期刊
JOURNAL OF MOLECULAR ENDOCRINOLOGY
卷 59, 期 2, 页码 151-169出版社
BIOSCIENTIFICA LTD
DOI: 10.1530/JME-17-0121
关键词
Gaq signaling; hepatic gluconeogenesis; protein kinase B (AKT); type 2 diabetes mellitus (T2DM)
资金
- National Natural Science Foundation of China [81473141]
- NSFC-TRF collaboration projects [NSFC81561148011, 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)
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.
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