Article
Chemistry, Medicinal
Gabriele Carullo, Sarah Mazzotta, Margarita Vega-Holm, Fernando Iglesias-Guerra, Jose Manuel Vega-Perez, Francesca Aiello, Antonella Brizzi
Summary: The GPCRs activated by FFAs have become a new and exciting drug target, with a focus on GPR120 in diseases such as cancer and inflammatory conditions. Research on GPR120 agonists, particularly in the context of Type 2 diabetes mellitus, has paved the way for potential antidiabetic drug discovery.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Xiaodi Zhao, Dong-Oh Yoon, Jaeho Yoo, Hyun-Ju Park
Summary: The study identified two new GPR40 agonist lead compounds, 4k and 4o, which showed promising effects in improving glycemic control and increasing plasma-active GLP-1 secretion in in vivo efficacy studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Nutrition & Dietetics
Ivan Lopez-Mendez, Karla Mendez-Maldonado, Luis A. Manzo-Francisco, Eva Juarez-Hernandez, Misael Uribe, Varenka J. Barbero-Becerra
Summary: MAFLD is a hepatic disorder linked to active fatty acid metabolism and regulated by GPRs. Obesity, microbiota environment, and dietary characteristics are also associated with MAFLD. The role of active fatty acids in metabolic diseases is a promising area for further research.
NUTRITION RESEARCH
(2021)
Article
Oncology
Lili Zhang, Xiangzhong Zhao, Huijun Chu, Han Zhao, Xiaoying Lai, Jing Li, Teng Lv
Summary: This study found that serum levels of free fatty acids (FFAs) were increased in ovarian cancer (OC) patients and decreased after chemotherapy. High expression of free fatty acid receptors (FFARs) was associated with the prognosis of OC. The prognostic value of different FFARs differed depending on TP53 wild or TP53 mutant ovarian cancer.
FRONTIERS IN ONCOLOGY
(2022)
Article
Nutrition & Dietetics
Kiriko Watanabe, Moritake Higa, Yoshimasa Hasegawa, Akihiro Kudo, Richard C. Allsopp, Bradley J. Willcox, Donald C. Willcox, Masataka Sata, Hiroaki Masuzaki, Michio Shimabukuro
Summary: Regional differences in insulin response and sensitivity were observed in Japanese participants, with insulin secretion correlating positively with fat intake and negatively with fish, carbohydrates, and dietary fiber intake. This suggests that nutritional factors may play a role in these variations independently of body size/adiposity.
FRONTIERS IN NUTRITION
(2021)
Article
Chemistry, Medicinal
Lili Chen, Ying Yun, Shimeng Guo, Xiaoyan Wang, Muya Xiong, Tingting Zhao, Tifei Xu, Jianhua Shen, Xin Xie, Kai Wang
Summary: Danuglipron is a representative small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) that has shown positive results in clinical trials for the treatment of type 2 diabetes mellitus (T2DM) and obesity. However, it has limitations such as hERG inhibition, lower activity compared to endogenous GLP-1, and short action time. This study introduces a new class of 5,6-dihydro-1,2,4-triazine derivatives that eliminate hERG inhibition caused by danuglipron, and identifies compound 42 as a highly potent and selective GLP-1R agonist with improved efficacy and acceptable drug-like properties. Compound 42 demonstrates longer-lasting effects in reducing glucose excursion and inhibiting food intake, making it a feasible treatment for T2DM and obesity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biology
Mengyao Wu, Tak-Ho Lo, Liping Li, Jia Sun, Chujun Deng, Ka-Ying Chan, Xiang Li, Steve Ting-Yuan Yeh, Jimmy Tsz Hang Lee, Pauline Po Yee Lui, Aimin Xu, Chi-Ming Wong
Summary: This study found that adhesion G protein-coupled receptor F1 (Adgrf1) regulates hepatic lipid metabolism by controlling the expression of stearoyl-coA desaturase 1 (Scd1). The downregulation of Adgrf1 expression in the livers of obese subjects may serve as a protective mechanism to prevent the excessive accumulation of fat. These findings not only reveal a new mechanism for the progression of non-alcoholic fatty liver disease (NAFLD), but also propose a novel therapeutic approach to combat NAFLD by targeting Adgrf1.
Review
Pharmacology & Pharmacy
Patricio Atanes, Tanyel Ashik, Shanta J. Persaud
Summary: This study compared the expression of GPCR mRNA in human islets obtained from donors with normal weight range and those classified as obese. The altered expression of GPCRs in obesity may have an impact on islet function, and the study also considered the possible effects of adipokines on GPCRs showing altered expression in obesity.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Chemistry, Medicinal
Ying Yun, Chenlu Zhang, Shimeng Guo, Xiaoying Liang, Yuan Lan, Min Wang, Ning Zhuo, Jianpeng Yin, Huanan Liu, Min Gu, Jing Li, Xin Xie, Fajun Nan
Summary: A new series of betulinic acid derivatives were identified as potent TGR5 agonists which showed species difference in activity, and a key amino acid H88 (Y89) was found to contribute to the species difference. Introducing the mTGR5 (H88Y) mutation in mice resulted in significant glucose-lowering effects and stimulated GLP-1 and insulin secretion, highlighting the potential for further investigation of TGR5 agonists.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Nader H. Moniri, Qadan Farah
Summary: The dietary intake of fat, carbohydrates, protein, fiber, and probiotics can influence gut microbiota and GI health, particularly in the colon where fat and fiber can regulate inflammation and carcinogenesis. Short-chained fatty acids (SCFA), such as acetate, propionate, and butyrate, synthesized from dietary fiber by microbiota, play important roles in colorectal health by decreasing inflammation and oxidative stress. The discovery of G protein-coupled free-fatty acid receptors in the early 2000s suggests that many effects of SCFA are cell-surface receptor mediated, with FFA2, FFA3, and GPR109A known to modulate various functions in the GI tract in response to luminal SCFA.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Cell Biology
Chien-Ting Wu, Keren Hilgendorf, Romina J. Bevacqua, Yan Hang, Janos Demeter, Seung K. Kim, Peter K. Jackson
Summary: Multiple G protein-coupled receptors (GPCRs) are localized to primary cilia in pancreatic islet cells, with FFAR4 and PTGER4 stimulating cAMP signaling and hormone secretion. The transport of GPCRs to cilia requires TULP3, which plays a key role in regulating hormone secretion by islet cells.
GENES & DEVELOPMENT
(2021)
Article
Endocrinology & Metabolism
Guoying Wang, Jessie P. Buckley, Tami R. Bartell, Xiumei Hong, Colleen Pearson, Xiaobin Wang
Summary: The study aimed to identify a lipidomic signature associated with gestational diabetes mellitus (GDM) in the postpartum period and investigate its role in the progression to type 2 diabetes (T2D). A cohort of 1,409 women who delivered a singleton baby was followed up prospectively, and their lipidome was analyzed using liquid chromatography-tandem mass spectrometry. 33 postpartum lipid species were identified to be associated with GDM, and 4 of them were also associated with incident T2D, mediating the progression from GDM to T2D. Including these lipid species improved the prediction of T2D when considering the entire follow-up period.
Article
Biochemistry & Molecular Biology
Mingcheng Qian, Zhijie Luo, Wenwen Hou, Jingjing Sun, Xin Lu, Qianxi Zhang, Yi Wu, Caile Xue, Shuai Zhao, Xin Chen
Summary: In this study, fourteen new cholic acid derivatives were designed and synthesized, and one of them, B1, was found to be a highly potent TGR5 agonist, which can be used as a lead compound for further study.
BIOORGANIC CHEMISTRY
(2022)
Article
Endocrinology & Metabolism
Do-Hyung Lee, Kyung-Sun Heo, Chang-Seon Myung
Summary: This study investigated the mechanisms by which activation of orphan G protein-coupled receptor GPR41 enhances glucose uptake in C2C12 myotubes, using a GPR41-selective agonist. The results showed that AR420626 increased glucose uptake mediated by GPR41-dependent Ca2+ signaling, improving diabetes mellitus.
Review
Biochemistry & Molecular Biology
Han-Chow E. Koh, Chao Cao, Bettina Mittendorfer
Summary: Plasma insulin clearance plays an important role in determining plasma insulin concentration and is closely related to excess adiposity, insulin sensitivity, and type 2 diabetes. The lower insulin clearance rate observed in people with obesity is not a compensatory response to insulin resistance, but directly linked to insulin sensitivity. Additionally, postprandial insulin clearance decreases due to increased delivery of insulin to tissues that clear insulin.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Endocrinology & Metabolism
Annie Hasib, Ming T. Ng, Victor A. Gault, Dawood Khan, Vadivel Parthsarathy, Peter R. Flatt, Nigel Irwin
Article
Biochemistry & Molecular Biology
Dawood Khan, Srividya Vasu, R. Charlotte Moffett, Nigel Irwin, Peter R. Flatt
Article
Cell Biology
Nupur M. Pathak, Paul J. B. Millar, Varun Pathak, Peter R. Flatt, Victor A. Gault
MOLECULAR AND CELLULAR ENDOCRINOLOGY
(2018)
Article
Biochemistry & Molecular Biology
Aine M. McKillop, Claire L. Stevenson, Brian M. Moran, Yasser H. A. Abdel-Wahab, Peter R. Flatt
Article
Biochemistry & Molecular Biology
J. Michael Conlon, Milena Mechkarska, Yasser H. Abdel-Wahab, Peter R. Flatt
Article
Biochemistry & Molecular Biology
Brian M. Moran, Michael G. Miskelly, Yasser H. A. Abdel-Wahab, Peter R. Flatt, Aine M. McKillop
BIOLOGICAL CHEMISTRY
(2019)
Article
Pharmacology & Pharmacy
Dipak Sarnobat, Charlotte R. Moffett, Neil Tanday, Frank Reimann, Fiona M. Gribble, Peter R. Flatt, Andrei I. Tarasov
BIOCHEMICAL PHARMACOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Galyna Graham, J. Michael Conlon, R. Charlotte Moffett, Yasser H. Abdel-Wahab, Peter R. Flatt
Summary: The study showed that long-acting, dual-agonist anti-diabetic peptides can induce alpha-cell to beta-cell transdifferentiation, leading to increased pancreatic insulin content and plasma insulin concentrations. This suggests therapeutic potential for using proglucagon-derived peptides from phylogenetical ancient fish in diabetes treatment.
JOURNAL OF PEPTIDE SCIENCE
(2021)
Article
Endocrinology & Metabolism
D. Sarnobat, R. C. Moffett, P. R. Flatt, A. I. Tarasov
Summary: The study showed that metformin and rosiglitazone can help slow down the reduction of beta-cell pool in streptozotocin-induced diabetes, while tolbutamide may exacerbate beta-cell apoptosis but potentially protect beta-cells from chronic hyperglycemia by increasing insulin secretion directly.
JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION
(2022)
Article
Plant Sciences
Prawej Ansari, Peter R. Flatt, Patrick Harriott, J. M. A. Hannan, Yasser H. A. Abdel-Wahab
Summary: The study demonstrated the antidiabetic effects of Acacia arabica bark extract, showing potential as a treatment for diabetes. The isolated phytoconstituents, including quercetin and kaempferol, improved glucose tolerance and insulin secretion, indicating the benefits of using them as antidiabetic agents.
Review
Oncology
Ryan McGowan, Aine Sally, Anthony McCabe, Brian Michael Moran, Karen Finn
Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and deadly cancer often diagnosed at a late stage due to nonspecific symptoms and a lack of reliable biomarkers. This review highlights the potential use of circulating nucleic acid-based biomarkers for early detection and monitoring of PDAC. However, the lack of prognostic biomarkers remains a challenge for assessing treatment efficacy.
Review
Oncology
Aine Sally, Ryan McGowan, Karen Finn, Brian Michael Moran
Summary: Pancreatic cancer is a major cause of cancer-related death worldwide, primarily due to delayed diagnosis and resistance to traditional chemotherapy. Delayed diagnosis is often caused by the wide range of non-specific symptoms associated with the disease. Resistance to current chemotherapies, such as gemcitabine, develops due to genetic mutations that are either intrinsic or acquired. This has resulted in poor patient prognosis and justifies the requirement for new targeted therapies. Synthetic lethality approaches targeting specific loss-of-function mutations have shown great potential in pancreatic cancer treatment. Immunotherapies have also yielded promising results and are currently undergoing clinical trials. Monoclonal antibodies, immune checkpoint inhibitors, adoptive cell transfer, and vaccines have shown success in other cancers and could hold the same potential in pancreatic cancer treatment. This review focuses on currently approved therapies, challenges, and future directions in pancreatic cancer therapy, including synthetic lethality approaches, immunotherapy, and clinical trials.
Article
Medicine, Research & Experimental
Julie Turbitt, Lorraine Brennan, R. Charlotte Moffett, Peter R. Flatt, Paul R. V. Johnson, Andrei I. Tarasov, Neville H. McClenaghan
Summary: The study found that taurine, alanine, and proline can promote insulin secretion through the regulation of ion transport and inhibition of the sodium-potassium-chloride cotransporter. This action of taurine may have potential value in the treatment of diabetes.
Article
Endocrinology & Metabolism
Vadivel Parthsarathy, Christopher Hogg, Peter R. Flatt, Finbarr P. M. O'Harte
DIABETES OBESITY & METABOLISM
(2018)
Article
Biochemistry & Molecular Biology
Dawood Khan, Srividya Vasu, R. Charlotte Moffett, Victor A. Gault, Peter R. Flatt, Nigel Irwin
BIOLOGICAL CHEMISTRY
(2018)