PMID- 28637808 OWN - NLM STAT- MEDLINE DCOM- 20180510 LR - 20190214 IS - 1479-6813 (Electronic) IS - 0952-5041 (Linking) VI - 59 IP - 2 DP - 2017 Aug TI - DMT efficiently inhibits hepatic gluconeogenesis by regulating the Galphaq signaling pathway. PG - 151-169 LID - 10.1530/JME-17-0121 [doi] AB - 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 Galphas, Galphai and Galphaq. Galphas-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Galphai-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Galphaq-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 Galphaq/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca(2+))/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 Galphaq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM. CI - (c) 2017 Society for Endocrinology. FAU - Zhou, Ting-Ting AU - Zhou TT AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - University of Chinese Academy of SciencesBeijing, China. FAU - Ma, Fei AU - Ma F AD - School of PharmacyEast China University of Science and Technology, Shanghai, China. FAU - Shi, Xiao-Fan AU - Shi XF AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - University of Chinese Academy of SciencesBeijing, China. FAU - Xu, Xin AU - Xu X AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - University of Chinese Academy of SciencesBeijing, China. FAU - Du, Te AU - Du T AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - University of Chinese Academy of SciencesBeijing, China. FAU - Guo, Xiao-Dan AU - Guo XD AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - University of Chinese Academy of SciencesBeijing, China. FAU - Wang, Gai-Hong AU - Wang GH AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. FAU - Yu, Liang AU - Yu L AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - University of Chinese Academy of SciencesBeijing, China. FAU - Rukachaisirikul, Vatcharin AU - Rukachaisirikul V AD - Department of ChemistryFaculty of Science, Prince of Songkla University, Songkhla, Thailand. FAU - Hu, Li-Hong AU - Hu LH AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China lhhu@simm.ac.cn jingchen@simm.ac.cn xshen@simm.ac.cn. AD - University of Chinese Academy of SciencesBeijing, China. FAU - Chen, Jing AU - Chen J AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China lhhu@simm.ac.cn jingchen@simm.ac.cn xshen@simm.ac.cn. AD - University of Chinese Academy of SciencesBeijing, China. FAU - Shen, Xu AU - Shen X AD - Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China lhhu@simm.ac.cn jingchen@simm.ac.cn xshen@simm.ac.cn. AD - University of Chinese Academy of SciencesBeijing, China. AD - Key Laboratory of Drug Target and Drug for Degenerative DiseaseSchool of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170621 PL - England TA - J Mol Endocrinol JT - Journal of molecular endocrinology JID - 8902617 RN - 0 (Calmodulin) RN - 0 (Forkhead Box Protein O1) RN - 0 (Inositol 1,4,5-Trisphosphate Receptors) RN - 0 (Insulin) RN - 0 (Thiophenes) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.1.4.- (Type C Phospholipases) RN - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gq-G11) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/metabolism MH - Calmodulin/metabolism MH - Forkhead Box Protein O1/metabolism MH - GTP-Binding Protein alpha Subunits, Gq-G11/*metabolism MH - Gluconeogenesis/*drug effects MH - Hyperglycemia/drug therapy/pathology MH - Inositol 1,4,5-Trisphosphate Receptors/metabolism MH - Insulin/pharmacology MH - Liver/drug effects/*metabolism MH - Male MH - Mice, Inbred C57BL MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction/*drug effects MH - Thiophenes/blood/chemistry/pharmacokinetics/*pharmacology MH - Type C Phospholipases/metabolism OTO - NOTNLM OT - Galphaq signaling OT - hepatic gluconeogenesis OT - protein kinase B (AKT) OT - type 2 diabetes mellitus (T2DM) EDAT- 2017/06/24 06:00 MHDA- 2018/05/11 06:00 CRDT- 2017/06/23 06:00 PHST- 2017/06/19 00:00 [received] PHST- 2017/06/21 00:00 [accepted] PHST- 2017/06/24 06:00 [pubmed] PHST- 2018/05/11 06:00 [medline] PHST- 2017/06/23 06:00 [entrez] AID - JME-17-0121 [pii] AID - 10.1530/JME-17-0121 [doi] PST - ppublish SO - J Mol Endocrinol. 2017 Aug;59(2):151-169. doi: 10.1530/JME-17-0121. Epub 2017 Jun 21.