The early history of GIP 1969-2000: From enterogastrone to major metabolic hormone

摘要

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.