GPR40 Agonism Modulates Inflammatory Reactions in Vascular Endothelial Cells

Kim, Joo Won; Roh, Eun; Choi, Kyung Mook; Yoo, Hye Jin; Hwang, Hwan-Jin; Baik, Sei Hyun

doi:10.4093/dmj.2021.0092

Cited by 10 publications

(6 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LY2922470 is a GPR40 agonist that has shown an effective and persistent dose‐dependent reduction in glucose levels and a significant increase in insulin and GLP‐1 secretion in preclinical trials 653 . GPR40 agonists might also regulate inflammatory responses and thus play a role in improving the development of diabetes complications 654,655 …”

Section: Antidiabetic Drugsmentioning

confidence: 99%

See 1 more Smart Citation

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

Cao

Tian

Zhang

et al. 2023

MedComm

View full text Add to dashboard Cite

Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID‐19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.

show abstract

Section: Antidiabetic Drugsmentioning

confidence: 99%

“… 653 GPR40 agonists might also regulate inflammatory responses and thus play a role in improving the development of diabetes complications. 654 , 655 …”

Section: Antidiabetic Drugsmentioning

confidence: 99%

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

Cao

Tian

Zhang

et al. 2023

MedComm

View full text Add to dashboard Cite

show abstract

“…7,8 In addition to T2DM, studies have shown that GPR40 is also a potential target for the complications of T2DM and metabolic syndrome (MetS) such as nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases. [9][10][11][12][13][14] A large number of studies have shown that GPR40 is expressed by not only pancreatic β-cells, but also various types of cells including macrophage, 15 vascular endothelial cell, 14 hepatocyte, 16,17 and fibroblast. 15 Consistently, many studies have shown that GPR40 has anti-inflammatory properties that contribute to improvement of complications of T2DM and MetS.…”

Section: Introductionmentioning

confidence: 99%

GPR40 deficiency worsens metabolic syndrome‐associated periodontitis in mice

Kirkwood

et al. 2023

J of Periodontal Research

View full text Add to dashboard Cite

Background and Objective: G protein-coupled receptor 40 (GPR40) is a receptor for medium-and long-chain free fatty acids (FFAs). GPR40 activation improves type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and the complications of T2DM and MetS. Periodontitis, a common oral inflammatory disease initiated by periodontal pathogens, is another complication of T2DM and MetS. Since FFAs play a key role in the pathogenesis of MetS which exacerbates periodontal inflammation and GPR40 is a FFA receptor with anti-inflammatory properties, it is important to define the role of GPR40 in MetS-associated periodontitis. Materials and Methods:We induced MetS and periodontitis by high-fat diet and periodontal injection of lipopolysaccharide (LPS), respectively, in wild-type and GPR40deficient mice and determined alveolar bone loss and periodontal inflammation using micro-computed tomography, histology, and osteoclast staining. We also performed in vitro study to determine the role of GPR40 in the expression of proinflammatory genes. Results:The primary outcome of the study is that GPR40 deficiency increased alveolar bone loss and enhanced osteoclastogenesis in control mice and the mice with both MetS and periodontitis. GPR40 deficiency also augmented periodontal inflammation in control mice and the mice with both MetS and periodontitis. Furthermore, GPR40 deficiency led to increased plasma lipids and insulin resistance in control mice but had no effect on the metabolic parameters in mice with MetS alone. For mice with both MetS and periodontitis, GPR40 deficiency increased insulin resistance. Finally, in vitro studies with macrophages showed that deficiency or inhibition of GPR40 upregulated proinflammatory genes while activation of GPR40 downregulated proinflammatory gene expression stimulated synergistically by LPS and palmitic acid. Conclusion:GPR40 deficiency worsens alveolar bone loss and periodontal inflammation in mice with both periodontitis and MetS, suggesting that GPR40 plays a favorable role in MetS-associated periodontitis. Furthermore, GPR40 deficiency or inhibition in macrophages further upregulated proinflammatory and pro-osteoclastogenic genes induced by LPS and palmitic acid, suggesting that GPR40 has anti-inflammatory and anti-osteoclastogenic properties.

show abstract

“…Agonists of GPR40 have been shown to reduce neuronal damage caused by Alzheimer's disease GPR40 [15]. LY2922470, a novel small-molecule GPR40 activator, has been demonstrated to be a viable treatment option for type 2 diabetes due to its ability to stimulate insulin production [16][17][18]. However, whether LY2922470 has shown protective effects against ischemic stroke and cerebral I/R injury remains unknown.…”

Section: Introductionmentioning

confidence: 99%

G Protein-Coupled Receptor 40 Agonist LY2922470 Alleviates Ischemic-Stroke-Induced Acute Brain Injury and Functional Alterations in Mice

Lu,

Zhou,

Cui

et al. 2023

IJMS

View full text Add to dashboard Cite

Stroke is a major cause of fatalities and disabilities around the world, yet the available treatments for it are still limited. The quest for more efficacious drugs and therapies is still an arduous task. LY2922470 is currently used as a G protein-coupled receptor 40 (GPR40) agonist for the treatment of type 2 diabetes. Previous studies have reported protective effects of other GPR40 activators on the brain; however, it remains unclear whether LY2922470 could be a new stroke therapy and improve the stroke-induced brain damage. Here, we first reveal that the transcriptomic gene signature induced by LY2922470 is highly similar to those induced by some agents being involved in defending from cerebrovascular accidents and transient ischemic attacks, including acetylsalicylic acid, progesterone, estradiol, dipyridamole, and dihydroergotamine. This result thus suggests that LY2922470 could have protective effects against ischemic stroke. As a result, further experiments show that giving the small molecule LY2922470 via oral administration or intraperitoneal injection was seen to have a positive effect on neuroprotection with a reduction in infarct size and an improvement in motor skills in mice. Finally, it was demonstrated that LY2922470 could successfully mitigate the harm to the brain caused by ischemic stroke.

show abstract

GPR40 Agonism Modulates Inflammatory Reactions in Vascular Endothelial Cells

Cited by 10 publications

References 19 publications

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

GPR40 deficiency worsens metabolic syndrome‐associated periodontitis in mice

G Protein-Coupled Receptor 40 Agonist LY2922470 Alleviates Ischemic-Stroke-Induced Acute Brain Injury and Functional Alterations in Mice

Contact Info

Product

Resources

About