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• W2016983316 endingPage "e64946" @default.
• W2016983316 startingPage "e64946" @default.
• W2016983316 abstract "Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response) and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway." @default.
• W2016983316 created "2016-06-24" @default.
• W2016983316 creator A5021870511 @default.
• W2016983316 creator A5027392833 @default.
• W2016983316 creator A5028083286 @default.
• W2016983316 creator A5048267141 @default.
• W2016983316 creator A5064432529 @default.
• W2016983316 creator A5079580517 @default.
• W2016983316 date "2013-06-20" @default.
• W2016983316 modified "2023-09-23" @default.
• W2016983316 title "RNAi Screening in Primary Human Hepatocytes of Genes Implicated in Genome-Wide Association Studies for Roles in Type 2 Diabetes Identifies Roles for CAMK1D and CDKAL1, among Others, in Hepatic Glucose Regulation" @default.
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• W2016983316 doi "https://doi.org/10.1371/journal.pone.0064946" @default.
• W2016983316 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3688709" @default.
• W2016983316 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23840313" @default.
• W2016983316 hasPublicationYear "2013" @default.
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