CoChat
Sign Up
Cited by 91Neuroendocrine Tumor Research AdvancesPancreatic function and diabetesPancreatic and Hepatic Oncology Research

Approach to the Patient: Insulinoma

Open access
Hofland, Johannes, Refardt, Julie C, Feelders, Richard A, Christ, Emanuel, de Herder, Wouter W·2024·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgad641PMC PMC10940262
Open this paper in CoChat — free accountOpen PDF

Abstract

Insulinomas are hormone-producing pancreatic neuroendocrine neoplasms with an estimated incidence of 1 to 4 cases per million per year. Extrapancreatic insulinomas are extremely rare. Most insulinomas present with the Whipple triad: (1) symptoms, signs, or both consistent with hypoglycemia; (2) a low plasma glucose measured at the time of the symptoms and signs; and (3) relief of symptoms and signs when the glucose is raised to normal. Nonmetastatic insulinomas are nowadays referred to as “indolent” and metastatic insulinomas as “aggressive.” The 5-year survival of patients with an indolent insulinoma has been reported to be 94% to 100%; for patients with an aggressive insulinoma, this amounts to 24% to 67%. Five percent to 10% of insulinomas are associated with the multiple endocrine neoplasia type 1 syndrome. Localization of the insulinoma and exclusion or confirmation of metastatic disease by computed tomography is followed by endoscopic ultrasound or magnetic resonance imaging for indolent, localized insulinomas. Glucagon-like peptide 1 receptor positron emission tomography/computed tomography or positron emission tomography/magnetic resonance imaging is a highly sensitive localization technique for seemingly occult, indolent, localized insulinomas. Supportive measures and somatostatin receptor ligands can be used for to control hypoglycemia. For single solitary insulinomas, curative surgical excision remains the treatment of choice. In aggressive malignant cases, debulking procedures, somatostatin receptor ligands, peptide receptor radionuclide therapy, everolimus, sunitinib, and cytotoxic chemotherapy can be valuable options.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1210/clinem/dgad641

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • NICTH has an estimated incidence of 1/1,000,000, which is approximately 4 times less than that of insulinomas.

    “Non-islet cell tumor hypoglycemia (NICTH) has an estimated incidence of 1/1,000,000, which is ~4x less than that of insulinomas [41,42].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [41]

    The Incidence and Epidemiology section reports an insulinoma incidence of 0.7–4 cases per million per year. Our copy does not give an incidence for non-islet cell tumor hypoglycemia (NICTH), so it does not establish either the claimed 1-per-million estimate or the approximately fourfold comparison. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Insulinomas are insulin-producing tumors that arise from pancreatic β-cells and have an annual incidence of <4 cases per million.

    “Insulinomas are insulin-producing tumors that arise from pancreatic β -cells and have an annual incidence of &lt;4 cases per million [41].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [41]

    The Incidence and Epidemiology section describes insulinomas as hormone-producing pancreatic neuroendocrine neoplasms and reports 0.7 to 4 cases per million per year, rather than strictly fewer than 4. The Pathology section says indolent insulinomas are closely related to normal β cells, but does not state that all insulinomas arise from β cells; it also describes aggressive insulinomas as resembling α cells. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Classically, patients with insulinoma present with fasting hypoglycemia, but this is neither sensitive nor specific, as 20% may also experience postprandial hypoglycemia.

    “Classically, patients with an insulinoma present with fasting hypoglycemia. However, this is neither sensitive nor specific, as 20% may also experience postprandial hypoglycemia [41].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [41]

    The Diagnosis and Presentation section says symptoms occur mainly in the fasting state, but up to 20% of patients also described postprandial symptoms. This supports the usual presentation and the 20% figure, but the section does not establish that fasting hypoglycemia is neither sensitive nor specific for insulinoma. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Endoscopic ultrasound is the preferred imaging modality for localization of insulinoma, due to its high sensitivity (81%) and specificity (90%).

    “Once endogenous insulin-mediated hypoglycemia is uncovered, localization with endoscopic ultrasound is the preferred imaging modality, due to its high sensitivity (81%) and specificity (90%) [41].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [41]

    The Localization section, Table 1, gives EUS sensitivity of 81% and specificity of 90%. But the same section says CT is the preferred initial localization modality, followed by EUS or MRI; it does not identify EUS as the preferred first imaging test. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • Survival rates of patients with aggressive (metastatic) insulinomas are lower, ranging between 24 and 67%.

    “However, survival rates of patients with aggressive (i.e., metastatic) insulinomas are lower, ranging between 24 and 67% [41].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [41]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 139

  1. [1]Service FJ, Natt N. The prolonged fast. J Clin Endocrinol Metab. 2000; 85(11): 3973‐ 3974. 11095416
  2. [3]Whipple AO, Frantz VK. Adenoma of islet cells with hyperinsulinism: A review. Ann Surg. 1935; 101(6): 1299‐ 1335. 17856569 PMC1390871
  3. [4]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; 66(7): 711‐ 719. 1677058
  4. [5]Harrington MG, McGeorge AP, Ballantyne JP, Beastall G. A prospective survey for insulinomas in a neurology department. Lancet. 1983; 1(8333): 1094‐ 1095. 6133118
  5. [6]Service FJ. Hypoglycemic disorders. N Engl J Med. 1995; 332(17): 1144‐ 1152. 7700289
  6. [7]Hofland J, Falconi M, Christ E, et al European Neuroendocrine tumor society 2023 guidance paper for functioning pancreatic neuroendocrine tumour syndromes. J Neuroendocrinol. 2023; 35(8): e13318. 37578384
  7. [8]Hirshberg B, Livi A, Bartlett DL, et al Forty-eight-hour fast: the diagnostic test for insulinoma. J Clin Endocrinol Metab. 2000; 85(9): 3222‐ 3226. 10999812
  8. [9]Wiesli P, Schwegler B, Schmid B, Spinas GA, Schmid C. Mini-Mental state examination is superior to plasma glucose concentrations in monitoring patients with suspected hypoglycaemic disorders during the 72-hour fast. Eur J Endocrinol. 2005; 152(4): 605‐ 610. 15817917
  9. [11]Dieterle MP, Husari A, Prozmann SN, et al Adult-Onset nesidioblastosis/non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS): review of the literature of a rare cause of hyperinsulinemic hypoglycemia. Biomedicines. 2023; 11(6): 1732. 37371827 PMC10296556
  10. [12]de Herder WW, Klöppel G. One hundred years after the discovery of insulin and glucagon: the history of tumors and hyperplasias that hypersecrete these hormones. Endocr Relat Cancer. 2023; 30(9): e220327. 37310813
  11. [13]Sempoux C, Klöppel G. Pathological features in non-neoplastic congenital and adult hyperinsulinism: from nesidioblastosis to current terminology and understanding. Endocr Relat Cancer. 2023; 30(9): e230034. 37279235
  12. [14]Christ E, Iacovazzo D, Korbonits M, Perren A. Insulinomatosis: new aspects. Endocr Relat Cancer. 2023; 30(6): e220327. 36952647
  13. [15]Hofland J, Kaltsas G, de Herder WW. Advances in the diagnosis and management of well-differentiated neuroendocrine neoplasms. Endocr Rev. 2020; 41(2): 371‐ 403. 31555796 PMC7080342
  14. [16]Svensson E, Muth A, Hedenström P, Ragnarsson O. The incidence of insulinoma in western Sweden between 2002 and 2019. Ann Gastroenterol. 2022; 35(4): 434‐ 440. 35784630 PMC9210785
  15. [17]Kurakawa KI, Okada A, Manaka K, et al Clinical characteristics and incidences of benign and malignant insulinoma using a national inpatient database in Japan. J Clin Endocrinol Metab. 2021; 106(12): 3477‐ 3486. 34343300
  16. [18]Halfdanarson TR, Rubin J, Farnell MB, Grant CS, Petersen GM. Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer. 2008; 15(2): 409‐ 427. 18508996 PMC2693313
  17. [19]Mehrabi A, Fischer L, Hafezi M, et al A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas. 2014; 43(5): 675‐ 686. 24921202
  18. [21]La Rosa S, Pariani D, Calandra C, et al Ectopic duodenal insulinoma: a very rare and challenging tumor type. Description of a case and review of the literature. Endocr Pathol. 2013; 24(4): 213‐ 219. 24006218
  19. [22]Shames JM, Dhurandhar NR, Blackard WG. Insulin-secreting bronchial carcinoid tumor with widespread metastases. Am J Med. 1968; 44(4): 632‐ 637. 4296076
  20. [23]Adamson AR, Grahame-Smith DG, Bogomoletz V, Maw DS, Rothnie NG. Malignant argentaffinoma with carcinoid syndrome and hypoglycaemia. Br Med J. 1971; 3(5766): 93‐ 94. 5314568 PMC1800185
  21. [24]Pelletier G, Cortot A, Launay JM, et al Serotonin-secreting and insulin-secreting ileal carcinoid tumor and the use of in vitro culture of tumoral cells. Cancer. 1984; 54(2): 319‐ 322. 6372987
  22. [25]Zhang X, Jia H, Li F, et al Ectopic insulinoma diagnosed by 68Ga-exendin-4 PET/CT: A case report and review of literature. Medicine (Baltimore). 2021; 100(13): e25076. 33787590 PMC8021326
  23. [26]Garg R, Memon S, Patil V, Bandgar T. Extrapancreatic insulinoma. World J Nucl Med. 2020; 19(02): 162‐ 164. 32939209 PMC7478312
  24. [27]Rindi G, Mete O, Uccella S, et al Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol. 2022; 33(1): 115‐ 154. 35294740
  25. [28]Sada A, Habermann EB, Szabo Yamashita T, et al Comparison between sporadic and multiple endocrine neoplasia type 1-associated insulinoma. J Am Coll Surg. 2022; 235(5): 756‐ 763. 35752874
  26. [30]Hackeng WM, Brosens LAA, Dreijerink KMA. Aggressive versus indolent insulinomas: new clinicopathological insights. Endocr Relat Cancer. 2023; 30(5): e220321. 36779771
  27. [31]Sada A, Yamashita TS, Glasgow AE, et al Comparison of benign and malignant insulinoma. Am J Surg. 2021; 221(2): 437‐ 447. 32873371
  28. [32]de Mestier L, Hentic O, Cros J, et al Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study. Ann Intern Med. 2015; 162(10): 682‐ 689. 25984844
  29. [33]Crona J, Norlén O, Antonodimitrakis P, Welin S, Stålberg P, Eriksson B. Multiple and secondary hormone secretion in patients with metastatic pancreatic neuroendocrine tumours. J Clin Endocrinol Metab. 2016; 101(2): 445‐ 452. 26672633
  30. [34]Thakker RV, Newey PJ, Walls GV, et al Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012; 97(9): 2990‐ 3011. 22723327
  31. [35]Newey PJ, Newell-Price J. MEN1 Surveillance guidelines: time to (Re)Think? J Endocr Soc. 2022; 6(2): bvac001. 35079671 PMC8783614
  32. [36]Niederle B, Selberherr A, Bartsch DK, et al Multiple endocrine neoplasia type 1 and the pancreas: diagnosis and treatment of functioning and non-functioning pancreatic and duodenal neuroendocrine neoplasia within the MEN1 syndrome—an international consensus statement. Neuroendocrinology. 2021; 111(7): 609‐ 630. 32971521
  33. [37]Klein Haneveld MJ, van Treijen MJC, Pieterman CRC, et al Initiating pancreatic neuroendocrine tumor (pNET) screening in young MEN1 patients: results from the DutchMEN study group. J Clin Endocrinol Metab. 2021; 106(12): 3515‐ 3525. 34333645
  34. [38]Goudet P, Dalac A, Le Bras M, et al MEN1 Disease occurring before 21 years old: a 160-patient cohort study from the groupe d'étude des tumeurs endocrines. J Clin Endocrinol Metab. 2015; 100(4): 1568‐ 1577. 25594862
  35. [39]de Laat JM, Tham E, Pieterman CRC, et al Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors. Eur J Endocrinol. 2012; 167(2): 181‐ 187. 22581216
  36. [40]Perren A, Wiesli P, Schmid S, et al Pancreatic endocrine tumors are a rare manifestation of the neurofibromatosis type 1 phenotype: molecular analysis of a malignant insulinoma in a NF-1 patient. Am J Surg Pathol. 2006; 30(8): 1047‐ 1051. 16861979
  37. [41]Dworakowska D, Grossman AB. Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review. Endocr Relat Cancer. 2009; 16(1): 45‐ 58. 18978035
  38. [42]Kang MY, Yeoh J, Pondicherry A, Rahman H, Dissanayake A. Insulinoma and tuberous sclerosis: A possible mechanistic target of rapamycin (mTOR) pathway abnormality? J Endocr Soc. 2017; 1(9): 1120‐ 1123. 29264566 PMC5686638
  39. [43]Harris S. Hyperinsulinism and dysinsulinism. J Am Med Assoc. 1924; 83(10): 729‐ 733.
  40. [44]Harris S. Hyperinsulinism, a definite disease entity. Etiology, pathology, symptoms, diagnosis, prognosis and treatment of spontaneous insulinogenic hypoglycemia (hyperinsulinism). J Am Med Assoc. 1933; 101(25): 1958‐ 1965.
  41. [45]van Heerden JA, Churchward MM. Dr Dickinson Ober Wheelock–a case of sporadic insulinoma or multiple endocrine neoplasia type 1? Mayo Clin Proc. 1999; 74(7): 735‐ 738. 10405707
  42. [46]Wilder RM, Allan FN, Power MH, Robertson HE. Carcinoma of the islands of the pancreas. J Am Med Assoc. 1927; 89(5): 348‐ 355.
  43. [47]Howland G, Campbell WR, Maltby EJ, Robinson WL. Dysinsulinism: convulsions and coma due to islet-cell tumor of the pancreas with operation and cure. J Am Med Assoc. 1929; 93(9): 674‐ 679.
  44. [48]Howland G, Campbell WR, Maltby EJ, Robinson WL. Dysinsulinism: convulsions and coma due to islet-cell tumor of pancreas: operation and cure. Trans Am Neurol Assoc. 1929; 55: 551‐ 556.
  45. [49]Campbell WR, Graham RR, Robinson WL. Islet cell tumors of the pancreas. Am J Med Sci. 1939; 198(4): 445‐ 454.
  46. [50]Yang Y, Shi J, Zhu J. Diagnostic performance of noninvasive imaging modalities for localization of insulinoma: A meta-analysis. Eur J Radiol. 2021; 145: 110016. 34763145
  47. [51]Wang H, Ba Y, Xing Q, Du JL. Diagnostic value of endoscopic ultrasound for insulinoma localization: A systematic review and meta-analysis. PLoS One. 2018; 13(10): e0206099. 30352083 PMC6198953
  48. [52]Wang H, Ba Y, Xing Q, Cai RC. Diagnostic value of ASVS for insulinoma localization: A systematic review and meta-analysis. PLoS One. 2019; 14(11): e0224928. 31743337 PMC6863549
  49. [53]Shah R, Garg R, Majmundar M, et al Exendin-4-based imaging in insulinoma localization: systematic review and meta-analysis. Clin Endocrinol (Oxf). 2021; 95(2): 354‐ 364. 33386617
  50. [54]Sada A, McKenzie TJ, Vella A, Levy MJ, Halfdanarson TR. Interventional vs surgical procedures in localized/nonmetastatic insulinomas (ablation vs surgery). Endocr Relat Cancer. 2023; 30(6): e220362. 36952635
  51. [55]Reubi JC, Perren A, Rehmann R, et al Glucagon-like peptide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinaemic hypoglycaemia following gastric bypass. Diabetologia. 2010; 53(12): 2641‐ 2645. 20835917
  52. [56]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; 52(7): 1073‐ 1078. 21680696
  53. [57]Refardt J, Hofland J, Wild D, Christ E. Molecular imaging of neuroendocrine neoplasms. J Clin Endocrinol Metab. 2022; 107(7): e2662‐ e2670. 35380158
  54. [58]Antwi K, Fani M, Nicolas G, et al Localization of hidden insulinomas with 68Ga-DOTA-exendin-4 PET/CT: A pilot study. J Nucl Med. 2015; 56(7): 1075‐ 1078. 25999434
  55. [60]Christ E, Wild D, Ederer S, et al Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. Lancet Diabetes Endocrinol. 2013; 1(2): 115‐ 122. 24622317
  56. [61]Druce MR, Muthuppalaniappan VM, O'Leary B, et al Diagnosis and localisation of insulinoma: the value of modern magnetic resonance imaging in conjunction with calcium stimulation catheterisation. Eur J Endocrinol. 2010; 162(5): 971‐ 978. 20207727
  57. [62]de Herder WW. GEP-NETS update: functional localisation and scintigraphy in neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP-NETs). Eur J Endocrinol. 2014; 170(5): R173‐ R183. 24723670
  58. [63]Morera J, Guillaume A, Courtheoux P, et al Preoperative localization of an insulinoma: selective arterial calcium stimulation test performance. J Endocrinol Invest. 2016; 39(4): 455‐ 463. 26577133
  59. [64]Wang H, Bender A, Wang P, et al Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas. Nat Commun. 2017; 8(1): 767. 28974674 PMC5626682
  60. [65]Cao Y, Gao Z, Li L, et al Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun. 2013; 4(1): 2810. 24326773
  61. [66]Karakose E, Wang H, Inabnet W, et al Aberrant methylation underlies insulin gene expression in human insulinoma. Nat Commun. 2020; 11(1): 5210. 33060578 PMC7566641
  62. [67]Rindi G, Falconi M, Klersy C, et al TNM Staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst. 2012; 104(10): 764‐ 777. 22525418
  63. [68]Rindi G, Klersy C, Albarello L, et al Competitive testing of the WHO 2010 versus the WHO 2017 grading of pancreatic neuroendocrine neoplasms: data from a large international cohort study. Neuroendocrinology. 2019; 107(4): 375‐ 386. 30300897
  64. [69]Hackeng WM, Schelhaas W, Morsink FHM, et al Alternative lengthening of telomeres and differential expression of endocrine transcription factors distinguish metastatic and non-metastatic insulinomas. Endocr Pathol. 2020; 31(2): 108‐ 118. 32103422 PMC7250793
  65. [70]Baudin E, Caron P, Lombard-Bohas C, et al Malignant insulinoma: recommendations for characterisation and treatment. Ann Endocrinol (Paris). 2013; 74(5-6): 523‐ 533. 23993836
  66. [71]Aida A, Noto H. Diagnosis and treatment course of insulinoma presenting as hypoglycemia unawareness using a factory-calibrated continuous glucose monitoring system. Am J Case Rep. 2022; 23: e936723. 35908172 PMC9350881
  67. [72]Yamaguchi N, Yamada E, Matsumoto S, et al A case of insulinoma-induced hypoglycemia managed by dexcom G4 platinum. Neuro Endocrinol Lett. 2022; 43(3): 161‐ 166. 36179727
  68. [73]Yuan T, Liu S, Zhu C, et al Continuous glucose monitoring in patients with insulinoma treated by endoscopic ultrasound-guided ethanol injection. Pancreas. 2021; 50(2): 183‐ 188. 33560091
  69. [74]Kawasaki A, Suzuki K, Miyamoto M, et al Disruptive nocturnal behavior due to insulinoma revealed by continuous glucose monitoring. Eur J Neurol. 2014; 21(5): e46‐ e47. 24712551
  70. [75]Brown E, Watkin D, Evans J, Yip V, Cuthbertson DJ. Multidisciplinary management of refractory insulinomas. Clin Endocrinol (Oxf). 2018; 88(5): 615‐ 624. 29205458
  71. [76]Altszuler N, Moraru E, Hampshire J. On the mechanism of diazoxide-induced hyperglycemia. Diabetes. 1977; 26(10): 931‐ 935. 908462
  72. [77]Warren AM, Topliss DJ, Hamblin PS. Successful medical management of insulinoma with diazoxide for 27 years. Endocrinol Diabetes Metab Case Rep. 2020; 2020: 20-0132. PMC7576657 33434168
  73. [78]Gill GV, Rauf O, MacFarlane IA. Diazoxide treatment for insulinoma: a national UK survey. Postgrad Med J. 1997; 73(864): 640‐ 641. 9497974 PMC2431498
  74. [79]Goode PN, Farndon JR, Anderson J, Johnston ID, Morte JA. Diazoxide in the management of patients with insulinoma. World J Surg. 1986; 10(4): 586‐ 592. 3019020
  75. [80]Alexandraki KI, Kaltsas GA, Grozinsky-Glasberg S. Emerging therapies for advanced insulinomas and glucagonomas. Endocr Relat Cancer. 2023; 30(9): e230020. 37343152
  76. [81]Vezzosi D, Bennet A, Rochaix P, et al Octreotide in insulinoma patients: efficacy on hypoglycemia, relationships with octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies. Eur J Endocrinol. 2005; 152(5): 757‐ 767. 15879362
  77. [82]Vezzosi D, Bennet A, Courbon F, Caron P. Short- and long-term somatostatin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism. Clin Endocrinol (Oxf). 2008; 68(6): 904‐ 911. 18031316
  78. [83]Gama R, Marks V, Wright J, Teale JD. Octreotide exacerbated fasting hypoglycaemia in a patient with a proinsulinoma; the glucostatic importance of pancreatic glucagon. Clin Endocrinol (Oxf). 1995; 43(1): 117‐ 120. 7641403
  79. [84]Stehouwer CD, Lems WF, Fischer HR, Hackeng WH, Naafs MA. Aggravation of hypoglycemia in insulinoma patients by the long-acting somatostatin analogue octreotide (sandostatin). Acta Endocrinol (Copenh). 1989; 121(1): 34‐ 40. 2545062
  80. [85]Kvols LK, Oberg KE, O'Dorisio TM, et al Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study. Endocr Relat Cancer. 2012; 19(5): 657‐ 666. 22807497
  81. [86]Cives M, Kunz PL, Morse B, et al Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr Relat Cancer. 2015; 22(1): 1‐ 9. 25376618 PMC4643672
  82. [87]Feelders RA, de Herder WW, Neggers SJ, van der Lely AJ, Hofland LJ. Pasireotide, a multi-somatostatin receptor ligand with potential efficacy for treatment of pituitary and neuroendocrine tumors. Drugs Today (Barc). 2013; 49(2): 89‐ 103. 23462624
  83. [88]Wolin EM, Jarzab B, Eriksson B, et al Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015; 9: 5075‐ 5086. PMC4562767 26366058
  84. [89]Feelders RA, Hofland LJ, van Aken MO, et al Medical therapy of acromegaly: efficacy and safety of somatostatin analogues. Drugs. 2009; 69(16): 2207‐ 2226. 19852525
  85. [90]Öberg K, Lamberts SW. Somatostatin analogues in acromegaly and gastroenteropancreatic neuroendocrine tumours: past, present and future. Endocr Relat Cancer. 2016; 23(12): R551‐ R566. 27697899
  86. [91]Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A. Advances in the medical treatment of Cushing's Syndrome. Lancet Diabetes Endocrinol. 2019; 7(4): 300‐ 312. 30033041
  87. [92]Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013; 98(8): 3446‐ 3453. 23733372
  88. [93]Hendren NS, Panach K, Brown TJ, et al Pasireotide for the treatment of refractory hypoglycaemia from malignant insulinoma. Clin Endocrinol (Oxf). 2018; 88(2): 341‐ 343. 29055143
  89. [94]Husni H, Khan SA, Alghaieb B, Abusamaan MS, Donner TW, Hamrahian AH. Pasireotide use for the treatment of endogenous hyperinsulinemic hypoglycemia refractory to conventional medical therapy: A case report and review of the literature. Clin Case Rep. 2022; 10(3): e05650. 35356161 PMC8940600
  90. [95]Ito T, Lee L, Jensen RT. Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies. Expert Opin Pharmacother. 2016; 17(16): 2191‐ 2205. 27635672 PMC5545682
  91. [96]Oziel-Taieb S, Maniry-Quellier J, Chanez B, Poizat F, Ewald J, Niccoli P. Pasireotide for refractory hypoglycemia in malignant insulinoma- case report and review of the literature. Front Endocrinol (Lausanne). 2022; 13: 860614. 35518928 PMC9063459
  92. [97]Siddiqui M, Vora A, Ali S, Abramowitz J, Mirfakhraee S. Pasireotide: A novel treatment for tumor-induced hypoglycemia due to insulinoma and non-islet cell tumor hypoglycemia. J Endocr Soc. 2021; 5(1): bvaa171. 33294765 PMC7692539
  93. [98]Blum I, Aderka D, Doron M, Laron Z. Suppression of hypoglycemia by DL-propranolol in malignant insulinoma. N Engl J Med. 1978; 299(9): 487. 210384
  94. [99]Blum I, Rusecki Y, Doron M, Lahav M, Laron Z, Atsmon A. Evidence for a therapeutic effect of dl-propranolol in benign and malignant insulinoma: report of three cases. J Endocrinol Invest. 1983; 6(1): 41‐ 45. 6302161
  95. [100]Stehouwer CD, Lems WF, Fischer HR, Hackeng WH. Malignant insulinoma: is combined treatment with verapamil and the long-acting somatostatin analogue octreotide (SMS 201-995) more effective than single therapy with either drug? Neth J Med. 1989; 35(1-2): 86‐ 94. 2550827
  96. [101]Imanaka S, Matsuda S, Ito K, Matsuoka T, Okada Y. Medical treatment for inoperable insulinoma: clinical usefulness of diphenylhydantoin and diltiazem. Jpn J Clin Oncol. 1986; 16(1): 65‐ 71. 3009920
  97. [102]Osataphan S, Vamvini M, Rosen ED, et al Anti-Insulin receptor antibody for malignant insulinoma and refractory hypoglycemia. N Engl J Med. 2023; 389(8): 767‐ 769. 37611129 PMC10506502
  98. [103]Howe JR, Merchant NB, Conrad C, et al The north American neuroendocrine tumor society consensus paper on the surgical management of pancreatic neuroendocrine tumors. Pancreas. 2020; 49(1): 1‐ 33. 31856076 PMC7029300
  99. [104]Dusch N, Lietzmann A, Barthels F, Niedergethmann M, Rückert F, Wilhelm TJ. International study group of pancreatic surgery definitions for postpancreatectomy complications: applicability at a high-volume center. Scand J Surg. 2017; 106(3): 216‐ 223. 28376656
  100. [105]van Beek DJ, Takkenkamp TJ, Wong-Lun-Hing EM, et al Risk factors for complications after surgery for pancreatic neuroendocrine tumors. Surgery. 2022; 172(1): 127‐ 136. 35341591
  101. [106]Gurusamy KS, Koti R, Fusai G, Davidson BR. Somatostatin analogues for pancreatic surgery. Cochrane Database Syst Rev. 2013; 2013(4): Cd008370. 23633353 PMC7175835
  102. [107]Heidsma CM, Tsilimigras DI, van Dieren S, et al Indications and outcomes of enucleation versus formal pancreatectomy for pancreatic neuroendocrine tumors. HPB (Oxford). 2021; 23(3): 413‐ 421. 32771338
  103. [108]Sallinen VJ, Le Large TYS, Tieftrunk E, et al Prognosis of sporadic resected small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors—a multi-institutional study. HPB (Oxford). 2018; 20(3): 251‐ 259. 28988702
  104. [109]Hofland J, de Herder WW, Kann PH. Turning up the heat: endoscopic ablation of pancreatic neuroendocrine neoplasms. J Clin Endocrinol Metab. 2019; 104(11): 5053‐ 5055. 31058975
  105. [110]Oleinikov K, Dancour A, Epshtein J, et al Endoscopic ultrasound-guided radiofrequency ablation: A new therapeutic approach for pancreatic neuroendocrine tumors. J Clin Endocrinol Metab. 2019; 104(7): 2637‐ 2647. 31102458
  106. [111]Crinò SF, Napoleon B, Facciorusso A, et al Endoscopic ultrasound-guided radiofrequency ablation versus surgical resection for treatment of pancreatic insulinoma. Clin Gastroenterol Hepatol. 2023; 21(11): 2834‐ 2843. 36871765
  107. [112]Kann PH. Relevance of endoscopic ultrasound in endocrinology today: multiple endocrine neoplasia type 1, insulinoma, primary aldosteronism-an Expert's Perspective based on three decades of scientific and clinical experience. Cancers (Basel). 2023; 15(13): 3494. 37444604 PMC10340175
  108. [113]Myrehaug S, Hallet J, Chu W, et al Proof of concept for stereotactic body radiation therapy in the treatment of functional neuroendocrine neoplasms. J Radiosurg SBRT. 2020; 6(4): 321‐ 324. 32185093 PMC7065890
  109. [114]van Vliembergen ENM, Eijkelenkamp H, Valk GD, et al Precision radiotherapy using MR-linac for pancreatic neuroendocrine tumors in MEN1 patients (PRIME): a protocol for a phase I-II trial, and systematic review on available evidence for radiotherapy of pNETs. Front Endocrinol (Lausanne). 2023; 14: 994370. 37305036 PMC10250693
  110. [115]van Beek DJ, Nell S, Vorselaars WMCM, et al Complications after Major surgery for duodenopancreatic neuroendocrine tumors in patients with MEN1: results from a nationwide cohort. Ann Surg Oncol. 2021; 28(8): 4387‐ 4399. 33521900 PMC8253708
  111. [116]Antwi K, Nicolas G, Fani M, et al 68Ga-Exendin-4 PET/CT detects insulinomas in patients with endogenous hyperinsulinemic hypoglycemia in MEN-1. J Clin Endocrinol Metab. 2019; 104(12): 5843‐ 5852. 31298706
  112. [117]Levy MJ, Thompson GB, Topazian MD, Callstrom MR, Grant CS, Vella A. US-guided ethanol ablation of insulinomas: a new treatment option. Gastrointest Endosc. 2012; 75(1): 200‐ 206. 22078104
  113. [118]Halfdanarson TR, Strosberg JR, Tang L, et al The north American neuroendocrine tumor society consensus guidelines for surveillance and medical management of pancreatic neuroendocrine tumors. Pancreas. 2020; 49(7): 863‐ 881. 32675783
  114. [119]Habibollahi P, Bai HX, Sanampudi S, Soulen MC, Dagli M. Effectiveness of liver-directed therapy for the management of intractable hypoglycemia in metastatic insulinoma. Pancreas. 2020; 49(6): 763‐ 767. 32541627
  115. [120]Caplin ME, Pavel M, Ćwikła JB, et al Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014; 371(3): 224‐ 233. 25014687
  116. [121]Brabander T, van der Zwan WA, Teunissen JJM, et al Long-Term efficacy, survival, and safety of [(177)Lu-DOTA(0), tyr(3)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017; 23(16): 4617‐ 4624. 28428192
  117. [122]Hofland J, Brabander T, Verburg FA, Feelders RA, de Herder WW. Peptide receptor radionuclide therapy. J Clin Endocrinol Metab. 2022; 107(12): 3199‐ 3208. 36198028 PMC9693835
  118. [123]Becx MN, Minczeles NS, Brabander T, de Herder WW, Nonnekens J, Hofland J. A clinical guide to peptide receptor radionuclide therapy with (177)Lu-DOTATATE in neuroendocrine tumor patients. Cancers (Basel). 2022; 14: 23. PMC9737149 36497273
  119. [124]van Schaik E, van Vliet EI, Feelders RA, et al Improved control of severe hypoglycemia in patients with malignant insulinomas by peptide receptor radionuclide therapy. J Clin Endocrinol Metab. 2011; 96(11): 3381‐ 3389. 21917872
  120. [125]Veltroni A, Cosaro E, Spada F, et al Clinico-pathological features, treatments and survival of malignant insulinomas: a multicenter study. Eur J Endocrinol. 2020; 182(4): 439‐ 446. 32061159
  121. [126]Zandee WT, Brabander T, Blažević A, et al Symptomatic and radiological response to 177Lu-DOTATATE for the treatment of functioning pancreatic neuroendocrine tumors. J Clin Endocrinol Metab. 2019; 104(4): 1336‐ 1344. 30566620
  122. [127]Yao JC, Shah MH, Ito T, et al Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364(6): 514‐ 523. 21306238 PMC4208619
  123. [128]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; 94(9): 3157‐ 3162. 19567519
  124. [129]Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med. 2009; 360(2): 195‐ 197. 19129539
  125. [130]de Herder WW, van Schaik E, Kwekkeboom D, Feelders RA. New therapeutic options for metastatic malignant insulinomas. Clin Endocrinol (Oxf). 2011; 75(3): 277‐ 284. 21649688
  126. [131]Raymond E, Dahan L, Raoul JL, et al Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364(6): 501‐ 513. 21306237
  127. [132]Billemont B, Medioni J, Taillade L, et al Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib. Br J Cancer. 2008; 99(9): 1380‐ 1382. 18841151 PMC2579676
  128. [133]Pavel M, Öberg K, Falconi M, et al Gastroenteropancreatic neuroendocrine neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020; 31(7): 844‐ 860. 32272208
  129. [134]Garcia-Carbonero R, Anton-Pascual B, Modrego A. Del carmen riesco-martinez M, Lens-pardo A, carretero-puche C, rubio-cuesta B, Soldevilla B. Advances in the treatment of gastroenteropancreatic neuroendocrine carcinomas: are we moving forward? Endocr Rev. 2023; 44(4): 724‐ 736. 36879384 PMC10335166
  130. [135]Garcia-Carbonero R, Rinke A, Valle JW, et al ENETS Consensus guidelines for the standards of care in neuroendocrine neoplasms. Systemic therapy 2: chemotherapy. Neuroendocrinology. 2017; 105(3): 281‐ 294. 28380493
  131. [136]Strosberg JR, Coppola D, Klimstra DS, et al The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas. 2010; 39(6): 799‐ 800. 20664477 PMC3100733
  132. [137]Jensen RT, Cadiot G, Brandi ML, et al ENETS Consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012; 95(2): 98‐ 119. 22261919 PMC3701449
  133. [138]Kulke MH, Anthony LB, Bushnell DL, et al North American neuroendocrine tumor S. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010; 39(6): 735‐ 752. 20664472 PMC3100728
  134. [139]Eads JR, Halfdanarson TR, Asmis T, et al Expert consensus practice recommendations of the north American neuroendocrine tumor society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms. Endocr Relat Cancer. 2023; 30(8): e220206. 37184955 PMC10388681
  135. [140]Garcia-Carbonero R, Sorbye H, Baudin E, et al ENETS Consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016; 103(2): 186‐ 194. 26731334
  136. [141]Strosberg JR, Fine RL, Choi J, et al First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011; 117(2): 268‐ 275. 20824724 PMC4665634
  137. [142]de Mestier L, Walter T, Evrard C, et al Temozolomide alone or combined with capecitabine for the treatment of advanced pancreatic neuroendocrine tumor. Neuroendocrinology. 2020; 110(1-2): 83‐ 91. 31071715 PMC6979423
  138. [143]Chan DL, Bergsland EK, Chan JA, et al Temozolomide in grade 3 gastroenteropancreatic neuroendocrine neoplasms: A multicenter retrospective review. Oncologist. 2021; 26(11): 950‐ 955. 34342086 PMC8571741
  139. [144]Kunz PL, Graham NT, Catalano PJ, et al Randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol. 2023; 41(7): 1359‐ 1369. 36260828 PMC9995105

Cited by

Sorted by citations

Authors
Hofland, J., Refardt, J. C., Feelders, R. A., Christ, E., & de Herder, W. W.
Affiliations
  • Erasmus MC (NL)
  • University Hospital of Basel (CH)
  • ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus MC and Erasmus MC Cancer Institute , 3015 GD Rotterdam , The Netherlands
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2023-10-31
Volume
109
Issue
4
Pages
1109-1118
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgad641
PMC
PMC10940262
OpenAlex
W4388378675
Cited by
91
References
2
Citations by year
2026: 27 · 2025: 47 · 2024: 17
FWCI
18.17
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Keywords
insulinoma, pancreatic neuroendocrine neoplasms, hypoglycemia, Whipple triad, multiple endocrine neoplasia type 1, endoscopic ultrasound, magnetic resonance imaging, somatostatin analogues, surgical excision, cytoreductive surgery, peptide receptor radionuclide therapy, everolimus, sunitinib, cytotoxic chemotherapy, metastatic insulinoma
MeSH terms
Humans, Hypoglycemia, Insulinoma, Pancreatic Neoplasms, Receptors, Somatostatin, Neuroendocrine Tumors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review