University of Surrey, 68, Walpole House, 126 Westminster Bridge Road, London, SE1 7UN, Guildford, UK.
Peptides. 2019 Dec;122:170155. doi: 10.1016/j.peptides.2019.170155. Epub 2019 Sep 17.
This paper describes the early history of Gastric Inhibitory Polypeptide, better referred to simply as GIP, from its isolation by purification from a crude preparation of CCK-PZ (cholecystokinin/pancreozymin) to its recognition as a key player in the pathogenesis of obesity and other metabolic disorders far removed from the enterogastrone properties by which it was originally identified. Augmentation of glucose mediated insulin release, the incretin effect, was discovered soon after GIP was first isolated and only much later was its important role in the pathogenesis of obesity, through mechanism other than insulin secretion, appreciated. Immunoassay - the only method by which the concentration of GIP was measured in plasma until quite recently - was found to be flawed and to depend upon which specific epitope of the hormone an assay detected. This was especially true if it was an amino-acid sequence specific to porcine rather than human GIP. A further confounder was the discovery that much of the GIP measured by immunoassay was its biological antagonist produced by cleavage of its two N-terminal amino-acids in the circulation by the same dipeptidyl-peptidase as de-activates GLP-1. Potential use of synthetic agonistic and antagonistic GIP analogues in therapeutics was barely alluded to before year 2000.
本文描述了胃抑制多肽（Gastric Inhibitory Polypeptide，简称 GIP）的早期历史，从最初从 CCK-PZ（胆囊收缩素/胰高血糖素）的粗制剂中分离出来，到认识到它是肥胖症和其他远离肠促胰岛素特性的代谢紊乱的发病机制中的关键因素。GIP 最初被鉴定为肠促胰岛素，其促进葡萄糖介导的胰岛素释放（肠促胰岛素效应）在被首次分离后不久就被发现，而直到很晚才认识到其在肥胖症发病机制中的重要作用，其作用机制并非通过胰岛素分泌。直到最近，免疫测定法（唯一可以测量血浆中 GIP 浓度的方法）被发现存在缺陷，并且取决于测定中检测到激素的哪个特定表位。如果是针对猪源而不是人源 GIP 的特定氨基酸序列，则尤其如此。另一个混杂因素是发现，通过与使 GLP-1 失活的相同二肽基肽酶在循环中裂解其两个 N 端氨基酸，免疫测定法所测量的大部分 GIP 都是其生物拮抗剂。在 2000 年之前，几乎没有提到过使用合成的 GIP 激动剂和拮抗剂类似物进行治疗的潜力。
