Food-dependent Cushing's syndrome : Characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients

• Published in: The journal of clinical endocrinology and metabolism Vol. 83; no. 12; pp. 4514 - 4519
• Main Authors: LEBRETHON, M. C, AVALLET, O, REZNIK, Y, ARCHAMBEAUD, F, COMBES, J, USDIN, T. B, NARBONI, G, MAHOUDEAU, J, SAEZ, J. M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-12-1998
• Subjects: Adrenal Gland Neoplasms - metabolism; Adrenal Gland Neoplasms - pathology; Adrenal Glands - physiopathology; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adrenocorticotropic Hormone - pharmacology; Adult; Biological and medical sciences; Cushing Syndrome - etiology; Cushing Syndrome - physiopathology; DNA - biosynthesis; Endocrinopathies; Enzymes - genetics; Enzymes - metabolism; Female; Food; Gastric Inhibitory Polypeptide - pharmacology; Humans; Hydrocortisone - biosynthesis; In Situ Hybridization; Life Sciences; Medical sciences; Middle Aged; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Steroids - biosynthesis; Tumor Cells, Cultured; France; United States; North America; Europe; America; Endocrinopathy; Human; Cell culture; Adrenal cortex diseases; Adrenal glands; Pathogenesis; Cushing syndrome; Clinical form; Hyperadrenocorticism; Gene expression; In vitro; Biological activity; Gastrointestinal hormone; Adrenocorticotropic hormone; Adenohypophyseal hormone; Enzymatic activity; Adrenal gland diseases; Adult; Female; Steroidogenesis; Gastric inhibitory peptide; Hormonal receptor; SYNDROME DE CUSHING; SURRENALE; GIP
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.83.12.4514

In the present work, the presence of gastric inhibitory polypeptide (GIP) receptors and their functional role in the adrenal cells of three patients with food-dependent Cushing's syndrome were studied. RT-PCR and in situ hybridization studies demonstrated the presence of GIP receptor in the adrenals of the three patients. The presence of this receptor was also demonstrated in two human fetal adrenals, but not in two normal adult human adrenals or in the adrenals of one patient with nonfood-dependent Cushing's syndrome. Freshly isolated cells from patient adrenals responded in a dose-dependent manner to the steroidogenic action of both ACTH and GIP, whereas cells from normal adrenals responded only to ACTH. Treatment of cultured normal adrenal cells with ACTH, but not with GIP, increased the messenger ribonucleic acid (mRNA) levels of cholesterol side-chain cleavage cytochrome P-450, P450c17, and 3beta-hydroxysteroid dehydrogenase, whereas both hormones enhanced these mRNAs in patients' adrenal cells, although the effects of ACTH were greater than those of GIP. Moreover, pretreatment with ACTH enhanced the steroidogenic responsiveness of both normal and patient adrenal cells, whereas GIP caused homologous desensitization, and this was associated with a marked reduction of GIP receptor mRNA levels, as demonstrated by RT-PCR and in situ hybridization. Finally, both ACTH and GIP inhibited DNA synthesis in one patient's adrenal cells, whereas in normal adrenal cells only ACTH had this effect. In conclusion, the present data demonstrate that ectopic expression of functional GIP receptors is the main cause of food-dependent Cushing's syndrome.