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

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. RTPCR 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 3b-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. (J Clin Endocrinol Metab 83: 4514–4519, 1998) T CAUSES of endogenous Cushing’s syndrome are divided into two main groups, ACTH dependent and ACTH independent. In the former, ACTH causes hyperplasia and hyperfunction of both adrenal glands, whereas in most of the ACTH-independent cases, adrenal adenoma and carcinoma are unilateral (1). Among the less common pathological processes that can also produce Cushing’s syndrome are disorders in which nodular adrenal hyperfunction of both adrenals occur independently of ACTH stimulation. However, both in vivo and in vitro studies have demonstrated that most cases retain a sensitivity to the stimulatory effects of ACTH (2). In addition, in vitro studies have demonstrated the presence of ectopic receptors in some adrenal tumors, suggesting that they may not be functionally autonomous (3–5). One particular form of truly ACTH-independent Cushing’s syndrome has been described recently by several groups (6–10). All the patients had food-dependent Cushing’s syndrome resulting from an inappropriate sensitivity of their adrenocortical gland to a normal postprandial increase in the secretion of gastric inhibitory polypeptide (GIP). In the present work we have investigated the acute effects of both ACTH and GIP on freshly isolated cells from adrenals of three patients with food-dependent Cushing’s syndrome, as well as the long term effects of both peptides on the expression of three key steroidogenic enzymes. In addition, RT-PCR and in situ hybridization demonstrated the presence of GIP receptor messenger ribonucleic acid (mRNA) in the three cases, but not in normal human adrenals. Subjects and Methods