Salt-inducible kinases (SIKs) are members of the AMPK-related kinase family, which control glucose homeostasis by inhibiting CREB-regulated transcriptional coactivators (CRTCs). We previously showed that treatment of primary hepatocytes with a pan-SIK inhibitor induced dephosphorylation and nuclear enrichment of CRTC2, leading to increased expression of gluconeogenic genes and glucose production. These data indicate that SIK family members act as molecular gatekeeper of hepatic glucose production by maintaining the gluconeogenic program repressed. However, the importance of this regulation has not been clearly established in vivo, and its impact on blood glucose control is unknown. Furthermore, it is not known which SIK isoforms are involved in the regulation of hepatic gluconeogenesis, given that all SIK isoforms (SIK1, SIK2 and SIK3) are expressed in the liver. To explore the contribution of SIK isoforms to hepatic glucose production, we generated single knockout mice in which each SIK isoform was specifically deleted in the liver. We found that blood glucose levels and glucose tolerance in these three KO mouse models were comparable to those in control mice, indicating that a single deletion of SIK isoforms in the liver is not sufficient to impact blood glucose levels and gluconeogenesis. We hypothesize that there is functional redundancy between SIK isoforms in the control hepatic gluconeogenesis. To further investigate the role of SIKs in the regulation of hepatic glucose production and blood glucose levels, we are currently generating mouse models exhibiting a combination of SIK isoform deletions in the liver.