DMT efficiently inhibits hepatic gluconeogenesis by regulating the G alpha q signaling pathway
文献类型：期刊论文
| 作者 | Zhou, Ting-Ting2,3; Ma, Fei1; Shi, Xiao-Fan2,3; Xu, Xin2,3; Du, Te2,3; Guo, Xiao-Dan2,3; Wang, Gai-Hong2; Yu, Liang2,3 ; Rukachaisirikul, Vatcharin4; Hu, Li-Hong2,3
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| 刊名 | JOURNAL OF MOLECULAR ENDOCRINOLOGY
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| 出版日期 | 2017-08 |
| 卷号 | 59期号:2页码:151-169 |
| 关键词 | Gaq signaling hepatic gluconeogenesis protein kinase B (AKT) type 2 diabetes mellitus (T2DM) |
| ISSN号 | 0952-5041 |
| DOI | 10.1530/JME-17-0121 |
| 文献子类 | Article |
| 英文摘要 | Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated pathogenesis and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. G protein-coupled receptors (GPCRs) are classified as distinct families by heterotrimeric G proteins, primarily including G alpha s, G alpha i and G alpha q. G alpha s-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and G alpha i-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of G alpha q-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7-(thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3',2': 4,5] thieno[3,2-d] pyrimidin-4(1H)-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in db/db mice decreased fasting blood glucose and hemoglobin A1C (HbA1c) levels, while improved glucose tolerance and pyruvate tolerance. Mechanism study demonstrated that DMT-inhibited gluconeogenesis by regulating the G alpha q/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca2+)/calmodulin (CaM)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling pathway. To our knowledge, DMT might be the first reported small molecule able to suppress hepatic gluconeogenesis by regulating Gaq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM. |
| WOS关键词 | GLUCAGON RECEPTOR ANTAGONIST ; PROTEIN-COUPLED RECEPTOR ; GLUCOSE-PRODUCTION ; PHOSPHATIDYLINOSITOL 3-KINASE ; MODULATES GLUCONEOGENESIS ; SMALL-MOLECULE ; IP3 RECEPTOR ; IN-VIVO ; ACTIVATION ; METFORMIN |
| 资助项目 | National Natural Science Foundation of China[81473141] ; NSFC-TRF collaboration projects[NSFC81561148011] ; NSFC-TRF collaboration projects[DBG5980001] ; Key Laboratory of Receptor Research of the Chinese Academy of Sciences[SIMM1606YZZ-04] ; Personalized Medicines: Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040313] ; Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)[00000000] |
| WOS研究方向 | Endocrinology & Metabolism |
| 语种 | 英语 |
| WOS记录号 | WOS:000409180400006 |
| 出版者 | BIOSCIENTIFICA LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272536]  |
| 专题 | 药物安全性评价中心 |
| 通讯作者 | Hu, Li-Hong; Chen, Jing; Shen, Xu |
| 作者单位 | 1.East China Univ Sci & Technol, Sch Pharm, Shanghai, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai, Peoples R China; 3.Univ Chinese Acad Sci, Beijing, Peoples R China; 4.Prince Songkla Univ, Dept Chem, Fac Sci, Hat Yai, Thailand; 5.Nanjing Univ Chinese Med, Sch Med & Life Sci, Key Lab Drug Target & Drug Degenerat Dis, Nanjing, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Ting-Ting,Ma, Fei,Shi, Xiao-Fan,et al. DMT efficiently inhibits hepatic gluconeogenesis by regulating the G alpha q signaling pathway[J]. JOURNAL OF MOLECULAR ENDOCRINOLOGY,2017,59(2):151-169. |
| APA | Zhou, Ting-Ting.,Ma, Fei.,Shi, Xiao-Fan.,Xu, Xin.,Du, Te.,...&Shen, Xu.(2017).DMT efficiently inhibits hepatic gluconeogenesis by regulating the G alpha q signaling pathway.JOURNAL OF MOLECULAR ENDOCRINOLOGY,59(2),151-169. |
| MLA | Zhou, Ting-Ting,et al."DMT efficiently inhibits hepatic gluconeogenesis by regulating the G alpha q signaling pathway".JOURNAL OF MOLECULAR ENDOCRINOLOGY 59.2(2017):151-169. |
入库方式： OAI收割
来源：上海药物研究所
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