biostudies-literatureQiao AAmerican Heart AssociationAmerican Diabetes Association11469https://www.ebi.ac.uk/biostudies/studies/S-EPMC9569775biostudies-literatureUnknown23(19)Hepatic glucose production (HGP) is an important component of glucose homeostasis, and deregulated HGP, particularly through gluconeogenesis, contributes to hyperglycemia and pathology of type-2 diabetes (T2D). It has been shown that the gluconeogenic gene expression is governed primarily by the transcription factor cAMP-response element (CRE)-binding protein (CREB) and its coactivator, CREB-regulated transcriptional coactivator 2 (CRTC2). Recently, we have discovered that Sam68, an adaptor protein and Src kinase substrate, potently promotes hepatic gluconeogenesis by promoting CRTC2 stability; however, the detailed mechanisms remain unclear. Here we show that in response to glucagon, Sam68 increases CREB/CRTC2 transactivity by interacting with CRTC2 in the CREB/CRTC2 complex and occupyingInternational journal of molecular sciencesHepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity.PMC956977519TPA349102271-15-BS-14819CDA34630052Jiang YQiao AYan BQin GHan CMa WZhou JfalseHepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity.Hepatic glucose production (HGP) is an important component of glucose homeostasis, and deregulated HGP, particularly through gluconeogenesis, contributes to hyperglycemia and pathology of type-2 diabetes (T2D). It has been shown that the gluconeogenic gene expression is governed primarily by the transcription factor cAMP-response element (CRE)-binding protein (CREB) and its coactivator, CREB-regulated transcriptional coactivator 2 (CRTC2). Recently, we have discovered that Sam68, an adaptor protein and Src kinase substrate, potently promotes hepatic gluconeogenesis by promoting CRTC2 stability; however, the detailed mechanisms remain unclear. Here we show that in response to glucagon, Sam68 increases CREB/CRTC2 transactivity by interacting with CRTC2 in the CREB/CRTC2 complex and occupying2022-01-01T00:00:00Z2022 Sep2026-06-20T03:23:19.145Z2025-04-20T01:47:12.506ZS-EPMC95697753623277010.3390/ijms231911469