GIP(3–30)NH2 is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release

Sparre-Ulrich, Alexander Hovard; Gabe, M; Gasbjerg, Lærke S.; Christiansen, C.; Svendsen, Berit; Hartmann, Bolette; Holst, Jens J.; Rosenkilde, Mette M.

doi:10.1016/j.bcp.2017.02.012

Cited by 60 publications

(43 citation statements)

References 67 publications

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“…On the basis of our previous in vitro studies [17,37], we hypothesised that GIP(3-30)NH 2 would be able to inhibit the GIP-induced potentiation of glucose-stimulated insulin secretion in humans. We found that GIP(3-30)NH 2 at an approximately 600-fold higher plasma concentration compared with GIP(1-42) antagonised the GIP receptor and resulted in an 82% inhibition of the GIP-potentiated glucosestimulated insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…For selection of the GIP(1-42) infusion rate (1.5 pmol kg −1 min −1 ), we aimed at postprandial levels (50-80 pmol/l). Based on the in vitro affinity data [17,37] and inspired by human studies with the GLP-1 receptor antagonist exendin(9-39) [38][39][40], we estimated that an agonistantagonist relationship of around 500-fold would result in at least 50% inhibition of GIP-induced insulin secretion. It is possible that infusion of GIP(3-30)NH 2 at the chosen rate (i.e.…”

Section: Calculation Of the Inhibitory Effectmentioning

confidence: 99%

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

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Section: Calculation Of the Inhibitory Effectmentioning

confidence: 99%

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

et al. 2017

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“…For GIP, a receptor antagonist suitable for human use was recently identified after systematic studies of various truncations of the GIP molecule in the laboratory of Mette Rosenkilde at the University of Copenhagen, which confirmed some receptor antagonistic properties of the truncated forms of GIP, GIP 3-42 and also GIP 5-42 [80,81]. The GIP molecule has a cleavage site for proteolytic endopeptidases (i.e.…”

Section: The Physiological Roles Of Gip and Glp-1: The Receptor Antagmentioning

confidence: 91%

The incretin system in healthy humans: The role of GIP and GLP-1

2019

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The incretin effect, the amplification of insulin secretion occurring when glucose is taken in orally as compared to infused intravenously, is one of the factors that help the body to tolerate carbohydrate/glucose ingestion. These include 1) amount and type of carbohydrates; 2) gastric emptying rate; 3) digestion and absorption of the carbohydrates; 4) secretion and effect of the incretin hormones; 5) disposition of absorbed nutrients/glucose. The incretin effect can also be viewed as the fraction of the ingested glucose load handled via gastrointestinal mechanisms (including the incretin effect); it is calculated by comparison of the amount of glucose required to copy, by intravenous infusion, the oral load. Typically, for 75 g of oral glucose, about 25 g are required. This means that the GastroIntestinal Glucose Disposal (GIGD) is 66%. Both the GIGD and the incretin effect depend on the amount of glucose ingested: for higher doses the GIGD may amount to 80%, which shows that this effect is a major contributor to glucose tolerance. The main mechanism behind it is stimulation of insulin secretion by a proportional secretion of the insulinotropic hormones GIP and GLP-1. Recently it has become possible to estimate their contributions in healthy humans using specific and potent receptor antagonists. Both hormones act to improve glucose tolerance (i.e. the antagonists impair tolerance) and their effects are additive. GIP seems to be quantitatively the most important, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly displayed via inhibition of glucagon secretion.

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“…It has been hypothesized that the GIPR might be desensitized in the beta cells of patients with T2DM based on studies in diabetic rats, but this remains to be proven in humans. Previously described differences between the rodent and human GIP system exemplifies the necessity for studies on the human GIPR . Interestingly, it has been shown that the GIPR function in bone metabolism of patients with T2DM is not abolished, which may point towards a cell, tissue and possibly species‐specific down‐regulation.…”

Section: Introductionmentioning

confidence: 99%

Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long‐term impairment of the GIP system

Gabe

Velden

Gadgaard

et al. 2019

Basic Clin Pharma Tox

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In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP-1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP-1-based therapies.Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose. Here, we present an in-depth molecular pharmacological phenotyping of GIPR-[E354Q]. In silico modelling suggested similar interaction of the endogenous agonist GIP(1-42) to [E354Q] as to GIPR wt. This was supported by homologous competition binding in COS-7 cells revealing GIPR wt-like affinities of GIP(1-42) with K d values of ~2 nmol/L and wt-like agonist association rates (K on ). In contrast, the dissociation rates (K off ) were slower, resulting in 25% higher agonist residence time for GIPR-[E354Q]. Moreover, in G αs signalling (cAMP production) GIP(1-42) was ~2-fold more potent and more efficacious on GIPR-[E354Q] compared to wt with 17.5% higher basal activity. No difference from GIPR wt was found in the recruitment of β-arrestin 2, whereas the agonist-induced internalization rate was 2.1-to 2.3fold faster for [E354Q]. Together with the previously described impaired recycling of [E354Q], our findings with enhanced signalling and internalization rate possibly explained by an altered ligand-binding kinetics will lead to receptor desensitization and down-regulation. This could explain the long-term functional impairment of the GIP system in bone metabolism and blood sugar maintenance for [E354Q] carriers and may shed light on the desensitization of the insulinotropic action of GIP in patients with T2DM. K E Y W O R D SGIP receptor, GIPR-[E354Q], internalization, signalling

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GIP(3–30)NH2 is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release

Cited by 60 publications

References 67 publications

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

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

The incretin system in healthy humans: The role of GIP and GLP-1

Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long‐term impairment of the GIP system

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