GIP(3-30)NH 2 Is an Efficacious GIP Receptor Antagonist in Humans: A Randomised, Double-Blinded, Placebo-Controlled, Crossover Study

Diabetologia. 2018 Feb;61(2):413-423. doi: 10.1007/s00125-017-4447-4. Epub 2017 Sep 25.

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, HbA1c 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blood Glucose / drug effects
  • COS Cells
  • Chlorocebus aethiops
  • Cross-Over Studies
  • Double-Blind Method
  • Gastric Inhibitory Polypeptide / metabolism
  • Gastric Inhibitory Polypeptide / pharmacology*
  • Glucagon / metabolism
  • Glucagon-Like Peptide 2 / metabolism
  • Humans
  • Insulin / metabolism
  • Male
  • Peptide Fragments / pharmacology*
  • Receptors, Gastrointestinal Hormone / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism
  • Receptors, Pituitary Hormone-Regulating Hormone / metabolism
  • Secretin / metabolism
  • Young Adult

Substances

  • Blood Glucose
  • Glucagon-Like Peptide 2
  • Insulin
  • Peptide Fragments
  • Receptors, Gastrointestinal Hormone
  • Receptors, Neuropeptide
  • Receptors, Pituitary Hormone-Regulating Hormone
  • gastric inhibitory polypeptide (3-30)-amide
  • Secretin
  • Gastric Inhibitory Polypeptide
  • Glucagon
  • gastric inhibitory polypeptide receptor
  • somatotropin releasing hormone receptor

Associated data

  • ClinicalTrials.gov/NCT02747472