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

Abstract

Aims/hypothesis: 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.

Methods: 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.

Results: 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.

Conclusions/interpretation: 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.

Trial registration: ClinicalTrials.gov registration no. NCT02747472.

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

Keywords: Class B G protein-coupled receptor (GPCR); Glucose-dependent insulinotropic polypeptide (GIP); Hyperglycaemic clamp; Incretin physiology; Insulin secretion in vivo; Pharmacology.