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

Gasbjerg, Lærke S.; Christensen, Mikkel B.; Hartmann, Bolette; Lanng, Amalie R.; Sparre-Ulrich, Alexander Hovard; Gabe, M; Dela, Flemming; Vilsbøll, Tina; Holst, Jens J.; Knop, Filip K.

doi:10.1007/s00125-017-4447-4

Cited by 72 publications

(58 citation statements)

References 51 publications

(57 reference statements)

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“…Given the sensitivity of this molecule towards DPP-4, it was assumed that the truncated form GIP 3-30NH2 would also exist. This form turned out to be a high potency antagonist on the human GIP receptor [84]. Being a natural product, it was also considered safe to administer this molecule to humans.…”

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

confidence: 99%

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

confidence: 99%

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

2019

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“…However, several studies reported elevated GIP levels in obese humans compared with lean humans [39]. Recently, GIP (3-30) NH2, a naturally occurring peptide, was shown to block the GIPR in humans and decrease GIP-induced insulin secretion as well as adipose tissue blood flow and TG uptake [40]. Killion et al [41] provided a preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.…”

Section: Discussionmentioning

confidence: 99%

Enhanced GIP Secretion in Obesity Is Associated with Biochemical Alteration and miRNA Contribution to the Development of Liver Steatosis

et al. 2020

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Nutrient excess enhances glucose-dependent insulinotropic polypeptide (GIP) secretion, which may in turn contribute to the development of liver steatosis. We hypothesized that elevated GIP levels in obesity may affect markers of liver injury through microRNAs. The study involved 128 subjects (body mass index (BMI) 25–40). Fasting and postprandial GIP, glucose, insulin, and lipids, as well as fasting alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), cytokeratin-18, fibroblast growth factor (FGF)-19, and FGF-21 were determined. TaqMan low density array was used for quantitative analysis of blood microRNAs. Fasting GIP was associated with ALT [β = 0.16 (confidence interval (CI): 0.01–0.32)], triglycerides [β = 0.21 (95% CI: 0.06–0.36], and FGF-21 [β = 0.20 (95%CI: 0.03–0.37)]; and postprandial GIP with GGT [β = 0.17 (95%CI: 0.03–0.32)]. The odds ratio for elevated fatty liver index (>73%) was 2.42 (95%CI: 1.02–5.72) for high GIP versus low GIP patients. The miRNAs profile related to a high GIP plasma level included upregulated miR-136-5p, miR-320a, miR-483-5p, miR-520d-5p, miR-520b, miR-30e-3p, and miR-571. Analysis of the interactions of these microRNAs with gene expression pathways suggests their potential contribution to the regulation of the activity of genes associated with insulin resistance, fatty acids metabolism, and adipocytokines signaling. Exaggerated fasting and postprandial secretion of GIP in obesity are associated with elevated liver damage markers as well as FGF-21 plasma levels. Differentially expressed microRNAs suggest additional, epigenetic factors contributing to the gut–liver cross-talk.

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“…Gasbjerg et al (3) performed studies in healthy human subjects receiving oral glucose loads of 75 g in the fasting state on four different days. The known incretin hormones, GIP and GLP-1, which are secreted in response to glucose administration/absorption, were antagonized with the established peptide receptor antagonist exendin , blocking the stimulation of GLP-1 receptors, or with the novel GIP receptor antagonist, GIP amide, a naturally occurring fragment of intact GIP (full sequence 1-42), which has recently been characterized as a specific GIP receptor antagonist for use in human studies (4). A similar GIP receptor antagonist, GIP(7-30)amide, had previously been used in animal studies but had not been validated for human experiments (5).…”

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confidence: 99%

“…Overall, the elegant studies by Gasberg and colleagues (3,4) have demonstrated that the incretin hormones GIP and GLP-1 are rather unequal with respect to their physiological contribution to the incretin effect, thus behaving more like stepchildren than monozygotic twins within the incretin family.…”

mentioning

confidence: 99%

“…Details will have to be explored in future studies. Gasbjerg and colleagues (3,4) are to be congratulated to Figure 1-A: Role of GLP-1 and GIP (as assessed by employing specific receptor antagonists) on glycemic excursions (left), insulin secretion rates (calculated by deconvolution of C-peptide concentrations) (middle), and increments in insulin secretion rates (ISR) divided by rises in plasma glucose concentrations normalized for a glycemic rise as observed with oral glucose (in the absence of incretin receptor antagonists) (right). The difference from placebo conditions should be an estimate of the contribution to the incretin effect (overall, ;2/3, the major proportion of which is due to GIP).…”

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confidence: 99%

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GIP and GLP-1: Stepsiblings Rather Than Monozygotic Twins Within the Incretin Family

Nauck

2019

Diabetes

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The importance of the incretin effect for the postprandial augmentation of insulin released has long been recognized (1). However, there has been a long-standing controversy as to the relative importance of the various gastrointestinal hormones in mediating this effect. While earlier studies suggested a contribution of gastrin, secretin, and cholecystokinin (2), it later became obvious that in humans, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are the predominant incretin hormones (1). Which of the two incretins is the most relevant one is still a matter of debate.Gasbjerg et al.(3) performed studies in healthy human subjects receiving oral glucose loads of 75 g in the fasting state on four different days. The known incretin hormones, GIP and GLP-1, which are secreted in response to glucose administration/absorption, were antagonized with the established peptide receptor antagonist exendin(9-39), blocking the stimulation of GLP-1 receptors, or with the novel GIP receptor antagonist, GIP(3-30)amide, a naturally occurring fragment of intact GIP (full sequence 1-42), which has recently been characterized as a specific GIP receptor antagonist for use in human studies (4). A similar GIP receptor antagonist, GIP(7-30)amide, had previously been used in animal studies but had not been validated for human experiments (5). These incretin receptor antagonists were compared with placebo and used alone and in combination. The result was a slight rise in postload glucose concentrations and a minor reduction in insulin secretory responses, when the GLP-1 receptor was blocked, and a substantial rise in glycemic excursions after the glucose load and a more pronounced reduction in insulin secretory responses, when the recently validated GIP antagonist GIP(3-30)amide was administered at an approximately 1,000-fold excess (;60 nmol/L) over endogenous peak GIP concentrations (;60 pmol/L). The combination of exendin(9-39) and GIP(3-30)amide further raised plasma glucose and reduced insulin secretory responses over and above the degree observed with single receptor blockers. The difference between experiments with exendin(9-39) and GIP(3-30)amide used as single receptor blockers was significant with respect to plasma glucose rises, insulin and C-peptide responses, insulin secretion rates calculated by deconvolution, and various measures of in vivo b-cell function (3). Therefore, the main conclusion from this important study is that blocking GIP receptors has more impact on postglucose insulin secretory responses and on oral glucose tolerance than interfering with GLP-1 action. GIP, thus, is the more effective and more important incretin hormone in healthy subjects receiving an oral glucose challenge of this (75 g) size, which is a standardized challenge used in diagnosing disturbances of glucose tolerance. These findings revise the commonly expressed view that GLP-1 is the most important incretin hormone, a misconception that was mainly based on its therapeutic effectiveness in patients with ...

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

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

Cited by 72 publications

References 51 publications

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

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

Enhanced GIP Secretion in Obesity Is Associated with Biochemical Alteration and miRNA Contribution to the Development of Liver Steatosis

GIP and GLP-1: Stepsiblings Rather Than Monozygotic Twins Within the Incretin Family

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