GIP(3-30)NH₂ is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled,...

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)NH₂ in in vivo and in in vitro receptor studies.

In transiently transfected COS-7 cells, GIP(3-30)NH₂ 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_1c 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)NH₂ (800 pmol kg^-1 min^-1), GIP (1.5 pmol kg^-1 min^-1), 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)NH₂ neither bound, stimulated nor antagonised a series of related receptors in vitro. The elimination plasma half-life of GIP(3-30)NH₂ 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 < 0.0001) during co-infusion with GIP(3-30)NH₂, and the need for glucose was reduced to placebo levels. There were no effects of GIP(3-30)NH₂ alone or of GIP with or without GIP(3-30)NH₂ on plasma glucagon, GLP-1, somatostatin, triacylglycerols, cholesterol, glycerol or NEFA. GIP(3-30)NH₂ administration was well tolerated and without side effects.

We conclude that GIP(3-30)NH₂ is an efficacious and specific GIP receptor antagonist in humans suitable for studies of GIP physiology and pathophysiology.

ClinicalTrials.gov registration no. NCT02747472.

The study was funded by Gangstedfonden, the European Foundation for the Study of Diabetes, and Aase og Ejnar Danielsens fond.