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.