Diagnostic Considerations

Factitious hypoglycemia can occur in patients who have psychiatric disturbances or a need for attention and access to insulin or sulfonylurea drugs (eg, medical staff).^[26]The triad of hypoglycemia, high immunoreactive insulin levels, and suppressed plasma C-peptide immunoreactivity is pathognomonic of exogenous origin. Insulin-induced hypoglycemia can be detected by a ratio of insulin to C-peptide that is greater than 1.0.

Hypoglycemia can occur after inadvertent ingestion of sulfonylurea due to patient or pharmacist error.

Autoimmune hypoglycemia is a rare disorder caused by the interaction of endogenous antibodies with insulin or the insulin receptor.^[27]The condition is more common in Japan than in the United States or Europe. The syndrome may produce severe neuroglycopenic symptoms, making immunosuppressive therapy occasionally necessary.^[20]

Nesidioblastosis is defined as hyperplasia of the islet cells causing hyperinsulinemic hypoglycemia. It is a predominantly neonatal disorder, although cases in adults have been reported, most commonly after bariatric procedures.^{[28, 29]}Features may closely mimic insulinoma and concurrence of the two conditions has been reported.^[30]

Noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS) is a condition in which pancreatic islet hyperplasia is present.^[31]This is manifested with postprandial neuroglycopenia, a negative normal fasting test, negative pancreatic imaging results, and positive intra-arterial calcium stimulation of serum insulin.

Familial persistent hyperinsulinemia is manifested with inappropriately high insulin secretions seen in families with mutations in the glucokinase enzymes, glutamate dehydrogenase and short-chain3-hydroxyacyl1-CoA dehydrogenase.

Other causes for hypoglycemia include liver disease, endocrine deficiencies, extrapancreatic insulin-producing tumors (an insulin-secreting small-cell carcinoma of the cervix has been described^[32]), and pentamidine-induced hypoglycemia.^[33]

Workup

Zhuo F, Anastasopoulou C. Insulinoma. 2021 Jan. [QxMD MEDLINE Link]. [Full Text].
Vinik A, Feliberti E, Perry RR, Feingold KR, Anawalt B, Boyce A, et al. Insulinomas. 2000. [QxMD MEDLINE Link]. [Full Text].
Kirkeby H, Vilmann P, Burcharth F. Insulinoma diagnosed by endoscopic ultrasonography-guided biopsy. J Laparoendosc Adv Surg Tech A. 1999 Jun. 9(3):295-8. [QxMD MEDLINE Link].
Proye C, Malvaux P, Pattou F, et al. Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery. 1998 Dec. 124(6):1134-43; discussion 1143-4. [QxMD MEDLINE Link].
McLean A. Endoscopic ultrasound in the detection of pancreatic islet cell tumours. Cancer Imaging. 2004 Mar 29. 4(2):84-91. [QxMD MEDLINE Link].
Zhu L, Xue H, Sun Z, Li P, Qian T, Xing X, et al. Prospective comparison of biphasic contrast-enhanced CT, volume perfusion CT, and 3 Tesla MRI with diffusion-weighted imaging for insulinoma detection. J Magn Reson Imaging. 2017 Apr 17. [QxMD MEDLINE Link].
Zhao K, Patel N, Kulkarni K, Gross JS, Taslakian B. Essentials of Insulinoma Localization with Selective Arterial Calcium Stimulation and Hepatic Venous Sampling. J Clin Med. 2020 Sep 25. 9 (10):[QxMD MEDLINE Link]. [Full Text].
Nockel P, Babic B, Millo C, Herscovitch P, Patel D, Nilubol N, et al. Localization of Insulinoma Using 68Ga-DOTATATE PET/CT Scan. J Clin Endocrinol Metab. 2017 Jan 1. 102 (1):195-199. [QxMD MEDLINE Link].
Fernandez-Cruz L, Blanco L, Cosa R, Rendon H. Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors?. World J Surg. 2008 May. 32(5):904-17. [QxMD MEDLINE Link].
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 Mar. 147 (3):261-6. [QxMD MEDLINE Link]. [Full Text].
Phan GQ, Yeo CJ, Hruban RH, et al. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. 1998 Sep-Oct. 2(5):472-82. [QxMD MEDLINE Link].
Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am. 2009 Oct. 89(5):1105-21. [QxMD MEDLINE Link].
Service FJ, McMahon MM, O'Brien PC, Ballard DJ. Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc. 1991 Jul. 66 (7):711-9. [QxMD MEDLINE Link].
Henquin JC, Nenquin M, Guiot Y, Rahier J, Sempoux C. Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro. Diabetes. 2015 Oct. 64 (10):3543-53. [QxMD MEDLINE Link]. [Full Text].
Zhan HX, Cong L, Zhao YP, Zhang TP, Chen G, Zhou L, et al. Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis. J Surg Oncol. 2012 Dec. 106(8):972-80. [QxMD MEDLINE Link].
[Guideline] Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, et al. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology. 2016. 103 (2):153-71. [QxMD MEDLINE Link]. [Full Text].
Larijani B, Aghakhani S, Lor SS, Farzaneh Z, Pajouhi M, Bastanhagh MH. Insulinoma in Iran: a 20-year review. Ann Saudi Med. 2005 Nov-Dec. 25(6):477-80. [QxMD MEDLINE Link].
Shin JJ, Gorden P, Libutti SK. Insulinoma: pathophysiology, localization and management. Future Oncol. 2010 Feb. 6 (2):229-37. [QxMD MEDLINE Link]. [Full Text].
Mehrabi A, Fischer L, Hafezi M, Dirlewanger A, Grenacher L, Diener MK, et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas. 2014 Jul. 43 (5):675-86. [QxMD MEDLINE Link].
Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas. Am J Med. 1999 Mar. 106(3):307-10. [QxMD MEDLINE Link].
Schmitt J, Boullu-Sanchis S, Moreau F, Drui S, Louis B, Chabrier G, et al. Association of malignant insulinoma and type 2 diabetes mellitus: a case report. Ann Endocrinol (Paris). 2008 Feb. 69(1):69-72. [QxMD MEDLINE Link].
Ruby RJ, Armato JP, Pyke C, Peters AL. GLP-1 provoked severe hypoglycemia in an individual with type 2 diabetes and a benign insulinoma. Diabetes Care. 2014 Aug. 37 (8):e177-8. [QxMD MEDLINE Link].
Hrascan R, Pecina-Slaus N, Martic TN, Colic JF, Gall-Troselj K, Pavelic K. Analysis of selected genes in neuroendocrine tumours: insulinomas and phaeochromocytomas. J Neuroendocrinol. 2008 Aug. 20(8):1015-22. [QxMD MEDLINE Link].
Bhatti TR, Ganapathy K, Huppmann AR, Conlin L, Boodhansingh KE, MacMullen C, et al. Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect. J Clin Endocrinol Metab. 2016 Jan 12. 161 (3):jc20152914. [QxMD MEDLINE Link].
Cao Y, Gao Z, Li L, Jiang X, Shan A, Cai J, et al. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun. 2013. 4:2810. [QxMD MEDLINE Link]. [Full Text].
Waickus CM, de Bustros A, Shakil A. Recognizing factitious hypoglycemia in the family practice setting. J Am Board Fam Pract. 1999 Mar-Apr. 12(2):133-6. [QxMD MEDLINE Link].
Redmon JB, Nuttall FQ. Autoimmune hypoglycemia. Endocrinol Metab Clin North Am. 1999 Sep. 28(3):603-18, vii. [QxMD MEDLINE Link].
Eriguchi N, Aoyagi S, Hara M, et al. Nesidioblastosis with hyperinsulinemic hypoglycemia in adults: report of two cases. Surg Today. 1999. 29(4):361-3. [QxMD MEDLINE Link].
Malik S, Mitchell JE, Steffen K, Engel S, Wiisanen R, Garcia L, et al. Recognition and management of hyperinsulinemic hypoglycemia after bariatric surgery. Obes Res Clin Pract. 2016 Jan-Feb. 10 (1):1-14. [QxMD MEDLINE Link]. [Full Text].
Dardano A, Daniele G, Lupi R, Napoli N, Campani D, Boggi U, et al. Nesidioblastosis and Insulinoma: A Rare Coexistence and a Therapeutic Challenge. Front Endocrinol (Lausanne). 2020. 11:10. [QxMD MEDLINE Link]. [Full Text].
Starke A, Saddig C, Kirch B, Tschahargane C, Goretzki P. Islet hyperplasia in adults: challenge to preoperatively diagnose non-insulinoma pancreatogenic hypoglycemia syndrome. World J Surg. 2006 May. 30(5):670-9. [QxMD MEDLINE Link].
Seckl MJ, Mulholland PJ, Bishop AE, Teale JD, Hales CN, Glaser M, et al. Hypoglycemia due to an insulin-secreting small-cell carcinoma of the cervix. N Engl J Med. 1999 Sep 2. 341 (10):733-6. [QxMD MEDLINE Link]. [Full Text].
Assan R, Perronne C, Assan D, Chotard L, Mayaud C, Matheron S, et al. Pentamidine-induced derangements of glucose homeostasis. Determinant roles of renal failure and drug accumulation. A study of 128 patients. Diabetes Care. 1995 Jan. 18 (1):47-55. [QxMD MEDLINE Link].
van Bon AC, Benhadi N, Endert E, Fliers E, Wiersinga WM. Evaluation of endocrine tests. D: the prolonged fasting test for insulinoma. Neth J Med. 2009 Jul-Aug. 67(7):274-8. [QxMD MEDLINE Link].
Guettier JM, Lungu A, Goodling A, Cochran C, Gorden P. The Role of Proinsulin and Insulin in the Diagnosis of Insulinoma: A Critical Evaluation of the Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2013 Sep 30. [QxMD MEDLINE Link].
Boukhman MP, Karam JM, Shaver J, et al. Localization of insulinomas. Arch Surg. 1999 Aug. 134(8):818-22; discussion 822-3. [QxMD MEDLINE Link].
Hashimoto LA, Walsh RM. Preoperative localization of insulinomas is not necessary. J Am Coll Surg. 1999 Oct. 189(4):368-73. [QxMD MEDLINE Link].
Liu Y, Song Q, Jin HT, Lin XZ, Chen KM. The value of multidetector-row CT in the preoperative detection of pancreatic insulinomas. Radiol Med. 2009 Sep 30. [QxMD MEDLINE Link].
Zhu L, Xue H, Sun H, Wang X, Wu W, Jin Z, et al. Insulinoma Detection With MDCT: Is There a Role for Whole-Pancreas Perfusion?. AJR Am J Roentgenol. 2017 Feb. 208 (2):306-314. [QxMD MEDLINE Link].
Hubalewska-Dydejczyk A, Sowa-Staszczak A, Tomaszuk M, Stefańska A. GLP-1 and exendin-4 for imaging endocrine pancreas. A review. Labelled glucagon-like peptide-1 analogues: past, present and future. Q J Nucl Med Mol Imaging. 2015 Jun. 59 (2):152-60. [QxMD MEDLINE Link]. [Full Text].
Sowa-Staszczak A, Trofimiuk-Müldner M, Stefańska A, Tomaszuk M, Buziak-Bereza M, Gilis-Januszewska A, et al. 99mTc Labeled Glucagon-Like Peptide-1-Analogue (99mTc-GLP1) Scintigraphy in the Management of Patients with Occult Insulinoma. PLoS One. 2016. 11 (8):e0160714. [QxMD MEDLINE Link]. [Full Text].
Christ E, Wild D, Forrer F, Brändle M, Sahli R, Clerici T, et al. Glucagon-Like Peptide-1 Receptor Imaging for Localization of Insulinomas. J Clin Endocrinol Metab. 2009 Oct 9. [QxMD MEDLINE Link].
Luo Y, Pan Q, Shao Y, Yu M, Wu W, Xue H, et al. Glucagon-like Peptide-1 Receptor PET/CT with 68Ga-NOTA-exendin-4 for Detecting Localized Insulinoma: a Prospective Cohort Study. J Nucl Med. 2016 Jan 21. [QxMD MEDLINE Link].
Wild D, Christ E, Caplin ME, et al. Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J Nucl Med. 2011 Jul. 52(7):1073-8. [QxMD MEDLINE Link].
Christ E, Antwi K, Fani M, Wild D. Innovative imaging of insulinoma: the end of sampling? A review. Endocr Relat Cancer. 2020 Jan 1. [QxMD MEDLINE Link]. [Full Text].
Schillaci O, Massa R, Scopinaro F. 111In-pentetreotide scintigraphy in the detection of insulinomas: importance of SPECT imaging. J Nucl Med. 2000 Mar. 41 (3):459-62. [QxMD MEDLINE Link]. [Full Text].
Berger M, Bordi C, Cüppers HJ, Berchtold P, Gries FA, Münterfering H, et al. Functional and morphologic characterization of human insulinomas. Diabetes. 1983 Oct. 32 (10):921-31. [QxMD MEDLINE Link].
[Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. NCCN. Available at http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Version 3.2021 — August 13, 2021; Accessed: November 11, 2021.
American Joint Committee on Cancer. Neuroendocrine Tumors of the Pancreas. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, et al, eds. AJCC Cancer Staging Manual. 8th Ed. Chicago: American College of Surgeons; 2017. 407-22.
Arnold R, Simon B, Wied M. Treatment of neuroendocrine GEP tumours with somatostatin analogues: a review. Digestion. 2000. 62 Suppl 1:84-91. [QxMD MEDLINE Link].
Tirosh A, Stemmer SM, Solomonov E, Elnekave E, Saeger W, Ravkin Y, et al. Pasireotide for malignant insulinoma. Hormones (Athens). 2016 Apr. 15 (2):271-6. [QxMD MEDLINE Link].
Keymeulen B, Bossuyt A, Peeters TL, Somers G. 111In-octreotide scintigraphy: a tool to select patients with endocrine pancreatic tumors for octreotide treatment?. Ann Nucl Med. 1995 Aug. 9(3):149-52. [QxMD MEDLINE Link].
Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG, Eastern Cooperative Oncology Group. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1. 23 (22):4897-904. [QxMD MEDLINE Link].
Bernard V, Lombard-Bohas C, Taquet MC, Caroli-Bosc FX, Ruszniewski P, Niccoli-Sire P, et al. Efficacy of Everolimus in Patients with Metastatic Insulinoma and Refractory Hypoglycemia. Eur J Endocrinol. 2013 Feb 7. [QxMD MEDLINE Link].
FDA approves new treatment for certain digestive tract cancers. U.S. Food & Drug Administration. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm. January 26, 2018; Accessed: January 30, 2018.
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 Trial of ¹⁷⁷Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017 Jan 12. 376 (2):125-135. [QxMD MEDLINE Link]. [Full Text].
Bourcier ME, Sherrod A, DiGuardo M, Vinik AI. Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. J Clin Endocrinol Metab. 2009 Sep. 94(9):3157-62. [QxMD MEDLINE Link].
Brown E, Watkin D, Evans J, Yip V, Cuthbertson DJ. Multidisciplinary management of refractory insulinomas. Clin Endocrinol (Oxf). 2018 May. 88 (5):615-624. [QxMD MEDLINE Link]. [Full Text].
Limmer S, Huppert PE, Juette V, Lenhart A, Welte M, Wietholtz H. Radiofrequency ablation of solitary pancreatic insulinoma in a patient with episodes of severe hypoglycemia. Eur J Gastroenterol Hepatol. 2009 Sep. 21(9):1097-101. [QxMD MEDLINE Link].
Mele C, Brunani A, Damascelli B, Tichà V, Castello L, Aimaretti G, et al. Non-surgical ablative therapies for inoperable benign insulinoma. J Endocrinol Invest. 2017 Jul 28. [QxMD MEDLINE Link].
Dąbkowski K, Gajewska P, Walter K, Londzin-Olesik M, Białek A, Andrysiak-Mammos E, et al. Successful EUS-guided ethanol ablation of insulinoma, four-year follow-up. Case report and literature review. Endokrynol Pol. 2017. 68 (4):472-479. [QxMD MEDLINE Link].
Lo CY, Lam KY, Fan ST. Surgical strategy for insulinomas in multiple endocrine neoplasia type I. Am J Surg. 1998 Apr. 175(4):305-7. [QxMD MEDLINE Link].
Fernandez Ranvier GG, Shouhed D, Inabnet WB 3rd. Minimally Invasive Techniques for Resection of Pancreatic Neuroendocrine Tumors. Surg Oncol Clin N Am. 2016 Jan. 25 (1):195-215. [QxMD MEDLINE Link].
Dexter SP, Martin IG, Leindler L, et al. Laparoscopic enucleation of a solitary pancreatic insulinoma. Surg Endosc. 1999 Apr. 13(4):406-8. [QxMD MEDLINE Link].
Grant CS. Surgical aspects of hyperinsulinemic hypoglycemia. Endocrinol Metab Clin North Am. 1999 Sep. 28(3):533-54. [QxMD MEDLINE Link].
Bosman FT, Carneiro F, Hruban RH, Theise ND. World Health Organization Classification of Tumours of the Digestive System. Lyons, France: IARC; 2010.
Rindi G, Klöppel G, Alhman H, et al., European Neuroendocrine Tumor Society (ENETS). TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006 Oct. 449 (4):395-401. [QxMD MEDLINE Link]. [Full Text].
Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007 Oct. 451 (4):757-62. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Pavel M, Öberg K, Falconi M, Krenning E, Sundin A, Perren A, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Apr 6. 23 Suppl 7:vii124-30. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013 May. 42 (4):557-77. [QxMD MEDLINE Link]. [Full Text].
Moscetti L, Saltarelli R, Giuliani R, et al. Intra-arterial liver chemotherapy and hormone therapy in malignant insulinoma: case report and review of the literature. Tumori. 2000 Nov-Dec. 86(6):475-9. [QxMD MEDLINE Link].
Rushakoff RJ, Siperstein A, Clark OH, et al. Insulinoma and other Hypoglycemias. 2000. [QxMD MEDLINE Link]. [Full Text].
Gonzalez-Gonzalez A, Recio-Cordova JM. Liver metastases 9 years after removal of a malignant insulinoma which was initially considered benign. JOP. 2006. 7(2):226-9. [Full Text].
Dadan J, Wojskowicz P, Wojskowicz A. Neuroendocrine tumors of the pancreas. Wiad Lek. 2008. 61(1-3):43-7. [QxMD MEDLINE Link].
Kuzin NM, Egorov AV, Kondrashin SA, Lotov AN, Kuznetzov NS, Majorova JB. Preoperative and intraoperative topographic diagnosis of insulinomas. World J Surg. 1998 Jun. 22 (6):593-7; discussion 597-8. [QxMD MEDLINE Link].
Smith MC, Liu J, Chen T, et al. OctreoTher: ongoing early clinical development of a somatostatin- receptor-targeted radionuclide antineoplastic therapy. Digestion. 2000. 62 Suppl 1:69-72. [QxMD MEDLINE Link].
[Guideline] Ramage JK, Ahmed A, Ardill J, et al, UK and Ireland Neuroendocrine Tumour Society. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012 Jan. 61 (1):6-32. [QxMD MEDLINE Link]. [Full Text].
Wiesli P, Uthoff H, Perren A, et al. Are biochemical markers of neuroendocrine tumors coreleased with insulin following local calcium stimulation in patients with insulinomas?. Pancreas. 2011 Oct. 40(7):995-9. [QxMD MEDLINE Link].
Begu-Le Corroller A, Valero R, Moutardier V, Henry JF, Le Treut YP, Gueydan M. Aggressive multimodal therapy of sporadic malignant insulinoma can improve survival: A retrospective 35-year study of 12 patients. Diabetes Metab. 2008 Jun 13. [QxMD MEDLINE Link].
Yao JC, Evans DB. Pancreatic endocrine tumors. De Vita V, Lawrence T, Rosenberg S. De Vita, Hellman, and Rosenberg's Cancer. Principles and Practice of Oncology. 10th ed. Philadelphia, PA: Wolters Kluwer Health; 2015. 1205-17.

Media Gallery

CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).
Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).