Control of
cortisol secretion by the abnormal expression of the
gastric inhibitory polypeptide receptor (GIP-R) have been observed in some rare cases of
ACTH-independent, food-dependent
Cushing's syndrome (FD-ACS) due to adrenal
adenoma (AA) or bilateral macronodular
hyperplasia (
AIMAH). This study was performed to determine the prevalence of GIP-R ectopic expression in ACS and its correlation with fasting
cortisol levels. GIP-R expression was studied by RT-PCR in 30 unilateral adrenal
tumors [16 AA and 14
adrenocortical cancer (AC)] and 8
AIMAH tissues. Fasting and postprandial
cortisol levels were assayed, respectively, at 0800 and 1200 h in AA, AC, and
AIMAH, and 1 h after a morning standard meal in 6
AIMAH patients. Similar expression of 2 GIP-R
isoforms was observed in 1 of 16 AA, 0 of 14 AC, and 4 of 8
AIMAH as well as in the 4
insulinomas used as positive controls. In vitro study of the GIP-R-expressing AA showed stimulation of
cortisol secretion and cAMP production by GIP. The fasting 0800-h plasma
cortisol level was above 276 nmol/liter in all patients except 1 AA case and 1
AIMAH case, both of whom expressed GIP-R. In the 3 additional
AIMAH cases that expressed the GIP-R, fasting plasma
cortisol levels were above 276 nmol/liter. This study demonstrates that ectopic expression of GIP-R is rare in AA and is usually associated with the low fasting plasma
cortisol levels that characterize FD-ACS. In contrast, GIP-R expression is frequent in
AIMAH and might not always be associated with a low fasting plasma
cortisol level. This suggests that maintenance of hypercortisolemia in GIP-R- expressing
AIMAH does not always depend solely on GIP-R, and that simultaneous abnormal expression of other membrane receptors might be present. The expression of GIP-R could not be observed during malignant transformation of the adrenal cortex. This study highlighted the major role of cAMP alterations secondary to GIP-R ectopic expression in the pathophysiology of
AIMAH and in some rare cases of well differentiated benign adrenocortical
tumors.