Abstract
AimIn this study, we investigated the role and mechanism of Salt-induced kinase 1 (SIK1) in regulation of hepatic glucose and lipid metabolism in a high-fat food (HFD) and streptozocin (STZ)-induced type 2 diabetes mellitus (T2DM) rat model.MethodsA diabetic rat model treated with HFD plus low-dose STZ was developed and was transduced to induce a high expression of SIK1 in vivo via a tail-vein injection of a recombinant adenoviral vector. The effects on hepatic glucogenetic and lipogenic gene expression, systemic metabolism and pathological changes were then determined.ResultsIn T2DM rats, SIK1 expression was reduced in the liver. Overexpression of SIK1 improved hyperglycaemia, hyperlipidaemia and fatty liver, reduced the expression of cAMP-response element binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), pS577 SIK1, sterol regulatory element binding-protein-1c (SREBP-1c) and its target genes, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), and increased the expression of SIK1, pT182 SIK1 and pS171 CRTC2 in diabetic rat livers with the suppression of gluconeogenesis and lipid deposition.ConclusionSIK1 plays a crucial role in the regulation of glucose and lipid metabolism in the livers of HFD/STZ-induced T2DM rats, where it suppresses hepatic gluconeogenesis and lipogenesis by regulating the SIK1/CRTC2 and SIK1/SREBP-1c signalling pathways. Strategies to activate SIK1 kinase in liver would likely have beneficial effects in patients with T2DM and nonalcoholic fatty liver disease (NAFLD).
Highlights
type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and insulin resistance (IR) and is the foremost type of diabetes around the world [1]
Salt-induced kinase 1 (SIK1) plays a crucial role in the regulation of glucose and lipid metabolism in the livers of high-fat food (HFD)/STZ-induced T2DM rats, where it suppresses hepatic gluconeogenesis and lipogenesis by regulating the SIK1/CREB-regulated transcription co-activator 2 (CRTC2) and SIK1/SREBP-1c signalling pathways
Seung-Hoi Koo et al [9] reported that knockdown of SIK1 in mice promoted both fasting hyperglycaemia and gluconeogenic gene expression, whereas mice treated with adenovirusexpressed SIK1 (Ad-SIK1) exhibited fasting hypoglycaemia and reduced gluconeogenic gene expression, and Ad-SIK1 was effective in reducing blood glucose levels in fasted db/db diabetic mice
Summary
T2DM is characterized by hyperglycemia and insulin resistance (IR) and is the foremost type of diabetes around the world [1]. Diabetes complications such as hyperlipidemia and NAFLD account for an increasing proportion of annual health care costs. A previous study suggested that skeletal muscle specific SIK1-KO mice, but not liver tissue SIK1-KO, enhanced insulin sensitivity after HFD feeding [10]. These observations demonstrate a key role of SIK1 on glucose metabolism in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
