Lebrethon M C, Avallet O, Reznik Y, Archambeaud F, Combes J, Usdin T B, Narboni G, Mahoudeau J, Saez J M
Unité INSERM-INRA U-418 and Institut Federatif de Recherchesen Endocrinologie de Lyon, Hôpital Debrousse, France.
J Clin Endocrinol Metab. 1998 Dec;83(12):4514-9. doi: 10.1210/jcem.83.12.5336.
In the present work, the presence of gastric inhibitory polypeptide (GIP) receptors and their functional role in the adrenal cells of three patients with food-dependent Cushing's syndrome were studied. RT-PCR and in situ hybridization studies demonstrated the presence of GIP receptor in the adrenals of the three patients. The presence of this receptor was also demonstrated in two human fetal adrenals, but not in two normal adult human adrenals or in the adrenals of one patient with nonfood-dependent Cushing's syndrome. Freshly isolated cells from patient adrenals responded in a dose-dependent manner to the steroidogenic action of both ACTH and GIP, whereas cells from normal adrenals responded only to ACTH. Treatment of cultured normal adrenal cells with ACTH, but not with GIP, increased the messenger ribonucleic acid (mRNA) levels of cholesterol side-chain cleavage cytochrome P-450, P450c17, and 3beta-hydroxysteroid dehydrogenase, whereas both hormones enhanced these mRNAs in patients' adrenal cells, although the effects of ACTH were greater than those of GIP. Moreover, pretreatment with ACTH enhanced the steroidogenic responsiveness of both normal and patient adrenal cells, whereas GIP caused homologous desensitization, and this was associated with a marked reduction of GIP receptor mRNA levels, as demonstrated by RT-PCR and in situ hybridization. Finally, both ACTH and GIP inhibited DNA synthesis in one patient's adrenal cells, whereas in normal adrenal cells only ACTH had this effect. In conclusion, the present data demonstrate that ectopic expression of functional GIP receptors is the main cause of food-dependent Cushing's syndrome.
在本研究中，对三名食物依赖型库欣综合征患者肾上腺细胞中胃抑制多肽（GIP）受体的存在及其功能作用进行了研究。逆转录聚合酶链反应（RT-PCR）和原位杂交研究表明，三名患者的肾上腺中存在GIP受体。在两个人类胎儿肾上腺中也证实了该受体的存在，但在两个正常成人肾上腺或一名非食物依赖型库欣综合征患者的肾上腺中未发现。从患者肾上腺中新鲜分离的细胞对促肾上腺皮质激素（ACTH）和GIP的类固醇生成作用均呈剂量依赖性反应，而正常肾上腺细胞仅对ACTH有反应。用ACTH而非GIP处理培养的正常肾上腺细胞，可增加胆固醇侧链裂解细胞色素P-450、P450c17和3β-羟基类固醇脱氢酶的信使核糖核酸（mRNA）水平，而这两种激素均可增强患者肾上腺细胞中的这些mRNA水平，尽管ACTH的作用大于GIP。此外，ACTH预处理可增强正常和患者肾上腺细胞的类固醇生成反应性，而GIP则导致同源脱敏，这与GIP受体mRNA水平的显著降低有关，RT-PCR和原位杂交证实了这一点。最后，ACTH和GIP均可抑制一名患者肾上腺细胞中的DNA合成，而在正常肾上腺细胞中只有ACTH有此作用。总之，目前的数据表明功能性GIP受体的异位表达是食物依赖型库欣综合征的主要原因。
