The Ectopic Expression of the Gastric Inhibitory Polypeptide Receptor Is Frequent in Adrenocorticotropin-Independent Bilateral Macronodular Adrenal Hyperplasia, but Rare in Unilateral Tumors

Abstract

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.

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

“…Considering that ACTH could play a role in this disease, it was then suggested to name it PBMAH, to avoid the confusing reference to 'ACTH-independence' (3). The concept of illegitimate receptor expression was mostly demonstrated after the investigation of PBMAH patients, and this phenomenon is observed in the majority of PBMAH patients (1,4,5,6).…”

Aberrant Expression of Hormone Receptors in Adrenal Cushing's Syndrome

“…Bertherat et al performed an in vivo and in vitro screening study for aberrant receptors in 4 consecutive patients with AIMAH and CS [85]: they reported 2 patients who responded to both GIP and hCG, 1 patient who responded to cisapride (5-HT4 receptor agonist) and upright posture in vivo and to serotonin, angiotensin II, and AVP in vitro, and 1 patient who responded to upright posture in vivo. In an in vitro screening study, the GIP receptor was found to be expressed in 4 of 8 adrenal glands from AIMAH patients and in only 1 of 16 unilateral adenomas [31]. Dall'Asta et al recently reported a higher frequency of aberrant cortisol responses in adrenal adenomas; he identified one or multiple aberrant responses in 3 of 4 patients with adrenal adenomas and overt CS [86].…”

“…The presence of GIP receptors in the adrenal gland was further suggested by adrenal imaging following the injection of [ 123 I] GIP [24]. Since these initial descriptions, GIP-dependent CS has been described in at least 17 patients with AIMAH [21,[24][25][26][27][28][29][30][31] and 7 patients with unilateral adenomas [21,23,[32][33][34][35]. Interestingly, GIPdependent combined oversecretion of androgen and, to a lesser extent, of cortisol has been described in a patient with an adrenal adenoma and hirsutism [35].…”

Subclinical Cushing's syndrome due to unilateral or bilateral adrenal incidentalomas. Problems of diagnostic and indication to surgical treatment. Review of literature

“…По данным ряда исследований, мето-дом проведения стимуляционных проб (на-пример, инсулиновая гипогликемия, при ем углеводистой пищи, стимуляция специальны-ми лигандами), иммуногистохимического и молекулярно-генетического исследований удаленного в ходе операции материала была идентифицирована экспрессия аберрантных или избыточно представленных рецепторов, а также их повышенная активность: рецепто-ры к глюкозозависимому инсулинотропному полипептиду (GIPR), β-адрено миметикам, ка-техоламинам (β-AR), вазопрессину (V1-3-AVPR или AVPR 1A, AVPR1B, AVPR2), лютеи-низирующему и хорионическому гонадо-тропному гормонам (LH/hCG-R), серотонину (5HT-4R или HTR4), ангиотензину II (AT-1R или AGR1), вазоинтестинальному пептиду (ВИП). В качестве стимулирующих агентов (лиганд) в исследованиях in vitro и in vivo использова-лись: очищенный хорионический гонадотро-пин (агонист к LH/hCG-R), цизаприд и мето-клопрамид (агонист 5HT-4R), норэпинеф-рин (адреномиметик), аргинин-вазопрессин (АВП), терлипрессин (агонисты к V1-3-AVPR), препараты гастроинтестинального пептида (ГИП) [74][75][76][77][78][79]. Автономная гипер продукция кортизола может быть вызвана наличием как одного, так и нескольких мембранных рецеп-торов, сопряженных с G-белком.…”

“…торы) [83,87] либо уменьшения влияния стимулирующих факторов (терапия леупро-лида ацетатом приводит к подавлению син-теза ЛГ, введение аналога соматостатина октреотида нивелирует повышение корти-зола при ГИП-зависимой гиперсекреции кортизола) [78,88].…”