View source for Insulinoma

{{Short description|Tumor of the pancreas which secretes insulin}}

{{Infobox medical condition (new)
| name            = Insulinoma
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| image           = Pancreatic insulinoma (2).JPG
| caption         = Pathology of pancreatic endocrine tumour (insulinoma).
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| field           = [[Oncology]]
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An '''insulinoma''' is a [[tumour]] of the [[pancreas]] that is derived from [[beta cell]]s and secretes [[insulin]]. It is a rare form of a [[neuroendocrine tumour]]. Most insulinomas are [[benign]] in that they grow exclusively at their origin within the pancreas, but a minority [[metastasis|metastasize]]. Insulinomas are one of the functional [[pancreatic neuroendocrine tumor|pancreatic neuroendocrine tumour]] (PNET) group ("functional" because it increases production of insulin).<ref>{{cite journal |last1=Burns |first1=William R. |last2=Edil |first2=Barish H. |title=Neuroendocrine Pancreatic Tumors: Guidelines for Management and Update |journal=Current Treatment Options in Oncology |date=March 2012 |volume=13 |issue=1 |pages=24–34 |doi=10.1007/s11864-011-0172-2 |pmid=22198808 |s2cid=7329783 }}</ref> In the [[Medical Subject Headings]] classification, insulinoma is the only subtype of "islet cell [[adenoma]]".<ref>[https://web.archive.org/web/20160319155137/http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?mode=&term=Carcinoma,+Islet+Cell&field=entry#TreeC04.588.322.475.500 MeSH website], tree at: "Pancreatic Neoplasms [C04.588.322.475]",{{dead link|date=July 2021}} accessed 16 October 2014</ref>

Beta cells secrete insulin in response to increases in [[blood glucose]]. The resulting increase in insulin acts to lower blood glucose back to normal levels, the point at which  further secretion of insulin is stopped. In contrast, the secretion of insulin by insulinomas is rather independent of blood glucose; these tumours continue to secrete insulin, causing blood glucose levels to fall further below normal.<ref name="auto">{{cite web |url=https://www.lecturio.com/concepts/insulinomas/ | title=Insulinomas |website=The Lecturio Medical Concept Library |access-date= 27 July 2021}}</ref>

As a result, patients present symptoms of low blood glucose ([[hypoglycemia]]), which are improved by eating. The diagnosis of an insulinoma is usually made biochemically with low blood glucose, elevated insulin, [[proinsulin]], and C-peptide levels, and confirmed by localizing the tumour with [[medical imaging]] or [[angiography]]. The definitive treatment is surgery.<ref name="auto"/>

==Signs and symptoms==
Patients with insulinomas usually develop [[neuroglycopenic]] symptoms. These include recurrent headache, [[lethargy]], [[diplopia]], altered mental status, and blurred vision, particularly with exercise or fasting. Severe hypoglycemia may result in [[seizure]]s, [[coma]], and permanent neurological damage. Neuroglycopenic symptoms are more prominent in insulinoma, however patients may also have symptoms resulting from the [[catecholaminergic]] response to hypoglycemia (i.e. tremulousness, palpitations, [[tachycardia]], sweating, hunger, anxiety, nausea). Weight gain is sometimes seen, as patients may eat more frequently to manage symptoms. <ref>{{cite journal |last1=Shin |first1=Joyce |last2=Gorden |first2=Philip |title=Insulinoma: pathophysiology, localization and management |journal=Future Oncology |date=Nov 2012 |volume=6 |issue=2 |pages=229–237 |doi=10.2217/fon.09.165 |pmid=20146582 |pmc=3498768 }}</ref>

==Diagnosis==
The diagnosis of insulinoma is suspected in a patient with symptomatic fasting hypoglycemia. The conditions of [[Whipple’s triad]] need to be met for the diagnosis of "true hypoglycemia" to be made:<ref>{{cite book |last1=Melmed |first1=Shlomo |title=Williams textbook of endocrinology |date=2016 |publisher=Elsevier |isbn=978-0-323-29738-7 |pages=1582–1607 |edition=13}}</ref><ref>{{cite journal |last1=Martens |first1=Pieter |last2=Tits |first2=Jos |title=Approach to the patient with spontaneous hypoglycemia |journal=European Journal of Internal Medicine |date=June 2014 |volume=25 |issue=5 |pages=415–421 |doi=10.1016/j.ejim.2014.02.011 |pmid=24641805 }}</ref>

# symptoms and signs of hypoglycemia,
# concomitant plasma glucose level of 45&nbsp;mg/dL (2.5&nbsp;mmol/L) or less, and
# reversibility of symptoms with administration of glucose.

===Blood tests===
These blood tests are needed to diagnose insulinoma:<ref>{{cite web |url=https://www.lecturio.com/concepts/insulinomas/| title=Insulinomas|website=The Lecturio Medical Concept Library |access-date= 22 July 2021}}</ref>
* low [[glucose]] levels
* elevated [[insulin]] levels
* elevated [[C-peptide]] levels

If available, a [[proinsulin]] level might be useful, as well. Other blood tests may help rule out other conditions which can cause hypoglycemia.

===Suppression tests===
Normally, endogenous insulin production is suppressed in the setting of hypoglycemia. A 72-hour fast, usually supervised in a hospital setting, can be done to see if insulin levels fail to suppress, which is a strong indicator of the presence of endogenous hyperinsulinemia, of which the most common cause is insulinoma (followed by autoimmune causes). <ref>{{cite journal |last1=Chang-Yun |first1=Woo |last2=Jeong |first2=Ji Yun |title=Clinical Features and Causes of Endogenous Hyperinsulinemic Hypoglycemia in Korea |journal=Diabetes and Metabolism Journal|date=Apr 2015 |volume=39 |issue=2 |pages=126–131 |doi=10.4093/dmj.2015.39.2.126 |pmid=25922806 |pmc=4411543 }}</ref>

During the test, the patient may have calorie-free and caffeine-free liquids. Capillary blood glucose is measured every 4 hours using a [[glucose meter|reflectance meter]], until values < 60 mg/dL (3.3 mmol/L) are obtained. Then, the frequency of blood glucose measurement is increased to every hour until values are < 49 mg/dL (2.7 mmol/L). At that point, or when the patient has symptoms of hypoglycemia, a blood test is drawn for serum glucose, insulin, proinsulin, and C-peptide levels. <ref>{{cite book |last=Rayas |first=Maria |author-link= |date=Jan 2024 |title=Non-Diabetic Hypoglycemia |publisher=MDText.com |pmid=27099902 |url=https://www.ncbi.nlm.nih.gov/books/NBK355894/ }}</ref> The fast is then stopped at that point, and the hypoglycemia is corrected with intravenous dextrose or carbohydrate-containing food or drink.{{citation needed|date=August 2020}}

===Diagnostic imaging===
The insulinoma might be localized by noninvasive means, using [[ultrasound]], [[CT scan]], or [[MRI]] techniques. An indium-111 pentetreotide scan is more sensitive than ultrasound, CT, or MRI for detection of somatostatin receptor positive tumours, but not a good diagnostic tool for insulinomas. An [[endoscopic ultrasound]] has a sensitivity of 40-93% (depending on the location of the tumour) for detecting insulinomas.<ref name="pmid17906369">{{cite journal |last1=Sotoudehmanesh |first1=Rasoul |last2=Hedayat |first2=Anooshirvan |last3=Shirazian |first3=Nahid |last4=Shahraeeni |first4=Shadi |last5=Ainechi |first5=Sanaz |last6=Zeinali |first6=Fatemeh |last7=Kolahdoozan |first7=Shadi |title=Endoscopic ultrasonography (EUS) in the localization of insulinoma |journal=Endocrine |date=17 September 2007 |volume=31 |issue=3 |pages=238–241 |doi=10.1007/s12020-007-0045-4 |pmid=17906369 |s2cid=5634475 }}</ref>

Sometimes, [[angiography]] with percutaneous transhepatic [[pancreatic vein]] [[catheterization]] to sample the blood for insulin levels is required. [[Calcium]] can be injected into selected arteries to stimulate insulin release from various parts of the pancreas, which can be measured by sampling blood from their respective veins. The use of calcium stimulation improves the specificity of this test.During surgery to remove an insulinoma, an intraoperative ultrasound can sometimes localize the tumour, which helps guide the surgeon in the operation and has a higher sensitivity than noninvasive imaging tests.{{citation needed|date=August 2020}}

==Treatment==
[[File:Insulinoma.jpg|thumb|Gross appearance of insulinoma showing the typical red-brown appearance of tumour]]
The definitive management is the surgical removal of the insulinoma. This may involve removing part of the pancreas, as well ([[Whipple procedure]] and [[distal pancreatectomy]]).
Medications such as [[diazoxide]] and [[somatostatin]] can be used to block the release of insulin for patients who are not surgical candidates or who otherwise have inoperable tumours.
[[Streptozotocin]] is used in [[islet cell carcinoma]]s which produce excessive insulin. Combination [[chemotherapy]] is used, either [[doxorubicin]] and streptozotocin, or [[fluorouracil]] and streptozocin in patients where doxorubicin is contraindicated.
In metastasizing tumours with intrahepatic growth, [[hepatic artery|hepatic arterial]] occlusion or [[embolization]] can be used.{{citation needed|date=August 2020}}

==Prognosis==
Most patients with benign insulinomas can be cured with surgery. Persistent or recurrent hypoglycemia after surgery tends to occur in patients with multiple tumours. About 2% of patients develop [[diabetes mellitus]] after their surgery.{{citation needed|date=August 2020}}

==Incidence==
Insulinomas are rare [[neuroendocrine tumour]]s with an incidence estimated at one to four new cases per million persons per year. Insulinoma is one of the most common types of tumours arising from the [[islets of Langerhans]] cells (pancreatic endocrine tumours). Estimates of malignancy (metastases) range from 5 to 30%. Over 99% of insulinomas originate in the pancreas, with rare cases from ectopic pancreatic tissue. About 5% of cases are associated with tumours of the parathyroid glands and the pituitary ([[multiple endocrine neoplasia type 1]]) and are more likely to be multiple and malignant. Most insulinomas are small, less than 2&nbsp;cm.{{citation needed|date=August 2020}}

==History==
Hypoglycemia was first recognized in the 19th century. In the 1920s, after the discovery of insulin and its use in the treatment of diabetics, hyperinsulinism was suspected to be a cause of hypoglycemia in nondiabetics. A pioneering description of hyperinsulinism as a cause of hypoglycemia was published by [[Seale Harris]] in 1924. The first report of a surgical cure of hypoglycemia by removing an islet cell tumour was in 1929.{{citation needed|date=June 2021}}

An insulinoma removed from a woman in Munich provided insulin mRNA that was used in the first human gene cloning experiment. In 1979, [[Axel Ulrich]] cloned this gene into ''E. coli''. Most therapeutic insulin used today derives from this woman's tumour.<ref>{{cite web|title=Genentech and Axel Ulrich clone the human insulin gene|url=https://tacomed.com/chapter-12-recombinant-dna-production-of-insulin/genentech-and-axel-ulrich-clone-the-human-insulin-gene/|website=Tacomed.com|access-date=13 June 2017|archive-url=https://web.archive.org/web/20170927202401/https://tacomed.com/chapter-12-recombinant-dna-production-of-insulin/genentech-and-axel-ulrich-clone-the-human-insulin-gene/|archive-date=27 September 2017|url-status=dead}}</ref>

==Additional images==
<gallery mode="packed" widths="360px" heights="220">
Image:Pancreatic insulinoma (1).JPG|Pancreatic insulinoma 
Image:Pancreatic insulinoma (2).JPG|Pancreatic insulinoma 
Image:Pancreatic insulinoma (3) Chromogranin A.JPG| Chromogranin A
Image:Pancreatic insulinoma (4) Insulin immuostain.JPG|Insulin immunostain
</gallery>

==See also==
* [[Causes of hypoglycemia]]
* [[Metastatic insulinoma]]

==References==
{{Reflist}}

==Further reading==
* {{cite book |vauthors=Larsen PR, Williams RL |title=Williams textbook of endocrinology |publisher=WB Saunders |location=Philadelphia |edition=10th |year=2003 |isbn=978-0-7216-9184-8}}
* {{cite journal |last1=Doppman |first1=John L. |title=Localization of Insulinomas to Regions of the Pancreas by Intra-arterial Stimulation with Calcium |journal=Annals of Internal Medicine |date=15 August 1995 |volume=123 |issue=4 |pages=269–273 |doi=10.7326/0003-4819-123-4-199508150-00004 |pmid=7611592 |s2cid=20993342 }}
* {{cite web |url=https://www.uptodate.com/contents/insulinoma |last1=Vella |first1=Adrian |title=Insulinoma |work=UpToDate }}

== External links ==
{{Medical resources
|  DiseasesDB      = 6830
|  ICD10           = {{ICD10|C|25|4|c|15}}, {{ICD10|D|13|7|d|10}}
|  ICD9            = {{ICD9|157.4}}, {{ICD9|211.7}}
|  ICDO            = {{ICDO|8151|1}}
|  OMIM            =
|  MedlinePlus     = 000387
|  eMedicineSubj   = med
|  eMedicineTopic  = 2677
|  MeshID          = D007340
}}
{{Disease of the pancreas and glucose metabolism|state=expanded}}
{{Tumor morphology}}
{{Endocrine gland neoplasia}}

[[Category:Endocrine neoplasia]]
[[Category:Rare cancers]]
[[Category:Amyloidosis]]