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Adrenocortical Overexpression of Gastric Inhibitory Polypeptide Receptor Underlies Food-Dependent Cushing’s Syndrome¹

Division of Endocrinology and Department of Medicine, Research Center, Campus Hôtel-Dieu, Centre Hospitalier de l’Université de Montréal, Montreal, Canada H2W 1T8; and the Department of Internal Medicine, University Hospital Rotterdam (W.W.D.H.), Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: André Lacroix, M.D., Division of Endocrinology, Research Center, Pavillon Hôtel-Dieu, Centre Hospitalier de l’Université de Montréal, 3850 St. Urbain Street, Montreal, Quebec, Canada H2W 1T8. E-mail: lacroixa{at}ere.umontreal.ca

Abnormal responsiveness of adrenocortical cells to gastric inhibitory polypeptide (GIP) in food-dependent Cushing’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 Cushing’s syndrome (adenoma, bilateral hyperplasia), five fetal or adult controls, one patient with Cushing’s disease, and four patients with non-food-dependent cortisol-secreting adenomas or bilateral hyperplasias and compared to that in normal pancreas. Hybridization of the RT-PCR-amplified ribonucleic acids with the human GIPR complementary DNA showed an overexpression of GIPR in the adrenals of the two GIP-dependent Cushing’s syndrome patients compared to that in normal adrenal tissues (2–3 orders of magnitude) or pancreas (10-fold); no signal could be seen in adrenal adenomas or macronodular hyperplasia from cases of non-food-dependent Cushing’s syndrome. No mutation of the GIPR was identified 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-dependent, but not in normal fetal, adult, or non-food-dependent Cushing’s syndrome, adrenals. We conclude that the GIPR overexpression and its coupling to steroidogenesis underlie GIP-dependent Cushing’s syndrome.

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