Download PDF
Horm Metab Res 2014; 46(12): 876-882
DOI: 10.1055/s-0034-1384522
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Abnormal Sensitivity to Glucagon and Related Peptides in Primary Adrenal Cushing’s Syndrome

E. Louiset
1   INSERM, U982, Laboratory of Differentiation & Neuronal and Neuroendocrine Communication, IRIB, University of Rouen, Mont-Saint-Aignan, France
,
C. Duparc
1   INSERM, U982, Laboratory of Differentiation & Neuronal and Neuroendocrine Communication, IRIB, University of Rouen, Mont-Saint-Aignan, France
,
L. Groussin
2   Department of Endocrinology, University Hospital Cochin and Cochin Institute, Assistance Publique des Hôpitaux de Paris, Université Paris V, Paris, France
,
F. Gobet
3   Department of Pathology, University Hospital of Rouen, Rouen, France
,
R. Desailloud
4   Department of Endocrinology, University Hospital of Amiens, Amiens, France
,
G. Barrande
5   Department of Endocrinology, Regional Hospital of Orléans, Orléans, France
,
Y. Reznik
6   Department of Endocrinology, University Hospital of Caen, Caen, France
,
J. Bertherat
2   Department of Endocrinology, University Hospital Cochin and Cochin Institute, Assistance Publique des Hôpitaux de Paris, Université Paris V, Paris, France
,
G. Prévost
1   INSERM, U982, Laboratory of Differentiation & Neuronal and Neuroendocrine Communication, IRIB, University of Rouen, Mont-Saint-Aignan, France
7   INSERM U982, Department of Endocrinology, University Hospital of Rouen, Rouen, France
,
H. Lefebvre
1   INSERM, U982, Laboratory of Differentiation & Neuronal and Neuroendocrine Communication, IRIB, University of Rouen, Mont-Saint-Aignan, France
7   INSERM U982, Department of Endocrinology, University Hospital of Rouen, Rouen, France
› Author Affiliations
Further Information

Publication History

received 18 March 2014

accepted 17 June 2014

Publication Date:
23 July 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Illegitimate G-protein coupled receptors are known to control cortisol secretion in adrenal adenomas and bilateral macronodular adrenal hyperplasias (BMAHs) causing Cushing’s syndrome. In the present study, we have evaluated the role of glucagon in the regulation of cortisol secretion in 13 patients with BMAH or adrenocortical adenoma causing subclinical or overt Cushing’s syndrome. Injection of glucagon provoked an increase in plasma cortisol in 2 patients. After surgery, immunohistochemical studies showed the presence of glucagon receptor-like immunoreactivity in clusters of spongiocytic cells in adrenal tissues from patients who were sensitive in vivo to glucagon. We also observed an in vitro cortisol response to vasoactive intestinal peptide from an adenoma, which was insensitive to glucagon and pituitary adenylate cyclase-activating peptide. Altogether, our data show that ectopic glucagon receptors are expressed in some adrenal cortisol-producing benign lesions. Our results also indicate that circulating glucagon may influence cortisol release under fasting conditions.

Key words

cortisol - adenoma - hyperplasia - ectopic receptor - glucagon - vasoactive intestinal peptide
 

  • References

  • 1 Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet 2006; 367: 1605-1617
    CrossrefPubMedGoogle Scholar
  • 2 Stratakis CA, Boikos SA. Genetics of adrenal tumors associated with Cushing’s syndrome: a new classification for bilateral adrenocortical hyperplasias. Nat Clin Pract Endocrinol Metab 2007; 3: 748-757
    CrossrefPubMedGoogle Scholar
  • 3 De Venanzi A, Alencar GA, Bourdeau I, Fragoso MCBV, Lacroix A. Primary bilateral macronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 2014; 21: 177-184
    CrossrefPubMedGoogle Scholar
  • 4 Arnaldi G, Boscaro M. Adrenal incidentaloma. Best Pract Res Clin Endocrinol Metab 2012; 26: 405-419
    CrossrefPubMedGoogle Scholar
  • 5 Bimpaki EI, Nesterova M, Stratakis CA. Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing syndrome despite the absence of mutations in known genes. Eur J Endocrinol 2009; 161: 153-161
    CrossrefPubMedGoogle Scholar
  • 6 Fragoso MCBV, Domenice S, Latronico AC, Martin RM, Pereira MAA, Zerbini MCN, Lucon AM, Mendonca BB. Cushing’s syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J Clin Endocrinol Metab 2003; 88: 2147-2151
    CrossrefPubMedGoogle Scholar
  • 7 Swords FM, Baig A, Malchoff DM, Malchoff CD, Thorner MO, King PJ, Hunyady L, Clark AJL. Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity. Mol Endocrinol 2002; 16: 2746-2753
    CrossrefPubMedGoogle Scholar
  • 8 Horvath A, Bertherat J, Groussin L, Guillaud-Bataille M, Tsang K, Cazabat L, Libé R, Remmers E, René-Corail F, Faucz FR, Clauser E, Calender A, Bertagna X, Carney JA, Stratakis CA. Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update. Hum Mutat 2010; 31: 369-379
    CrossrefPubMedGoogle Scholar
  • 9 Beuschlein F, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N Engl J Med 2014; 370: 1019-1028
    Google Scholar
  • 10 Cao Y, He M, Gao Z, Peng Y, Li Y, Li L, Zhou W, Li X, Zhong X, Lei Y, Su T, Wang H, Jiang Y, Yang L, Wei W, Yang X, Jiang X, Liu L, He J, Ye J, Wei Q, Li Y, Wang W, Wang J, Ning G. Activating Hotspot L205R Mutation in PRKACA and Adrenal Cushing’s Syndrome. Science 2014; 344: 913-917
    Google Scholar
  • 11 Goh G, Scholl UI, Healy JM, Choi M, Prasad ML, Nelson-Williams C, Kuntsman JW, Korah R, Suttorp A-C, Dietrich D, Haase M, Willenberg HS, Stålberg P, Hellman P, Akerström G, Björklund P, Carling T, Lifton RP. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet 2014; 46: 613-617
    Google Scholar
  • 12 Assié G, Libé R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, Barreau O, Lefèvre L, Sibony M, Guignat L, Rodriguez S, Perlemoine K, René-Corail F, Letourneur F, Trabulsi B, Poussier A, Chabbert-Buffet N, Borson-Chazot F, Groussin L, Bertagna X, Stratakis CA, Ragazzon B, Bertherat J. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med 2013; 369: 2105-2114
    CrossrefPubMedGoogle Scholar
  • 13 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) 2010; 73: 1-15
    PubMedGoogle Scholar
  • 14 Lacroix A, Baldacchino V, Bourdeau I, Hamet P, Tremblay J. Cushing’s syndrome variants secondary to aberrant hormone receptors. Trends Endocrinol Metab 2004; 15: 375-382
    CrossrefPubMedGoogle Scholar
  • 15 Lacroix A, Bolté E, Tremblay J, Dupré J, Poitras P, Fournier H, Garon J, Garrel D, Bayard F, Taillefer R. Gastric inhibitory polypeptide-dependent cortisol hypersecretion – a new cause of Cushing’s syndrome. N Engl J Med 1992; 327: 974-980
    CrossrefPubMedGoogle Scholar
  • 16 Reznik Y, Allali-Zerah V, Chayvialle JA, Leroyer R, Leymarie P, Travert G, Lebrethon MC, Budi I, Balliere AM, Mahoudeau J. Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med 1992; 327: 981-986
    CrossrefPubMedGoogle Scholar
  • 17 Bertherat J, Contesse V, Louiset E, Barrande G, Duparc C, Groussin L, Emy P, Bertagna X, Kuhn J-M, Vaudry H, Lefebvre H. 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 2005; 90: 1302-1310
    CrossrefPubMedGoogle Scholar
  • 18 Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P. Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing’s syndrome. N Engl J Med 1997; 337: 1429-1434
    CrossrefPubMedGoogle Scholar
  • 19 Daidoh H, Morita H, Hanafusa J, Mune T, Murase H, Sato M, Shibata T, Suwa T, Ishizuka T, Yasuda K. In vivo and in vitro effects of AVP and V1a receptor antagonist on Cushing’s syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia. Clin Endocrinol (Oxf) 1998; 49: 403-409
    CrossrefPubMedGoogle Scholar
  • 20 Mune T, Murase H, Yamakita N, Fukuda T, Murayama M, Miura A, Suwa T, Hanafusa J, Daido H, Morita H, Yasuda K. Eutopic overexpression of vasopressin v1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2002; 87: 5706-5713
    CrossrefPubMedGoogle Scholar
  • 21 Joubert M, Louiset E, Rego J-LD, Contesse V, Kong LC, Benhaim A, Mittre H, Lefebvre H, Reznik Y. Aberrant adrenal sensitivity to vasopressin in adrenal tumours associated with subclinical or overt autonomous hypercortisolism: is this explained by an overexpression of vasopressin receptors?. Clin Endocrinol (Oxf) 2008; 68: 692-699
    CrossrefPubMedGoogle Scholar
  • 22 Reznik Y, Lefebvre H, Rohmer V, Charbonnel B, Tabarin A, Rodien P, Lecomte P, Bardet S, Coffin C, Mahoudeau J. Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study. Clin Endocrinol (Oxf) 2004; 61: 311-319
    CrossrefPubMedGoogle Scholar
  • 23 Contesse V, Reznik Y, Louiset E, Duparc C, Cartier D, Sicard F, Laquerriere A, Parmentier F, Kuhn J-M, Vaudry H, Lefebvre H. Abnormal sensitivity of cortisol-producing adrenocortical adenomas to serotonin: in vivo and in vitro studies. J Clin Endocrinol Metab 2005; 90: 2843-2850
    CrossrefPubMedGoogle Scholar
  • 24 Louiset E, Contesse V, Groussin L, Cartier D, Duparc C, Barrande G, Bertherat J, Vaudry H, Lefebvre H. 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 2006; 91: 4578-4586
    CrossrefPubMedGoogle Scholar
  • 25 Lefebvre H, Duparc C, Chartrel N, Jegou S, Pellerin A, Laquerriere A, Ivell R, Vaudry H, Kuhn J-M. Intraadrenal adrenocorticotropin production in a case of bilateral macronodular adrenal hyperplasia causing Cushing’s syndrome. J Clin Endocrinol Metab 2003; 88: 3035-3042
    CrossrefPubMedGoogle Scholar
  • 26 Louiset E, Contesse V, Groussin L, Cartier D, Duparc C, Perraudin V, Bertherat J, Lefebvre H. Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing’s syndrome: molecular, immunohistochemical and pharmacological correlates. J Endocrinol 2008; 196: 1-9
    CrossrefPubMedGoogle Scholar
  • 27 Louiset E, Duparc C, Young J, Renouf S, Tetsi Nomigni M, Boutelet I, Libé R, Bram Z, Groussin L, Caron P, Tabarin A, Grunenberger F, Christin-Maitre S, Bertagna X, Kuhn J-M, Anouar Y, Bertherat J, Lefebvre H. Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia. N Engl J Med 2013; 369: 2115-2125
    CrossrefPubMedGoogle Scholar
  • 28 Christopoulos S, Bourdeau I, Lacroix A. Aberrant expression of hormone receptors in adrenal Cushing’s syndrome. Pituitary 2004; 7: 225-235
    CrossrefPubMedGoogle Scholar
  • 29 Matsukura S, Kakita T, Sueoka S, Yoshimi H, Hirata Y, Yokota M, Fujita T. Multiple hormone receptors in the adenylate cyclase of human adrenocortical tumors. Cancer Res 1980; 40: 3768-3771
    PubMedGoogle Scholar
  • 30 Libé R, Coste J, Guignat L, Tissier F, Lefebvre H, Barrande G, Ajzenberg C, Tauveron I, Clauser E, Dousset B, Bertagna X, Bertherat J, Groussin L. Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing’s syndrome. Eur J Endocrinol 2010; 163: 129-138
    CrossrefPubMedGoogle Scholar
  • 31 Sherwood NM, Krueckl SL, McRory JE. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 2000; 21: 619-670
    PubMedGoogle Scholar
  • 32 Chabre O, Liakos P, Vivier J, Chaffanjon P, Labat-Moleur F, Martinie M, Bottari SP, Bachelot I, Chambaz EM, Defaye G, Feige JJ. Cushing’s syndrome due to a gastric inhibitory polypeptide-dependent adrenal adenoma: insights into hormonal control of adrenocortical tumorigenesis. J Clin Endocrinol Metab 1998; 83: 3134-3143
    CrossrefPubMedGoogle Scholar
  • 33 Groussin L, Perlemoine K, Contesse V, Lefebvre H, Tabarin A, Thieblot P, Schlienger JL, Luton JP, Bertagna X, Bertherat J. 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 2002; 87: 1980-1985
    CrossrefPubMedGoogle Scholar
  • 34 Assie G, Louiset E, Sturm N, René-Corail F, Groussin L, Bertherat J, Thomas M, Lefebvre H, Feige J-J, Clauser E, Chabre O, Cherradi N. Systematic analysis of G protein-coupled receptor gene expression in adrenocorticotropin-independent macronodular adrenocortical hyperplasia identifies novel targets for pharmacological control of adrenal Cushing’s syndrome. J Clin Endocrinol Metab 2010; 95: E253-E262
    CrossrefPubMedGoogle Scholar
  • 35 Couvineau A, Laburthe M. The family B1 GPCR: structural aspects and interaction with accessory proteins. Curr Drug Targets 2012; 13: 103-115
    CrossrefPubMedGoogle Scholar
  • 36 de Miguel V, Redal MA, Viale ML, Kahan M, Glerean M, Beskow A, Fainstein Day P. Aberrant expression of glucagon receptors in adrenal glands of a patient with Cushing’s syndrome and ACTH-independent macronodular adrenal hyperplasia. Medicina (Mex) 2010; 70: 254-256
    PubMedGoogle Scholar
  • 37 Mazzocchi G, Gottardo L, Aragona F, Albertin G, Nussdorfer GG. Glucagon inhibits ACTH-stimulated cortisol secretion from dispersed human adrenocortical cells by activating unidentified receptors negatively coupled with the adenylate cyclase cascade. Horm Metab Res 2000; 32: 265-268
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Neri G, Andreis PG, Prayer-Galetti T, Rossi GP, Malendowicz LK, Nussdorfer GG. Pituitary adenylate-cyclase activating peptide enhances aldosterone secretion of human adrenal gland: evidence for an indirect mechanism, probably involving the local release of catecholamines. J Clin Endocrinol Metab 1996; 81: 169-173
    PubMedGoogle Scholar
  • 39 Conconi MT, Spinazzi R, Nussdorfer GG. Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland. Int Rev Cytol 2006; 249: 1-51
    PubMedGoogle Scholar
  • 40 Bornstein SR, Haidan A, Ehrhart-Bornstein M. Cellular communication in the neuro-adrenocortical axis: role of vasoactive intestinal polypeptide (VIP). Endocr Res 1996; 22: 819-829
    CrossrefPubMedGoogle Scholar
  • 41 Chafai M, Basille M, Galas L, Rostene W, Gressens P, Vaudry H, Gonzalez BJ, Louiset E. Pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide promote the genesis of calcium currents in differentiating mouse embryonic stem cells. Neuroscience 2011; 199: 103-115
    CrossrefPubMedGoogle Scholar