The pathogenic role of the GIP/GIPR axis in human endocrine tumors: emerging clinical mechanisms beyond diabetes

  • Daniela Regazzo
  • Mattia Barbot
  • Carla Scaroni
  • Nora Albiger
  • Gianluca OcchiEmail author


The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone produced in the gastrointestinal tract in response to nutrients. GIP has a variety of effects on different systems, including the potentiation of insulin secretion from pancreatic β-cells after food intake (i.e. incretin effect), which is probably the most important. GIP effects are mediated by the GIP receptor (GIPR), a G protein-coupled receptor expressed in several tissues, including islet β-cells, adipocytes, bone cells, and brain. As well as its involvement in metabolic disorders (e.g. it contributes to the impaired postprandial insulin secretion in type 2 diabetes (T2DM), and to the pathogenesis of obesity and associated insulin resistance), an inappropriate GIP/GIPR axis activation of potential diagnostic and prognostic value has been reported in several endocrine tumors in recent years. The ectopic GIPR expression seen in patients with overt Cushing syndrome and primary bilateral macronodular adrenal hyperplasia or unilateral cortisol-producing adenoma has been associated with an inverse rhythm of cortisol secretion, with low fasting morning plasma levels that increase after eating. On the other hand, most acromegalic patients with an unusual GH response to oral glucose suppression have GIPR-positive somatotropinomas, and a milder phenotype, and are more responsive to medical treatment. Neuroendocrine tumors are characterized by a strong GIPR expression that may correlate positively or inversely with the proliferative index MIB-1, and that seems an attractive target for developing novel radioligands. The main purpose of this review is to summarize the role of the GIP/GIPR axis in endocrine neoplasia, in the experimental and the clinical settings.


Glucose-dependent insulinotropic polypeptide receptor (GIPR) Endocrine disorders GH-secreting pituitary adenomas Neuroendocrine tumors food-dependent Cushing syndrome Aberrant expression 


Compliance with ethical standards

Not applicable.

Conflict of interest

The authors have no conflict of interest to disclose.


  1. 1.
    Baggio LL, Drucker DJ. Biology of Incretins: GLP-1 and GIP. Gastroenterology [Internet]. W.B. Saunders; 2007 [cited 2019 Aug 2];132:2131–57. Available from:
  2. 2.
    Brown JC. Gastric inhibitory polypeptide. Monogr Endocrinol [Internet]. 1982 [cited 2019 Feb 6];24:III–XI, 1–88. Available from:
  3. 3.
    Mortensen K, Christensen LL, Holst JJ, Orskov C. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul Pept [Internet]. 2003 [cited 2019 Jun 28];114:189–96. Available from: Scholar
  4. 4.
    Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in Man. J Clin Endocrinol Metab [Internet]. 1973 [cited 2019 Feb 6];37:826–8. Available from: Scholar
  5. 5.
    Vilsbøll T, Krarup T, Sonne J, Madsbad S, Vølund A, Juul AG, et al. Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol Metab [Internet]. 2003 [cited 2019 Jun 28];88:2706–13. Available from: CrossRefGoogle Scholar
  6. 6.
    Carr RD, Larsen MO, Winzell MS, Jelic K, Lindgren O, Deacon CF, et al. Incretin and islet hormonal responses to fat and protein ingestion in healthy men. Am J Physiol Endocrinol Metab [Internet]. 2008 [cited 2019 Jun 28];295:E779–84. Available from: PubMedCrossRefGoogle Scholar
  7. 7.
    Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes [Internet]. 1995 [cited 2019 Jun 28];44:1126–31. Available from: PubMedCrossRefGoogle Scholar
  8. 8.
    Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem [Internet]. 1993 [cited 2019 Aug 5];214:829–35. Available from: PubMedCrossRefGoogle Scholar
  9. 9.
    Gremlich S, Porret A, Hani EH, Cherif D, Vionnet N, Froguel P, et al. Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes [Internet]. American Diabetes Association; 1995 [cited 2019 Aug 7];44:1202–8. Available from: Scholar
  10. 10.
    Volz A, Göke R, Lankat-Buttgereit B, Fehmann H-C, Bode HP, Göke B. Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. FEBS Lett [Internet]. No longer published by Elsevier; 1995 [cited 2019 Aug 7];373:23–9. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Wheeler MB, Gelling RW, McIntosh CH, Georgiou J, Brown JC, Pederson RA. Functional expression of the rat pancreatic islet glucose-dependent insulinotropic polypeptide receptor: ligand binding and intracellular signaling properties. Endocrinology [Internet]. Narnia; 1995 [cited 2019 Aug 7];136:4629–39. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Yasuda K, Inagaki N, Yamada Y, Kubota A, Seino S, Seino Y. Hamster gastric inhibitory polypeptide receptor expressed in pancreatic islets and clonal insulin-secreting cells: its structure and functional properties. Biochem Biophys Res Commun [Internet]. Academic Press; 1994 [cited 2019 Aug 7];205:1556–62. Available from:
  13. 13.
    Yamada Y, Hayami T, Nakamura K, Kaisaki PJ, Someya Y, Wang C-Z, et al. Human gastric inhibitory polypeptide receptor: cloning of the gene (GIPR) and cDNA. Genomics [Internet]. Academic Press; 1995 [cited 2019 Aug 7];29:773–6. Available from:
  14. 14.
    Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology [Internet]. Oxford University Press; 1993 [cited 2018 Nov 21];133:2861–70. Available from:
  15. 15.
    Szecówka J, Grill V, Sandberg E, Efendić S. Effect of GIP on the secretion of insulin and somatostatin and the accumulation of cyclic AMP in vitro in the rat. Acta Endocrinol (Copenh) [Internet]. 1982 [cited 2019 Aug 7];99:416–21. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Lu M, Wheeler MB, Leng X-H, Boyd AE. The role of the free cytosolic calcium level in beta-cell signal transduction by gastric inhibitory polypeptide and glucagon-like peptide 1 (7–37) [Internet]. Available from:
  17. 17.
    Holz GG. Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic β-Cell. Diabetes [Internet]. American Diabetes Association; 2004 [cited 2019 Aug 5];53:5–13. Available from:
  18. 18.
    Yabe D, Seino Y. Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation. Prog Biophys Mol Biol [Internet]. 2011 [cited 2019 Aug 5];107:248–56. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Widenmaier SB, Ao Z, Kim S-J, Warnock G, McIntosh CHS. Suppression of p38 MAPK and JNK via Akt-mediated inhibition of apoptosis signal-regulating kinase 1 constitutes a core component of the beta-cell pro-survival effects of glucose-dependent insulinotropic polypeptide. J Biol Chem United States. 2009;284:30372–82.CrossRefGoogle Scholar
  20. 20.
    Kim S-J, Winter K, Nian C, Tsuneoka M, Koda Y, McIntosh CHS. Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regu. J Biol Chem US. 2005;280:22297–307.CrossRefGoogle Scholar
  21. 21.
    Trümper A, Trümper K, Hörsch D. Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in β(INS-1)-cells. J Endocrinol 2002;Google Scholar
  22. 22.
    Trümper A, Trümper K, Trusheim H, Arnold R, Göke B, Hörsch D. Glucose-dependent insulinotropic polypeptide is a growth factor for β (INS-1) cells by pleiotropic signaling. Mol Endocrinol [Internet]. 2001 [cited 2019 Aug 7];15:1559–70. Available from: Scholar
  23. 23.
    Ehses JA, Casilla VR, Doty T, Pospisilik JA, Winter KD, Demuth H-U, et al. Glucose-dependent insulinotropic polypeptide promotes beta-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase. Endocrinology [Internet]. 2003 [cited 2019 Aug 7];144:4433–45. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Verma MK, Goel R, Krishnadas N, Nemmani KVS. Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders. Expert Opin Ther Targets [Internet]. Taylor & Francis; 2018 [cited 2019 Apr 17];22:615–28. Available from:
  25. 25.
    Zhong Q, Itokawa T, Sridhar S, Ding K-H, Xie D, Kang B, et al. Effects of glucose-dependent insulinotropic peptide on osteoclast function. Am J Physiol Endocrinol Metab US. 2007;292:E543–8.CrossRefGoogle Scholar
  26. 26.
    Mabilleau G, Perrot R, Mieczkowska A, Boni S, Flatt PR, Irwin N, et al. Glucose-dependent insulinotropic polypeptide (GIP) dose-dependently reduces osteoclast differentiation and resorption. Bone [Internet]. Elsevier; 2016 [cited 2019 Aug 1];91:102–12. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Wu T, Rayner CK, Horowitz M. Incretins. Handb Exp Pharmacol [Internet]. 2015 [cited 2019 Aug 2]. p. 137–71. Available from:
  28. 28.
    Ceperuelo-Mallafré V, Duran X, Pachón G, Roche K, Garrido-Sánchez L, Vilarrasa N, et al. Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance. J Clin Endocrinol Metab [Internet]. 2014 [cited 2019 Aug 1];99:E908–19. Available from: CrossRefGoogle Scholar
  29. 29.
    Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia [Internet]. 2002 [cited 2019 Aug 1];45:1111–9. Available from: CrossRefGoogle Scholar
  30. 30.
    Kim S-J, Nian C, Karunakaran S, Clee SM, Isales CM, McIntosh CHS. GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. Maedler K, editor. PLoS One [Internet]. 2012 [cited 2019 Aug 1];7:e40156. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med [Internet]. 2002 [cited 2019 Aug 1];8:738–42. Available from: Scholar
  32. 32.
    McClean PL, Irwin N, Cassidy RS, Holst JJ, Gault VA, Flatt PR. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am J Physiol Metab [Internet]. 2007 [cited 2019 Aug 1];293:E1746–55. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Althage MC, Ford EL, Wang S, Tso P, Polonsky KS, Wice BM. Targeted ablation of glucose-dependent insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high-fat diet. J Biol Chem [Internet]. 2008 [cited 2019 Aug 1];283:18365–76. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Fulurija A, Lutz TA, Sladko K, Osto M, Wielinga PY, Bachmann MF, et al. Vaccination against GIP for the Treatment of Obesity. Bartolomucci A, editor. PLoS One [Internet]. 2008 [cited 2019 Aug 1];3:e3163. Available from:
  35. 35.
    Garg G, McGuigan FE, Kumar J, Luthman H, Lyssenko V, Akesson K. Glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) genes: an association analysis of polymorphisms and bone in young and elderly women. Bone Reports [Internet]. 2016 [cited 2019 Aug 1];4:23–7. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Saxena R, Hivert M-F, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet [Internet]. 2010 [cited 2019 Aug 1];42:142–8. Available from:
  37. 37.
    Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia [Internet]. 1986 [cited 2019 Jun 28];29:46–52. Available from:
  38. 38.
    Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ [Internet]. 2012 [cited 2019 Jun 28];344:e1369. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009. p. e1–34.PubMedCrossRefGoogle Scholar
  40. 40.
    Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet (London, England). England; 2015;386:913–27.Google Scholar
  41. 41.
    Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing’s Syndrome. Endocr Rev [Internet]. Narnia; 2001 [cited 2019 Jun 6];22:75–110. Available from: PubMedPubMedCentralGoogle Scholar
  42. 42.
    Groussin L, Perlemoine K, Contesse V, Lefebvre H, Tabarin A, Thieblot P, et al. The ectopic expression of the gastric inhibitory polypeptide receptor is frequent in adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia, but rare in unilateral tumors. J Clin Endocrinol Metab. United States; 2002;87:1980–5.CrossRefGoogle Scholar
  43. 43.
    Hamet P, Larochelle P, Franks DJ, Cartier P, Bolte E. Cushing syndrome with food-dependent periodic hormonogenesis. Clin Invest Med [Internet]. 1987 [cited 2019 Jun 18];10:530–3. Available from:
  44. 44.
    Lacroix A, Bolte E, Tremblay J, Dupre J, Poitras P, Fournier H, et al. Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing’s syndrome. N Engl J Med US. 1992;327:974–80.CrossRefGoogle Scholar
  45. 45.
    Reznik Y, Allali-Zerah V, Chayvialle JA, Leroyer R, Leymarie P, Travert G, et al. Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med US. 1992;327:981–6.CrossRefGoogle Scholar
  46. 46.
    Lebrethon MC, Avallet O, Reznik Y, Archambeaud F, Combes J, Usdin TB, et al. Food-dependent Cushing’s syndrome: characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients. J Clin Endocrinol Metab US. 1998;83:4514–9.Google Scholar
  47. 47.
    Chabre O, Liakos P, Vivier J, Chaffanjon P, Labat-Moleur F, Martinie M, et al. Cushing’s syndrome due to a gastric inhibitory polypeptide-dependent adrenal adenoma: insights into hormonal control of adrenocortical tumorigenesis. J Clin Endocrinol Metab US. 1998;83:3134–43.Google Scholar
  48. 48.
    Luton JP, Bertherat J, Kuhn JM, Bertagna X. [aberrant expression of the GIP (Gastric inhibitory polypeptide) receptor in an adrenal cortical adenoma responsible for a case of food-dependent Cushing’s syndrome]. Bull Acad Natl Med. Netherlands; 1998;182:1839–50.Google Scholar
  49. 49.
    El Ghorayeb N, Bourdeau I, Lacroix A. Multiple aberrant hormone receptors in Cushing’s syndrome. Eur J Endocrinol England. 2015;173:M45–60.CrossRefGoogle Scholar
  50. 50.
    St-Jean M, El Ghorayeb N, Bourdeau I, Lacroix A. Aberrant G-protein coupled hormone receptor in adrenal diseases. Best Pract res Clin Endocrinol Metab. Netherlands; 2018;32:165–87.CrossRefGoogle Scholar
  51. 51.
    N’Diaye N, Tremblay J, Hamet P, De Herder WW, Lacroix A. Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing’s syndrome. J Clin Endocrinol Metab US. 1998;83:2781–5.CrossRefGoogle Scholar
  52. 52.
    Zhong Q, Bollag R., Dransfield D., Gasalla-Herraiz J, Ding K-H, Min L, et al. Glucose-dependent insulinotropic peptide signaling pathways in endothelial cells. Peptides [Internet]. Elsevier; 2000 [cited 2019 Apr 1];21:1427–32. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Galac S, Kars VJ, Klarenbeek S, Teerds KJ, Mol JA, Kooistra HS. Expression of receptors for luteinizing hormone, gastric-inhibitory polypeptide, and vasopressin in normal adrenal glands and cortisol-secreting adrenocortical tumors in dogs. Domest Anim Endocrinol US. 2010;39:63–75.CrossRefGoogle Scholar
  54. 54.
    Mazzocchi G, Rebuffat P, Meneghelli V, Malendowicz LK, Tortorella C, Gottardo G, et al. Gastric inhibitory polypeptide stimulates glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase-dependent signaling pathway. Peptides US. 1999;20:589–94.CrossRefGoogle Scholar
  55. 55.
    Bates HE, Campbell JE, Ussher JR, Baggio LL, Maida A, Seino Y, et al. Gipr is essential for adrenocortical steroidogenesis; however, corticosterone deficiency does not mediate the favorable metabolic phenotype of Gipr(−/−) mice. Diabetes US. 2012;61:40–8.CrossRefGoogle Scholar
  56. 56.
    Costa MHS, Latronico AC, Martin RM, Barbosa AS, Almeida MQ, Lotfi CFP, et al. Expression profiles of the glucose-dependent insulinotropic peptide receptor and LHCGR in sporadic adrenocortical tumors. J Endocrinol England. 2009;200:167–75.CrossRefGoogle Scholar
  57. 57.
    de Herder WW, Hofland LJ, Usdin TB, de Jong FH, Uitterlinden P, van Koetsveld P, et al. Food-dependent Cushing’s syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells. J Clin Endocrinol Metab US. 1996;81:3168–72.Google Scholar
  58. 58.
    Lampron A, Bourdeau I, Oble S, Godbout A, Schurch W, Arjane P, et al. Regulation of aldosterone secretion by several aberrant receptors including for glucose-dependent insulinotropic peptide in a patient with an aldosteronoma. J Clin Endocrinol Metab US. 2009;94:750–6.CrossRefGoogle Scholar
  59. 59.
    Zwermann O, Suttmann Y, Bidlingmaier M, Beuschlein F, Reincke M. Screening for membrane hormone receptor expression in primary aldosteronism. Eur J Endocrinol. England; 2009;160:443–51.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Ye P, Mariniello B, Mantero F, Shibata H, Rainey WE. G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism. J Endocrinol [Internet]. 2007 [cited 2019 Jun 28];195:39–48. Available from: PubMedCrossRefGoogle Scholar
  61. 61.
    Tsagarakis S, Tsigos C, Vassiliou V, Tsiotra P, Pratsinis H, Kletsas D, et al. Food-dependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing’s syndrome: in vivo and in vitro studies. J Clin Endocrinol Metab US. 2001;86:583–9.Google Scholar
  62. 62.
    Stocco DM, Wang X, Jo Y, Manna PR. Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. Mol Endocrinol US. 2005;19:2647–59.CrossRefGoogle Scholar
  63. 63.
    Manna PR, Dyson MT, Stocco DM. Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectives. Mol Hum Reprod England. 2009;15:321–33.CrossRefGoogle Scholar
  64. 64.
    Lampron A, Bourdeau I, Hamet P, Tremblay J, Lacroix A. Whole genome expression profiling of glucose-dependent insulinotropic peptide (GIP)- and adrenocorticotropin-dependent adrenal hyperplasias reveals novel targets for the study of GIP-dependent Cushing’s syndrome. J Clin Endocrinol Metab [Internet]. Oxford University Press; 2006 [cited 2018 Nov 20];91:3611–8. Available from:
  65. 65.
    Mazzuco TL, Chabre O, Sturm N, Feige J-J, Thomas M. Ectopic expression of the gastric inhibitory polypeptide receptor gene is a sufficient genetic event to induce benign adrenocortical tumor in a xenotransplantation model. Endocrinology US. 2006;147:782–90.CrossRefGoogle Scholar
  66. 66.
    Antonini SR, Baldacchino V, Tremblay J, Hamet P, Lacroix A. Expression of ACTH receptor pathway genes in glucose-dependent insulinotrophic peptide (GIP)-dependent Cushing’s syndrome. Clin Endocrinol (Oxf). England; 2006;64:29–36.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Temel RE, Trigatti B, DeMattos RB, Azhar S, Krieger M, Williams DL. Scavenger receptor class B, type I (SR-BI) is the major route for the delivery of high-density lipoprotein cholesterol to the steroidogenic pathway in cultured mouse adrenocortical cells. Proc Natl Acad Sci U S A [Internet]. 1997 [cited 2019 Jul 15];94:13600–5. Available from: CrossRefGoogle Scholar
  68. 68.
    Bens S, Mohn A, Yüksel B, Kulle AE, Michalek M, Chiarelli F, et al. Congenital lipoid adrenal hyperplasia: functional characterization of three novel mutations in the STAR gene. J Clin Endocrinol Metab [Internet]. 2010 [cited 2019 Jul 15];95:1301–8. Available from: CrossRefGoogle Scholar
  69. 69.
    Fujii H, Tamamori-Adachi M, Uchida K, Susa T, Nakakura T, Hagiwara H, et al. Marked cortisol production by Intracrine ACTH in GIP-treated cultured adrenal cells in which the GIP receptor was exogenously Introduced. Isales CM, editor. PLoS One [Internet]. Public Library of Science; 2014 [cited 2019 Mar 14];9:e110543. Available from:
  70. 70.
    Enyeart JJ. Biochemical and ionic signaling mechanisms for ACTH-stimulated cortisol production. Vitam Horm US. 2005;70:265–79.CrossRefGoogle Scholar
  71. 71.
    Louiset E, Contesse V, Groussin L, Cartier D, Duparc C, Barrande G, et al. Expression of serotonin7 receptor and coupling of ectopic receptors to protein kinase A and ionic currents in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing’s syndrome. J Clin Endocrinol Metab US. 2006;91:4578–86.CrossRefGoogle Scholar
  72. 72.
    Louiset E, Duparc C, Young J, Renouf S, Tetsi Nomigni M, Boutelet I, et al. Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia. N Engl J Med US. 2013;369:2115–25.CrossRefGoogle Scholar
  73. 73.
    N’Diaye N, Hamet P, Tremblay J, Boutin JM, Gaboury L, Lacroix A. Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptide-dependent Cushing’s syndrome. J Clin Endocrinol Metab US. 1999;84:2616–22.CrossRefGoogle Scholar
  74. 74.
    Bourdeau I, Antonini SR, Lacroix A, Kirschner LS, Matyakhina L, Lorang D, et al. Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene [Internet]. Nature Publishing Group; 2004 [cited 2018 Nov 20];23:1575–85. Available from: PubMedCrossRefGoogle Scholar
  75. 75.
    Albiger NM, Occhi G, Mariniello B, Iacobone M, Favia G, Fassina A, et al. Food-dependent Cushing’s syndrome: from molecular characterization to therapeutical results. Eur J Endocrinol England. 2007;157:771–8.CrossRefGoogle Scholar
  76. 76.
    Mircescu H, Jilwan J, N’Diaye N, Bourdeau I, Tremblay J, Hamet P, et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s syndrome? J Clin Endocrinol Metab US. 2000;85:3531–6.Google Scholar
  77. 77.
    Bertherat J, Contesse V, Louiset E, Barrande G, Duparc C, Groussin L, et al. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing’s syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J Clin Endocrinol Metab US. 2005;90:1302–10.CrossRefGoogle Scholar
  78. 78.
    Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J, Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol (Oxf). England; 2010;73:1–15.Google Scholar
  79. 79.
    Antonini SR, N’Diaye N, Baldacchino V, Hamet P, Tremblay J, Lacroix A. Analysis of the putative regulatory region of the gastric inhibitory polypeptide receptor gene in food-dependent Cushing’s syndrome. J Steroid Biochem Mol Biol England. 2004;91:171–7.CrossRefGoogle Scholar
  80. 80.
    Baldacchino V, Oble S, Decarie P-O, Bourdeau I, Hamet P, Tremblay J, et al. The Sp transcription factors are involved in the cellular expression of the human glucose-dependent insulinotropic polypeptide receptor gene and overexpressed in adrenals of patients with Cushing’s syndrome. J Mol Endocrinol England. 2005;35:61–71.CrossRefGoogle Scholar
  81. 81.
    Swords FM, Aylwin S, Perry L, Arola J, Grossman AB, Monson JP, et al. The aberrant expression of the gastric inhibitory polypeptide (GIP) receptor in adrenal hyperplasia: does chronic adrenocorticotropin exposure stimulate up-regulation of GIP receptors in Cushing’s disease? J Clin Endocrinol Metab [Internet]. Narnia; 2005 [cited 2019 Jun 6];90:3009–16. Available from: CrossRefGoogle Scholar
  82. 82.
    Lecoq A-L, Stratakis CA, Viengchareun S, Chaligné R, Tosca L, Deméocq V, et al. Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome. JCI Insight [Internet]. American Society for Clinical Investigation; 2017 [cited 2019 Feb 28];2. Available from:
  83. 83.
    Mazzuco TL, Chabre O, Feige JJ, Thomas M. Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis. Mol Cell Endocrinol Ireland. 2007;265–266:23–8.CrossRefGoogle Scholar
  84. 84.
    Assie G, Libe R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med US. 2013;369:2105–14.CrossRefGoogle Scholar
  85. 85.
    Alencar GA, Lerario AM, Nishi MY, de Mariani BMP, Almeida MQ, Tremblay J, et al. ARMC5 mutations are a frequent cause of primary macronodular adrenal hyperplasia. J Clin Endocrinol Metab US. 2014;99:E1501–9.CrossRefGoogle Scholar
  86. 86.
    Gagliardi L, Hotu C, Casey G, Braund WJ, Ling K-H, Dodd T, et al. Familial vasopressin-sensitive ACTH-independent macronodular adrenal hyperplasia (VPs-AIMAH): clinical studies of three kindreds. Clin Endocrinol (Oxf). England; 2009;70:883–91.PubMedCrossRefGoogle Scholar
  87. 87.
    Lee S, Hwang R, Lee J, Rhee Y, Kim DJ, Chung U-I, et al. Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia. Clin Endocrinol (Oxf). England; 2005;63:625–30.PubMedCrossRefGoogle Scholar
  88. 88.
    Vezzosi D, Cartier D, Regnier C, Otal P, Bennet A, Parmentier F, et al. Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors. Eur J Endocrinol England. 2007;156:21–31.CrossRefGoogle Scholar
  89. 89.
    Miyamura N, Taguchi T, Murata Y, Taketa K, Iwashita S, Matsumoto K, et al. Inherited adrenocorticotropin-independent macronodular adrenal hyperplasia with abnormal cortisol secretion by vasopressin and catecholamines: detection of the aberrant hormone receptors on adrenal gland. Endocrine US. 2002;19:319–26.CrossRefGoogle Scholar
  90. 90.
    Drougat L, Espiard S, Bertherat J. Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing’s syndrome? Eur J Endocrinol [Internet]. 2015 [cited 2019 Jul 12];173:M121–31. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Skogseid B, Larsson C, Lindgren PG, Kvanta E, Rastad J, Theodorsson E, et al. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab [Internet]. 1992 [cited 2019 Jun 18];75:76–81. Available from: Scholar
  92. 92.
    Yoshida M, Hiroi M, Kikumori T, Himeno T, Nakamura Y, Sasano H, et al. A case of ACTH-independent macronodular adrenal hyperplasia associated with multiple endocrine neoplasia type 1 [Internet]. Endocr J 2011. Available from:
  93. 93.
    Costa MHS, Domenice S, Toledo RA, Lourenco DMJ, Latronico AC, Pinto EM, et al. Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus. Clinics (Sao Paulo). Brazil; 2011;66:529–33.Google Scholar
  94. 94.
    Espiard S, Drougat L, Libe R, Assie G, Perlemoine K, Guignat L, et al. ARMC5 mutations in a large cohort of primary macronodular adrenal hyperplasia: clinical and functional consequences. J Clin Endocrinol Metab US. 2015;100:E926–35.CrossRefGoogle Scholar
  95. 95.
    Albiger NM, Regazzo D, Rubin B, Ferrara AM, Rizzati S, Taschin E, et al. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype. Endocrine. 2017;55:959–68.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Faucz FR, Zilbermint M, Lodish MB, Szarek E, Trivellin G, Sinaii N, et al. Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation. J Clin Endocrinol Metab [Internet]. Oxford University Press; 2014 [cited 2018 Dec 19];99:E1113–9. Available from:
  97. 97.
    Miyashita K, Itoh H, Nakao K. [ACTH-independent macronodular adrenal hyperplasia]. Nihon Rinsho. Japan; 2006;Suppl 1:614–7.Google Scholar
  98. 98.
    Swain JM, Grant CS, Schlinkert RT, Thompson GB, VanHeerden JA, Lloyd R V, et al. Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation. Arch Surg. United States; 1998;133:541–6.Google Scholar
  99. 99.
    Christopoulos S, Bourdeau I, Lacroix A. Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors. Horm Res Switzerland. 2005;64:119–31.Google Scholar
  100. 100.
    Lacroix A, N’Diaye N, Mircescu H, Tremblay J, Hamet P. The diversity of abnormal hormone receptors in adrenal Cushing’s syndrome allows novel pharmacological therapies. Brazilian J Med biol res = rev bras Pesqui medicas e biol. Brazil; 2000;33:1201–9.Google Scholar
  101. 101.
    Croughs RJ, Zelissen PM, van Vroonhoven TJ, Hofland LJ, N’Diaye N, Lacroix A, et al. GIP-dependent adrenal Cushing’s syndrome with incomplete suppression of ACTH. Clin Endocrinol (Oxf). England; 2000;52:235–40.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Leal-Cerro A, Considine R V, Peino R, Venegas E, Astorga R, Casanueva FF, et al. Serum immunoreactive-leptin levels are increased in patients with Cushing’s syndrome. Horm Metab Res [Internet]. 1996 [cited 2019 Jul 24];28:711–3. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Pralong FP, Gomez F, Guillou L, Mosimann F, Franscella S, Gaillard RC. Food-dependent Cushing’s syndrome: possible involvement of leptin in cortisol hypersecretion. J Clin Endocrinol Metab [Internet]. Narnia; 1999 [cited 2019 Jul 19];84:3817–22. Available from: Google Scholar
  104. 104.
    Iacobone M, Albiger N, Scaroni C, Mantero F, Fassina A, Viel G, et al. The role of unilateral adrenalectomy in ACTH-independent macronodular adrenal hyperplasia (AIMAH). World J Surg [Internet]. 2008 [cited 2019 Jul 11];32:882–9. Available from:
  105. 105.
    Osswald A, Quinkler M, Di Dalmazi G, Deutschbein T, Rubinstein G, Ritzel K, et al. Long-term outcome of primary bilateral macronodular adrenocortical hyperplasia after unilateral adrenalectomy. J Clin Endocrinol Metab [Internet]. Narnia; 2019 [cited 2019 Jun 24];104:2985–93. Available from: CrossRefGoogle Scholar
  106. 106.
    Moss CE, Marsh WJ, Parker HE, Ogunnowo-Bada E, Riches CH, Habib AM, et al. Somatostatin receptor 5 and cannabinoid receptor 1 activation inhibit secretion of glucose-dependent insulinotropic polypeptide from intestinal K cells in rodents. Diabetologia Germany. 2012;55:3094–103.CrossRefGoogle Scholar
  107. 107.
    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 US. 2013;98:3446–53.CrossRefGoogle Scholar
  108. 108.
    Unger N, Serdiuk I, Sheu SY, Walz MK, Schulz S, Schmid KW, et al. Immunohistochemical determination of somatostatin receptor subtypes 1, 2A, 3, 4, and 5 in various adrenal tumors. Endocr Res England. 2004;30:931–4.CrossRefGoogle Scholar
  109. 109.
    Bourdeau I, D’Amour P, Hamet P, Boutin JM, Lacroix A. Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing’s syndrome. J Clin Endocrinol Metab US. 2001;86:5534–40.Google Scholar
  110. 110.
    Preumont V, Mermejo LM, Damoiseaux P, Lacroix A, Maiter D. Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing’s syndrome. Horm Metab res = Horm und Stoffwechselforsch = Horm Metab. Germany; 2011;43:287–91.PubMedCrossRefGoogle Scholar
  111. 111.
    Karapanou O, Vlassopoulou B, Tzanela M, Stratigou T, Tsatlidis V, Tsirona S, et al. Adrenocorticotropic hormone independent macronodular adrenal hyperplasia due to aberrant receptor expression: is medical treatment always an option? Endocr Pract US. 2013;19:e77–82.CrossRefGoogle Scholar
  112. 112.
    Ottlecz A, Samson WK, McCann SM. The effects of gastric inhibitory polypeptide (GIP) on the release of anterior pituitary hormones. Peptides [Internet]. Elsevier; 1985 [cited 2018 Nov 21];6:115–9. Available from: PubMedCrossRefGoogle Scholar
  113. 113.
    Westendorf JM, Schonbrunn A. Peptide specificity for stimulation of corticotropin secretion: activation of overlapping pathways by the vasoactive intestinal peptide family and corticotropin-releasing factor. Endocrinology [Internet]. 1985 [cited 2019 Apr 1];116:2528–35. Available from: PubMedCrossRefGoogle Scholar
  114. 114.
    Gallwitz B, Witt M, Morys-Wortmann C, Fölsch UR, Schmidt WE. GLP-1/GIP chimeric peptides define the structural requirements for specific ligand-receptor interaction of GLP-1. Regul Pept [Internet]. 1996 [cited 2019 Apr 2];63:17–22. Available from:
  115. 115.
    Kaplan AM, Vigna SR. Gastric inhibitory polypeptide (GIP) binding sites in rat brain. Peptides [Internet]. Elsevier; 1994 [cited 2018 Nov 21];15:297–302. Available from: PubMedCrossRefGoogle Scholar
  116. 116.
    Occhi G, Losa M, Albiger N, Trivellin G, Regazzo D, Scanarini M, et al. The glucose-dependent insulinotropic polypeptide receptor is overexpressed amongst GNAS1 mutation-negative somatotropinomas and drives growth hormone (GH)-promoter activity in GH3 cells. J Neuroendocrinol [Internet]. 2011 [cited 2018 Nov 22];23:641–9. Available from: Scholar
  117. 117.
    Turner HE, Nagy Z, Gatter KC, Esiri MM, Harris AL, Wass JA. Angiogenesis in pituitary adenomas and the normal pituitary gland. J Clin Endocrinol Metab [Internet]. 2000 [cited 2019 Apr 3];85:1159–62. Available from: CrossRefGoogle Scholar
  118. 118.
    Umahara M, Okada S, Ohshima K, Mori M. Glucose-dependent insulinotropic polypeptide induced growth hormone secretion in acromegaly. Endocr J [Internet]. The Japan Endocrine Society; 2003 [cited 2018 Nov 22];50:643–50. Available from: PubMedCrossRefGoogle Scholar
  119. 119.
    Regazzo D, Losa M, Albiger NM, Terreni MR, Vazza G, Ceccato F, et al. The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp-somatotropinomas. Eur J Endocrinol. 2017;176:543–53.PubMedCrossRefGoogle Scholar
  120. 120.
    Hage M, Chaligné R, Viengchareun S, Villa C, Salenave S, Bouligand J, et al. Hypermethylator phenotype and ectopic GIP receptor in GNAS mutation-negative somatotropinomas. J Clin Endocrinol Metab [Internet]. Narnia; 2019 [cited 2019 Apr 5];104:1777–87. Available from: CrossRefGoogle Scholar
  121. 121.
    Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature [Internet]. 1987 [cited 2019 May 7];330:566–8. Available from: PubMedCrossRefGoogle Scholar
  122. 122.
    Landis C, Masters S, Spada A, Pace A, Bourne H, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature. 1989;340:692–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Kato Y, Iwasaki Y, Iwasaki J, Abe H, Yanaihara N, Imura H. Prolactin release by vasoactive intestinal polypeptide in rats. Endocrinology [Internet]. 1978 [cited 2019 may 17];103:554–8. Available from: Scholar
  124. 124.
    Gourdji D, Bataille D, Vauclin N, Grouselle D, Rosselin G, Tixier-Vidal A. Vasoactive intestinal peptide (VIP) stimulates prolactin (PRL) release and cAMP production in a rat pituitary cell line (GH3/B6). Additive effects of VIP and TRH on PRL release. FEBS Lett [Internet]. 1979 [cited 2019 may 17];104:165–8. Available from: Scholar
  125. 125.
    Ruvkun G. A molecular growth industry. Nature [Internet]. 1992 [cited 2018 Apr 6];360:711–2. Available from: Scholar
  126. 126.
    Hammer RE, Brinster RL, Rosenfeld MG, Evans RM, Mayo KE. Expression of human growth hormone-releasing factor in transgenic mice results in increased somatic growth. Nature [Internet]. 1985;315:413–6. Available from: Scholar
  127. 127.
    Billestrup N, Swanson LW, Vale W. Growth hormone-releasing factor stimulates proliferation of somatotrophs in vitro. Proc Natl Acad Sci U S A. 1986;83:6854–7.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Välimäki N, Demir H, Pitkänen E, Kaasinen E, Karppinen A, Kivipelto L, et al. Whole-genome sequencing of growth hormone (GH)-secreting pituitary adenomas. J Clin Endocrinol Metab. 2015;100:3918–27.PubMedCrossRefGoogle Scholar
  129. 129.
    Ronchi CL, Peverelli E, Herterich S, Weigand I, Mantovani G, Schwarzmayr T, et al. Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas. Eur J Endocrinol. 2016;174:363–72.PubMedCrossRefGoogle Scholar
  130. 130.
    Bilezikjian LM, Vale WW. Stimulation of adenosine 3′,5′-monophosphate production by growth hormone-releasing factor and its inhibition by somatostatin in anterior pituitary cells in vitro. Endocrinology. 1983;113:1726–31.PubMedCrossRefGoogle Scholar
  131. 131.
    Bilezikjian LM, Erlichman J, Fleischer N, Vale WW. Differential activation of type I and type II 3′, 5′-cyclic adenosine monophosphate-dependent protein kinases by growth gormone-releasing factor. Mol Endocrinol. 1987;1:137–46.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Shepard AR, Zhang W, Eberhardt NL. Two CGTCA motifs and a GHF1/Pit1 binding site mediate cAMP-dependent protein kinase A regulation of human growth hormone gene expression in rat anterior pituitary GC cells. J Biol Chem. 1994;269:1804–14.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Beck P, Parker ML, Daughaday WH. Paradoxical hypersecretion of growth hormone in response to glucose. J Clin Endocrinol Metab [Internet]. 1966 [cited 2019 Apr 8];26:463–9. Available from: Scholar
  134. 134.
    Scaroni C, Albiger N, Daniele A, Dassie F, Romualdi C, Vazza G, et al. Paradoxical GH increase during OGTT is associated with first-generation somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab [Internet]. Narnia; 2019 [cited 2019 Apr 10];104:856–62. Available from: CrossRefGoogle Scholar
  135. 135.
    Mukai K, Otsuki M, Tamada D, Kitamura T, Hayashi R, Saiki A, et al. Clinical characteristics of acromegalic patients with paradoxical GH response to oral glucose load. J Clin Endocrinol Metab [Internet]. Narnia; 2019 [cited 2019 Apr 10];104:1637–44. Available from: CrossRefGoogle Scholar
  136. 136.
    De Marinis L, Mancini A, Bianchi A, Gentilella R, Valle D, Giampietro A, et al. Preoperative growth hormone response to thyrotropin-releasing hormone and oral glucose tolerance test in acromegaly: a retrospective evaluation of 50 patients. Metabolism. 2002;51:616–21.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Peracchi M, Porretti S, Gebbia C, Pagliari C, Bucciarelli P, Epaminonda P, et al. Increased glucose-dependent insulinotropic polypeptide (GIP) secretion in acromegaly. Eur J Endocrinol [Internet]. 2001 [cited 2018 Nov 21];145:R1–4. Available from:
  138. 138.
    Shekhawat VS, Bhansali S, Dutta P, Mukherjee KK, Vaiphei K, Kochhar R, et al. Glucose-dependent insulinotropic polypeptide (GIP) resistance and β-cell dysfunction contribute to hyperglycaemia in acromegaly. Sci Rep [Internet]. Nature Publishing Group; 2019 [cited 2019 Apr 19];9:5646. Available from:
  139. 139.
    Narayanan S, Kunz PL. Role of somatostatin analogues in the treatment of neuroendocrine tumors. J Natl Compr Canc Netw [Internet]. 2015 [cited 2019 Feb 25];13:109–17; quiz 117. Available from:
  140. 140.
    Oberg K, Knigge U, Kwekkeboom D, Perren A, ESMO Guidelines Working Group. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol [Internet]. 2012 [cited 2019 may 22];23:vii124–30. Available from:
  141. 141.
    Ganetsky A, Bhatt V. Gastroenteropancreatic neuroendocrine tumors: update on therapeutics. Ann Pharmacother [Internet]. 2012 [cited 2019 May 22];46:851–62. Available from:
  142. 142.
    Korse CM, Taal BG, van Velthuysen M-LF, Visser O. Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry. Eur J Cancer [Internet]. 2013 [cited 2019 May 22];49:1975–83. Available from: PubMedCrossRefGoogle Scholar
  143. 143.
    Wild D, Mäcke H, Christ E, Gloor B, Reubi JC. Glucagon-like peptide 1–receptor scans to localize occult insulinomas. N Engl J Med [Internet]. Massachusetts Medical Society; 2008 [cited 2019 Feb 21];359:766–8. Available from: PubMedCrossRefGoogle Scholar
  144. 144.
    Reubi JC, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging [Internet]. Springer-Verlag; 2003 [cited 2019 Feb 21];30:781–93. Available from:
  145. 145.
    Waser B, Rehmann R, Sanchez C, Fourmy D, Reubi JC. Glucose-dependent insulinotropic polypeptide receptors in most gastroenteropancreatic and bronchial neuroendocrine tumors. J Clin Endocrinol Metab [Internet]. Oxford University Press; 2012 [cited 2019 Feb 8];97:482–8. Available from:
  146. 146.
    Waser B, Beetschen K, Pellegata NS, Reubi JC. Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology [Internet]. Karger Publishers; 2011 [cited 2019 Feb 8];94:291–301. Available from: Scholar
  147. 147.
    Sherman SK, Maxwell JE, Carr JC, Wang D, O’Dorisio MS, O’Dorisio TM, et al. GIPR expression in gastric and duodenal neuroendocrine tumors. J Surg Res [Internet]. Academic Press; 2014 [cited 2019 Feb 19];190:587–93. Available from:
  148. 148.
    Sherman SK, Carr JC, Wang D, O’Dorisio MS, O’Dorisio TM, Howe JR. Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors. Surgery [Internet]. Mosby; 2013 [cited 2019 Feb 11];154:1206–14. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Wolfe HJ, Melvin KEW, Cervi-Skinner SJ, AL Saadi AA, Juliar JF, Jackson CE, et al. C-cell hyperplasia preceding medullary thyroid carcinoma. N Engl J Med [Internet]. 1973 [cited 2019 Feb 25];289:437–41. Available from: Scholar
  150. 150.
    Körner M, Waser B, Reubi JC. Does somatostatin or gastric inhibitory peptide receptor expression correlate with tumor grade and stage in gut neuroendocrine tumors? Neuroendocrinology [Internet]. 2015 [cited 2019 Feb 8];101:45–57. Available from:
  151. 151.
    Prabakaran D, Wang B, Feuerstein JD, Sinclair JA, Bijpuria P, Jepeal LI, et al. Glucose-dependent insulinotropic polypeptide stimulates the proliferation of colorectal cancer cells. Regul Pept [Internet]. Elsevier; 2010 [cited 2019 Feb 21];163:74–80. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Kim DH, Nagano Y, Choi I-S, White JA, Yao JC, Rashid A. Allelic alterations in well-differentiated neuroendocrine tumors (carcinoid tumors) identified by genome-wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors. Genes, Chromosom Cancer [Internet]. John Wiley & Sons, Ltd; 2008 [cited 2019 Feb 28];47:84–92. Available from:
  153. 153.
    Stålberg P, Westin G, Thirlwell C. Genetics and epigenetics in small intestinal neuroendocrine tumours. J Intern Med [Internet]. John Wiley & Sons, Ltd (10.1111); 2016 [cited 2019 Feb 28];280:584–94. Available from:
  154. 154.
    Pan C-C, Jong Y-J, Chen Y-J. Comparative genomic hybridization analysis of thymic neuroendocrine tumors. Mod Pathol [Internet]. Nature Publishing Group; 2005 [cited 2019 Mar 1];18:358–64. Available from:
  155. 155.
    Zhao J, de Krijger RR, Meier D, Speel E-JM, Saremaslani P, Muletta-Feurer S, et al. Genomic alterations in well-differentiated gastrointestinal and bronchial neuroendocrine tumors (carcinoids): marked differences indicating diversity in molecular pathogenesis. Am J Pathol [Internet]. Elsevier; 2000 [cited 2019 Mar 1];157:1431–8. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Gebauer N, Schmidt-Werthern C, Bernard V, Feller AC, Keck T, Begum N, et al. Genomic landscape of pancreatic neuroendocrine tumors. World J Gastroenterol [Internet]. Baishideng Publishing Group Inc.; 2014 [cited 2019 Feb 28];20:17498. Available from:
  157. 157.
    Ye L, Santarpia L, Cote GJ, El-Naggar AK, Gagel RF. High resolution array-comparative genomic hybridization profiling reveals deoxyribonucleic acid copy number alterations associated with medullary thyroid carcinoma. J Clin Endocrinol Metab [Internet]. Oxford University Press; 2008 [cited 2019 Feb 28];93:4367–72. Available from:
  158. 158.
    Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR, et al. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest [Internet]. American Society for Clinical Investigation; 2013 [cited 2019 Feb 28];123:2502–8. Available from: PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Tönnies H, Toliat MR, Ramel C, Pape UF, Neitzel H, Berger W, et al. Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation. Gut [Internet]. BMJ Publishing Group; 2001 [cited 2019 Feb 28];48:536–41. Available from: Scholar
  160. 160.
    Frisk T, Zedenius J, Lundberg J, Wallin G, Kytölä S, Larsson C. CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome. Int J Oncol [Internet]. 2001 [cited 2019 Feb 27];18:1219–25. Available from:
  161. 161.
    Marsh DJ, Theodosopoulos G, Martin-Schulte K, Richardson A-L, Philips J, Röher H-D, et al. Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab [Internet]. Oxford University Press; 2003 [cited 2019 Feb 26];88:1866–72. Available from:
  162. 162.
    Karpathakis A, Dibra H, Pipinikas C, Feber A, Morris T, Francis J, et al. Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumor. Clin Cancer Res [Internet]. American Association for Cancer Research; 2016 [cited 2019 Feb 22];22:250–8. Available from: Scholar
  163. 163.
    Gourni E, Waser B, Clerc P, Fourmy D, Reubi JC, Maecke HR. The glucose-dependent insulinotropic polypeptide receptor: a novel target for neuroendocrine tumor imaging-first preclinical studies. J Nucl Med [Internet]. Society of Nuclear Medicine; 2014 [cited 2019 Feb 19];55:976–82. Available from: Scholar
  164. 164.
    Willekens SMA, Joosten L, Boerman OC, Brom M, Gotthardt M. Characterization of 111In-labeled glucose-dependent insulinotropic polypeptide as a radiotracer for neuroendocrine tumors. Sci Rep [Internet]. Nature Publishing Group; 2018 [cited 2019 Feb 19];8:2948. Available from:
  165. 165.
    Reubi JC, Waser B. Triple-peptide receptor targeting in vitro allows detection of all tested gut and bronchial NETs. J Nucl Med [Internet]. Society of Nuclear Medicine; 2015 [cited 2019 Feb 19];56:613–5. Available from:
  166. 166.
    Stueven AK, Kayser A, Wetz C, Amthauer H, Wree A, Tacke F, et al. Somatostatin analogues in the treatment of neuroendocrine tumors: past, present and future. Int J Mol Sci [Internet]. Multidisciplinary Digital Publishing Institute; 2019 [cited 2019 Jul 25];20:3049. Available from: PubMedCentralCrossRefGoogle Scholar
  167. 167.
    Raue F, Zink A, Scherübl H, Scheriibl H. Regulation of calcitonin secretion and calcitonin gene expression. Recent results cancer Res [Internet]. 1992 [cited 2019 Feb 14];125:1–18. Available from:
  168. 168.
    Dall’Asta C, Ballare E, Mantovani G, Ambrosi B, Spada A, Barbetta L, et al. Assessing the presence of abnormal regulation of cortisol secretion by membrane hormone receptors: in vivo and in vitro studies in patients with functioning and non-functioning adrenal adenoma. Horm Metab Res=Horm und Stoffwechselforsch=Horm Metab. Germany; 2004;36:578–83.PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Noordam C, Hermus ARMM, Pesman G, N’Diaye N, Sweep CGJ, Lacroix A, et al. An adolescent with food-dependent Cushing’s syndrome secondary to ectopic expression of GIP receptor in unilateral adrenal adenoma. J Pediatr Endocrinol Metab. Germany; 2002;15:853–60.Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Medicine Endocrinology UnitPadova University HospitalPadovaItaly
  2. 2.Endocrinology ServicePadovaItaly
  3. 3.Department of BiologyUniversity of PadovaPadovaItaly

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