ADRENOCORTICAL OVEREXPRESSION OF GASTRIC-INHIBITORY POLYPEPTIDE RECEPTOR UNDERLIES FOOD-DEPENDENT CUSHINGS-SYNDROME

Abnormal responsiveness of adrenocortical cells to gastric inhibitory polypeptide (GIP) in food-dependent Gushing's syndrome suggested that adrenal expression of ectopic, overexpressed, or mutated GIP receptor (GIPR) underlies this syndrome. The expression of GIPR was studied by RT-PCR in human adrenal tissues from two patients with GIP-dependent G ushing's syndrome (adenoma, bilateral hyperplasia), five fetal or adul t controls, one patient with Gushing's disease, and four patients with non-food-dependent cortisol-secreting adenomas or bilateral hyperplas ias and compared to that in normal pancreas. Hybridization of the RT-P CR-amplified ribonucleic acids with the human GIPR complementary DNA s howed an overexpression of GIPR in the adrenals of the two GIP-depende nt Gushing's syndrome patients compared to that in normal adrenal tiss ues (2-3 orders of magnitude) or pancreas (10-fold); no signal could b e seen in adrenal adenomas or macronodular hyperplasia from cases of n on-food-dependent Gushing's syndrome. No mutation of the GIPR was iden tified by sequencing the full-length receptor in GIP-dependent adrenal tissue. New alternative spliced isoforms of the GIPR were found, but are identical in GIP-dependent and normal adrenal tissues. Incubation of adrenal cells with GIP stimulates cortisol secretion in GIP-depende nt, but not in normal fetal, adult, or non-food-dependent Gushing's sy ndrome, adrenals. We conclude that the GIPR overexpression and its cou pling to steroidogenesis underlie GIP-dependent Gushing's syndrome.