GIP(3-30)NH 2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study

• Published in: Diabetologia 2018-02, Vol.61 (2), p.413
• Main Authors: Gasbjerg, Lærke S, Christensen, Mikkel B, Hartmann, Bolette, Lanng, Amalie R, Sparre-Ulrich, Alexander H, Gabe, Maria B N, Dela, Flemming, Vilsbøll, Tina, Holst, Jens J, Rosenkilde, Mette M, Knop, Filip K
• Format: Article
• Language: English
• ISSN: 1432-0428

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NH in in vivo and in in vitro receptor studies. In transiently transfected COS-7 cells, GIP(3-30)NH was evaluated with homologous receptor binding and receptor activation (cAMP accumulation) studies at the glucagon-like peptide 1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucagon, secretin and growth hormone-releasing hormone (GHRH) receptors. Ten healthy men (eligibility criteria: age 20-30 years, HbA less than 6.5% [48 mmol/mol] and fasting plasma glucose [FPG] less than 7 mmol/l) were included in the clinical study. Data were collected as plasma and serum samples from a cubital vein cannula. As primary outcome, insulin secretion and glucose requirements were evaluated together with in a randomised, four-period, crossover design by infusing GIP(3-30)NH (800 pmol kg  min ), GIP (1.5 pmol kg  min ), a combination of these or placebo during hyperglycaemic clamp experiments. The content of the infusions were blinded to the study participants and experimental personnel. No study participants dropped out. GIP(3-30)NH neither bound, stimulated nor antagonised a series of related receptors in vitro. The elimination plasma half-life of GIP(3-30)NH in humans was 7.6 ± 1.4 min. Markedly larger amounts of glucose were required to maintain the clamp during GIP infusion compared with the other days. GIP-induced insulin secretion was reduced by 82% (p