{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:18:40Z","timestamp":1784557120784,"version":"3.55.0"},"reference-count":66,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:p>\n                    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\u03b1s, G\u03b1i and G\u03b1q. G\u03b1s-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)\/protein kinase A (PKA) pathway and G\u03b1i-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of G\u03b1q-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7-(thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3\u2032,2\u2032:4,5]thieno[3,2-d]pyrimidin-4(\n                    <jats:italic>1H<\/jats:italic>\n                    )-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in\n                    <jats:italic>db\/db<\/jats:italic>\n                    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\u03b1q\/phospholipase C (PLC)\/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    )\/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 G\u03b1q signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM.\n                  <\/jats:p>","DOI":"10.1530\/jme-17-0121","type":"journal-article","created":{"date-parts":[[2017,6,21]],"date-time":"2017-06-21T20:20:12Z","timestamp":1498076412000},"page":"151-169","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":12,"title":["DMT efficiently inhibits hepatic gluconeogenesis by regulating the G\u03b1q signaling pathway"],"prefix":"10.1530","volume":"59","author":[{"given":"Ting-Ting","family":"Zhou","sequence":"first","affiliation":[{"name":"1Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China"},{"name":"2University of Chinese Academy of Sciences, Beijing, 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