle membranes of the mollusc Anodonta cygnea]". Zh Evol Biokhim Fiziol. 49 (2): 111–7. PMID 23789396.
  2. ↑ Ahmad K (2014). "Insulin sources and types: a review of insulin in terms of its mode on diabetes mellitus". J Tradit Chin Med. 34 (2): 234–7. PMID 24783939.
  3. ↑ Dunning BE, Gerich JE (2007). "The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications". Endocr Rev. 28 (3): 253–83. doi:10.1210/er.2006-0026. PMID 17409288.
  4. ↑ Raju B, Cryer PE (2005). "Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans". Diabetes. 54 (3): 757–64. PMID 15734853.
  5. ↑ Dagogo-Jack SE, Craft S, Cryer PE (1993). "Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia". J Clin Invest. 91 (3): 819–28. doi:10.1172/JCI116302. PMC 288033. PMID 8450063.
  6. ↑ Geddes J, Schopman JE, Zammitt NN, Frier BM (2008). "Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes". Diabet Med. 25 (4): 501–4. doi:10.1111/j.1464-5491.2008.02413.x. PMID 18387080.
  7. ↑ Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER; et al. (2009). "Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 94 (3): 709–28. doi:10.1210/jc.2008-1410. PMID 19088155.
  8. ↑ 8.0 8.1 Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL; et al. (2013). "Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive". Endocr Rev. 34 (6): 798–826. doi:10.1210/er.2012-1033. PMID 23671155.
  9. ↑ Pociot F, Lernmark Å (2016). "Genetic risk factors for type 1 diabetes". Lancet. 387 (10035): 2331–9. doi:10.1016/S0140-6736(16)30582-7. PMID 27302272.
  10. ↑ Weksberg R, Shuman C, Smith AC (2005). "Beckwith-Wiedemann syndrome". Am J Med Genet C Semin Med Genet. 137C (1): 12–23. doi:10.1002/ajmg.c.30058. PMID 16010676.
  11. ↑ Murakami M, Mizuide M, Kashima K, Kojima A, Tomioka SI, Kohama T; et al. (2000). "Identification of monoclonal insulin autoantibodies in insulin autoimmune syndrome associated with HLA-DRB1*0401". Horm Res. 54 (1): 49–52. doi:63437 Check |doi= value (help). PMID 11182636.
  12. ↑ 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.
  13. ↑ Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y; et al. (2013). "Diagnosis and management of insulinoma". World J Gastroenterol. 19 (6): 829–37. doi:10.3748/wjg.v19.i6.829. PMC 3574879. PMID 23430217.
  14. ↑ de Herder WW, Niederle B, Scoazec JY, Pauwels S, Kloppel G, Falconi M; et al. (2006). "Well-differentiated pancreatic tumor/carcinoma: insulinoma". Neuroendocrinology. 84 (3): 183–8. doi:10.1159/000098010. PMID 17312378.
  15. ↑ Lloyd, Ricardo (2010). Endocrine pathology : differential diagnosis and molecular advances. New York London: Springer. ISBN 978-1441910684.
  16. ↑ 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.
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