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

In the present work, the presence of gastric inhibitory polypeptide (GTP) r eceptors and their functional role in the adrenal cells of three patients w ith food-dependent Cushing's syndrome were studied. RT-PCR and in situ hybr idization 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 adren al cells with ACTH, but not with GIP, increased the messenger ribonucleic a cid (mRNA) levels of cholesterol side-chain cleavage cytochrome P-450, P450 (c17), and 3 beta-hydroxysteroid dehydrogenase, whereas bath hormones enhan ced these mRNAs in patients' adrenal cells, although the effects of ACTH we re greater than those of GIP. Moreover, pretreatment with ACTH enhanced the steroidogenic responsiveness of both normal and patient adrenal cells, whe reas 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 h ad this effect. In conclusion, the present data demonstrate that ectopic ex pression of functional GIP receptors is the main cause of food-dependent Cu shing's syndrome.