DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway.
DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway.
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DOI：
10.1530/jme-17-0121
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发表时间：
2017-08
影响因子：
3.5
通讯作者：
Tingting Zhou;Fei Ma;Xiao-fan Shi;Xing Xu;T. Du;Xiao-dan Guo;Gai-hong Wang;Liang Yu;V. Rukachaisirikul;Li-Hong Hu;Jing Chen;Xu Shen
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文献类型：
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作者：
Tingting Zhou;Fei Ma;Xiao-fan Shi;Xing Xu;T. Du;Xiao-dan Guo;Gai-hong Wang;Liang Yu;V. Rukachaisirikul;Li-Hong Hu;Jing Chen;Xu Shen
2型糖尿病（T2 DM）是一种发病机制复杂的慢性代谢性疾病，靶向抑制糖尿病新生血管生成是开发抗糖尿病药物的重要策略。G蛋白偶联受体（GPCRs）是由异源三聚体G蛋白组成的不同家族，主要包括Gαs、Gαi和Gαq。Gα s-偶联的GPCR通过激活环磷酸腺苷（cAMP）/蛋白激酶A（PKA）途径参与肝细胞凋亡的调控，Gα i-偶联的GPCR对腺苷酸环化酶具有抑制作用，降低细胞内cAMP水平。然而，关于Gα q偶联的GPCRs在肝硬化发生中的调控知之甚少。在此，确定小分子2-（2，4-二甲氧基-3-甲基苯基）-7-（噻吩-2-基）-9-（三氟甲基）-2，3-二氢吡啶并[3 '，2'：4，5]噻吩并[3，2-d]嘧啶-4（1H）-酮（DMT）抑制肝葡萄糖产生并降低致肝细胞癌基因的mRNA水平。在db/db小鼠中，DMT治疗降低了空腹血糖和糖化血红蛋白（HbA 1c）水平，同时改善了葡萄糖耐量和丙酮酸耐量。机制研究表明，DMT通过调节Gαq/磷脂酶C（PLC）/肌醇-1，4，5-三磷酸受体（IP 3 R）介导的钙（Ca 2+）/钙调蛋白（CaM）/磷脂酰肌醇-4，5-二磷酸3-激酶（PI 3 K）/蛋白激酶B（AKT）/叉头盒蛋白O 1（FOXO 1）信号通路，从而抑制大鼠胚胎发育。据我们所知，DMT可能是第一个报道的能够通过调节Gαq信号来抑制肝硬化发生的小分子，并且我们目前的工作也突出了DMT在治疗T2 DM中的潜力。
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 Gαs, Gαi and Gαq. Gαs-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Gαi-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Gαq-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 Gαq/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 Gαq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM.