CUSHINGS-SYNDROME DUE TO A GASTRIC-INHIBITORY POLYPEPTIDE-DEPENDENT ADRENAL ADENOMA - INSIGHTS INTO HORMONAL-CONTROL OF ADRENOCORTICAL TUMORIGENESIS

We studied a patient with food-induced, ACTH-independent, Cushing's sy ndrome and a unilateral adrenocortical adenoma. In vivo cortisol secre tion was stimulated by mixed, glucidic, lipidic, or proteic meals. Pla sma ACTH levels were undetectable, but iv injection of ACTH stimulated cortisol secretion. Unilateral adrenalectomy was followed by hypocort isolism with loss of steroidogenic responses to both food and ACTH. In vitro, cortisol secretion by isolated tumor cells was stimulated by t he gut hormone gastric inhibitory polypeptide (GIP) and ACTH, but not by another gut hormone, glucagon-like peptide-1 (GLP-1). Both peptides stimulated the production of cAMP but not of inositol 1,4,5-trisphosp hate. In quiescent cells, GIP and ACTH stimulated [H-3]thymidine incor poration and p42-p44 mitogen-activated protein kinase activity. GIP re ceptor messenger ribonucleic acid (RNA), assessed by RT-PCR, was highl y expressed in the tumor, whereas it was undetectable in the adjacent hypotrophic adrenal tissue, in two adrenal tumors responsible for food -independent Cushing's syndrome, and in two hyperplastic adrenals asso ciated with ACTH hypersecretion. In situ hybridization demonstrated th at expression of GIP receptor RNA was confined to the adrenocortical t umor cells. Low levels of ACTH receptor messenger RNA were also detect able in the tumor. We conclude that abnormal expression of the GIP rec eptor allows adrenocortical cells to respond to food intake with an in crease in cAMP that may participate in the stimulation of both cortiso l secretion and proliferation of the tumor cells.