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

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

Author information

1
Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, 2900, Hellerup, Denmark.
2
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
5
Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
6
Department of Geriatrics, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
7
Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark.
8
Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, 2900, Hellerup, Denmark. filipknop@dadlnet.dk.
9
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. filipknop@dadlnet.dk.
10
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. filipknop@dadlnet.dk.

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

PMID:
28948296
DOI:
10.1007/s00125-017-4447-4
[Indexed for MEDLINE]

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