GIP(3-30)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study
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, 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.
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.
KeywordsClass B G protein-coupled receptor (GPCR) Glucose-dependent insulinotropic polypeptide (GIP) Hyperglycaemic clamp Incretin physiology Insulin secretion in vivo Pharmacology
Dipeptidyl peptidase 4
Fasting plasma glucose
Growth hormone-releasing hormone
Glucose-dependent insulinotropic polypeptide
G protein-coupled receptor
Insulin secretion rate
The authors sincerely thank the study participants for their dedication. We thank S. M. Schmidt (Center for Diabetes Research, Gentofte Hospital, Denmark) and I. A. Nachar (Center for Diabetes Research, Gentofte Hospital, Denmark) for laboratory assistance during the clinical study. In addition, the authors thank L. B. Albæk (Department for Biomedical Sciences, University of Copenhagen, Denmark) for GLP-1 measurements and J. Bach (Department for Biomedical Sciences, University of Copenhagen, Denmark) for NEFA and glycerol measurements.
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
The clinical studies were conducted at Center for Diabetes Research (Gentofte Hospital, Denmark) and the in vitro studies at Department of Biomedical Sciences (University of Copenhagen, Denmark), which were supported by Gangstedfonden, the European Foundation for the Study of Diabetes, and Aase og Ejnar Danielsens fond.
Duality of interest
GIP(3-30)NH2 as a therapeutic agent is protected by intellectual property rights owned by University of Copenhagen (PCT/DK2015/050266). AHS, MBC, FKK, MMR, JJH, LSG, and MBNG are co-founders of the company Antag Therapeutics ApS founded after the completion of the present study. TV has received lecture fees from, participated in advisory boards of, consulted for and/or received research grants from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD/Merck, Novo Nordisk and Sanofi. FKK has received lecture fees from, participated in advisory boards of, consulted for and/or received research grants from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD/Merck, Novo Nordisk, Sanofi and Zealand Pharma. Other authors declare that there is no duality of interest associated with their contribution to this manuscript.
LSG, MBC, AHS, TV, MMR, JJH, and FKK designed the clinical study, and LSG and ARL performed the clinical study and data acquisition. LSG, AHS, MBNG and MMR designed the in vitro studies, and MBNG performed them. LSG and BH performed the RIA and ELISA measurements. BH was responsible for RIA and ELISA data acquisition and interpretation. FD was responsible for the NEFA and glycerol measurements, analyses and interpretation of data in general. LSG, MMR, MBC, and FKK performed the data analyses, wrote the manuscript and approved the final version. MBC, BH, ARL, AHS, MBNG, FD, TV and JJH edited the manuscript and approved the final version. LSG and FKK are the guarantors of the clinical part of the study, had full access to all of these data and take responsibility for the integrity of the data and accuracy of the data analysis. LSG and MMR are guarantors of the in vitro part of the study, had full access to all of these data and take responsibility for the integrity of the data and accuracy of the data analysis.
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