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The Aberrant Expression of the Gastric Inhibitory Polypeptide (GIP) Receptor in Adrenal Hyperplasia: Does Chronic Adrenocorticotropin Exposure Stimulate Up-Regulation of GIP Receptors in Cushing’s Disease?

Department of Endocrinology (F.M.S., A.B.G., J.P.M., A.J.L.C.), William Harvey Research Institute, Barts & the London, Queen Mary University of London, London EC1A 7BE, United Kingdom; Department of Endocrinology (S.A.), King’s College Hospital, London, United Kingdom; Department of Clinical Biochemistry (L.P.), Barts & The London NHS Trust; and Haartman Institute of Pathology (J.A.), University of Helsinki, Finland

Address all correspondence and requests for reprints to: Professor A. J. L. Clark, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom. E-mail: a.j.clark{at}qmul.ac.uk.

Context: Cortisol secretion is usually under the control of ACTH. However, cortisol secretion occurs in response to gastric inhibitory polypeptide (GIP) in rare cases of food-dependent Cushing’s syndrome (CS).

Objective: We have investigated whether chronic ACTH stimulation or activation of the ACTH signaling pathway might be associated with GIP receptor (GIPR) expression.

Design: RT-PCR analysis and primary culture of hyperplastic adrenals.

Patients: All patients presented with CS: 20 unilateral adrenal adenomas, five Cushing’s disease, one food-dependent CS.

Results: RT-PCR revealed GIPR expression in all hyperplastic adrenals studied. No RT-PCR product could be detected in two normal adrenals or 20 hyperfunctioning adrenal adenomas. Primary culture revealed a significant cAMP response to ACTH in all adrenals available for study (EC₅₀, 8.1 x 10^–10 M in normals, 4.7 x 10^–10 M in Cushing’s disease, and 4.4 x 10^–10 M in food-dependent disease). However, cultures taken from all four ACTH-dependent and the one food-dependent hyperplastic adrenals studied were also responsive to GIP (EC₅₀ for cAMP, 1.3 x 10^–9 M in Cushing’s disease and 4.1 x 10^–10 M in food-dependent disease).

Fasting cortisol levels were low in the case of food-dependant Cushing’s, rising postprandially as predicted. However, there was no trend toward low fasting or high postprandial cortisol in the other cases, suggesting that the presence of detectable GIPR alone, albeit with definite function in vitro, is not sufficient to cause clinically food-dependent CS.

Conclusions: These data are consistent with the hypothesis that chronic ACTH stimulation or constitutive activation of the ACTH signaling pathway may be associated with aberrant GIPR expression, and suggest one mechanism for the pathogenesis of this phenomenon.

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