Food-Dependent Cushing’s Syndrome: Characterization and Functional Role of Gastric Inhibitory Polypeptide Receptor in the Adrenals of Three Patients1

Abstract

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.

Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors

“…We report for the first time that serotoninergic receptors can be expressed in familial AIMAH. The expression of adrenal aberrant receptors in familial AIMAH seems also similar to that observed in sporadic forms (1,4,17,40,41). Indeed, most of sporadic AIMAH and unilateral adrenal adenomas express adrenal aberrant receptors (42)(43)(44).…”

Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators

“…In vivo, GIP infusion increases cortisol production in these patients, but not in normal controls (Lacroix et al, 1992). Several investigators have demonstrated that the GIP receptors (a member of the G-protein-coupled receptors family) are overexpressed in adrenal adenoma or hyperplastic tissues from GIP-dependent CS compared to normal human adrenal cortex or non-GIP-dependent adrenal CS tissues (Lebrethon et al, 1998;N'Diaye et al, 1998). Although, the molecular mechanisms underlying abnormal adrenocortical expression of GIP receptors remain unclear, the specific and significant overexpression of WISP2 in food-dependent AIMAH and that of catenin-a-like 1 (CTNNAL1) in all AIMAH tissues suggests a previously unsuspected involvement of these pathways in AIMAH formation.…”

Aberrant Receptor-Mediated Cushing’s Syndrome

“…They reported two patients presenting with ACTH-independent Cushing’s syndrome due to AIMAH. Since these reports, five additional cases (four adenomas and one bilateral nodular hyperplasia) have been reported [9, 10, 11, 12]. In all these patients, oral glucose load, but not intravenous glucose injection, stimulated plasma cortisol levels in an ACTH-independent fashion.…”

“…Like the ACTH receptor, the GIP receptor is positively coupled to adenylyl cyclase, and GIP stimulates cAMP formation. Binding or reverse transcription-polymerase chain reaction studies have shown the abnormal expression of the GIP receptor in tumoral adrenal from patients with food-dependent hypercortisolism [11, 12, 13], while no or very low expression is observed in adjacent non-tumoral adrenal in adenomas from patients who do not have food-dependent Cushing’s syndrome or in normal adrenal.…”