Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

Yang, Bin; Gelfanov, Vasily; El, Kimberley; Chen, Alex; Rohlfs, Rebecca; DuBois, Barent; Hansen, Ann Maria Kruse; Pérez-Tilve, Diego; Knerr, Patrick J.; D’Alessio, David A.; Campbell, Jonathan E.; Douros, Jonathan D.; Finan, Brian

doi:10.1016/j.molmet.2022.101638

Cited by 22 publications

(6 citation statements)

References 49 publications

(71 reference statements)

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“…In contrast, GIP(1-30)NH2 is cleaved by DPP-4 to produce GIP(3-30)NH2, a high-affinity competitive antagonist of the GIP system that has been shown to be active in humans ( Asmar et al, 2017 ; Gasbjerg et al, 2018 ; Hansen et al, 2016 ). For research purposes, multiple GIP analogs that resist DPP-4 degradation have been synthesized, including N-AcGIP ( Mabilleau et al, 2014 ), Pro 3 GIP ( Yang et al, 2022 ), and D-Ala 2 -GIP ( Killion et al, 2020 ) to study various metabolic diseases.…”

Section: Gipmentioning

confidence: 99%

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis

Liu,

Xiao,

Lin

et al. 2024

Front. Pharmacol.

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Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.

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Section: Gipmentioning

confidence: 99%

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis

Liu,

Xiao,

Lin

et al. 2024

Front. Pharmacol.

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“…Interestingly, there is an ongoing debate on whether GIP agonism or antagonism is the appropriate way to engage GIP receptors [127,132]. Yang et al [133], by utilizing a GIPR antagonist based on human and mouse GIP sequences, showed that this peptide blocked GIP-induced insulin secretion and the subsequent reduction in glucose levels, while its co-administration with semaglutide provoked additive weight loss than semaglutide alone in a DIO mouse model. The greater weight loss induced by combined GLP-1RA and GIPR antagonist has also been validated in other animal studies [134][135][136].…”

Section: Closing Remarks and Future Perspectivesmentioning

confidence: 99%

Glucagon-like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature

Chrysavgis,

Kazanas,

Bafa

et al. 2024

IJMS

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Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic β-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2 diabetes mellitus (T2DM). Strongly related to those disorders, metabolic dysfunction-associated steatotic liver disease (MASLD), especially its aggressive form, defined as metabolic dysfunction-associated steatohepatitis (MASH), is a major healthcare burden associated with high morbidity and extrahepatic complications. GLP-1RAs have been explored in MASH patients with evident improvement in liver dysfunction enzymes, glycemic control, and weight loss. Importantly, the combination of GLP-1RAs with GIP and/or glucagon RAs may be even more effective via synergistic mechanisms in amelioration of metabolic, biochemical, and histological parameters of MASLD but also has a beneficial impact on MASLD-related complications. In this current review, we aim to provide an overview of incretins’ physiology, action, and signaling. Furthermore, we provide insight into the key pathophysiological mechanisms through which they impact MASLD aspects, as well as we analyze clinical data from human interventional studies. Finally, we discuss the current challenges and future perspectives pertinent to this growing area of research and clinical medicine.

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“…To circumvent this issue, we next used acute pharmacological antagonism of the incretin receptors in mouse islets. We applied a recently validated long-acting GIPR antagonist 23 , which prevented glucose lowering in response to an acylated GIPR agonist in wild-type mice (Extended Data Fig. 1a ).…”

Section: Mainmentioning

confidence: 99%

The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets

Douros

Willard

et al. 2023

Nat Metab

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The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance1. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity2, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity3,4. However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control5. Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.

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Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

Cited by 22 publications

References 49 publications

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis

Glucagon-like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature

The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets

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