三十年前，我们发现某些单侧腺瘤或双侧巨结节肾上腺增生（PBMAH）患者的皮质醇分泌受到食物摄入的刺激；这是由于病理性肾上腺对生理性餐后葡萄糖依赖性胰高血糖素生物反应增加的异常皮质醇反应性。这是由于这些患者的病理肾上腺组织中出现了非突变GIP受体的异位表达。虽然异位GIPR在目前仅在相对有限的病例中得到证实，但其阐明导致了识别PBMAH或皮质醇分泌腺瘤患者相当比例的异常G蛋白耦合受体调节类固醇合成和细胞增殖的广泛多样性。此外，异位GIPR还在其他内分泌肿瘤中得到了确认，包括对口服葡萄糖出现矛盾生长激素响应的垂体生长激素瘤、髓样甲状腺癌和其他神经内分泌肿瘤。第一个解释异位GIPR表达的分子致病机制是在单侧GIP依赖性腺瘤中阐明的，其中染色体区域19q13.32内的GIPR位点发生体细胞复制和重排，导致GIPR的表达增加。此外，GIPR的表达还受到糖皮质激素反应元件的活性增强。最近发现，伴有体细胞染色体1p缺失的生殖系赖氨酸去甲基化酶1A（KDM1A）突变特异地导致了散发性或家族性GIP依赖性PBMAH的异位GIPR，并可与肾上腺髓质脂肪瘤、MGUS或多发性骨髓瘤相关联。应在所有PBMAH患者中进行异位GIPR筛查；这些患者应提供遗传学研究，以识别KDM1A突变，以便检测受影响的成员，并提供PBMAH和其他潜在相关肿瘤的早期检测。 GIP依赖的CS的阐明表明，对罕见疾病进行仔细的床旁表型学研究可以识别出需要个性化研究和治疗的遗传性疾病。©作者（2023）OxfordUniversityPress代表（ESE）欧洲内分泌研究会出版。保留所有权利。有关权限，请发送电子邮件至：journals.permissions@oup.com。

Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma or primary bilateral macronodular adrenal hyperplasia (PBMAH) was stimulated by food intake; this was secondary to the abnormal adrenocortical responsiveness to physiological post prandial increase in glucose-dependent insulinotropic peptide (GIP). This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients. Although ectopic GIPR was confirmed in a relatively limited number of cases to date, its elucidation lead to the identification of a wide diversity of aberrant G-protein-coupled receptors regulating steroidogenesis and cell proliferation in a high proportion of patients with PBMAH or cortisol-secreting adenomas. In addition, ectopic GIPR was identified in other endocrine tumors including somatotroph pituitary tumors with paradoxical growth hormone response to oral glucose, medullary thyroid carcinomas and other neuroendocrine tumors. The first molecular pathogenic mechanism responsible for ectopic GIPR expression was elucidated in unilateral GIP-dependent adenomas in which somatic duplication and rearrangements in chromosome region 19q13.32 containing the GIPR locus lead to increased expression of GIPR which was enhanced by the activity of a glucocorticoid response element. Recently, germline lysine demythylase 1A (KDMIA) mutations combined with somatic chromosome 1p deletions were found to be specifically responsible for ectopic GIPR in sporadic or familial GIP-dependent PBMAH and can be associated with adrenal myelolipoma, MGUS or multiple myeloma. Screening for ectopic GIPR should be conducted in all patients with PBMAH; genetic studies to identify KDM1A mutations should be offered to such patients in order to detect affected members and provide early detection of PBMAH and other potential associated neoplasias. The elucidation of GIP-dependent CS illustrates that careful bedside phenotyping of rare conditions can lead to identification of genetically determined diseases requiring personalized approaches to investigation and therapy.© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.