Research Article: Adenovirus-mediated expression of SIK1 improves hepatic glucose and lipid metabolism in type 2 diabetes mellitus rats

Date Published: June 24, 2019

Publisher: Public Library of Science

Author(s): DaoFei Song, Lei Yin, Chang Wang, XiuYing Wen, Dong-Yan Jin.


In 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.

A 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.

In 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.

SIK1 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).

Partial Text

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. Tight glucose control has been associated with a reduced incidence of diabetes complications, underscoring efforts to characterize regulators that function importantly in the pathogenesis of T2DM [2].

Since the discovery of the SIK family, the roles of SIK isoforms (SIK1/2/3) in glucose and lipid metabolism have been extensively investigated [6–9, 13, 15, 18, 19]. However, the biological function of SIK1 remains poorly understood in HFD/STZ-induced T2DM rats. In this study, we found that the expression of hepatic SIK1 was markedly decreased in the HFD/STZ-induced T2DM rat model and that administration of Ad-SIK1 lowered fasting blood glucose and ameliorated fatty liver disease, suggesting that a reduction of SIK1 may contribute to the glucose and lipid metabolism disorder in diabetes. Additionally, metformin, a widely used hypoglycemic drug, which attenuated hyperglycaemia and NAFLD in HFD/STZ-induced diabetic rats [29], increased SIK1 expression levels in HepG2 cells cultured in high glucose conditions [19]. These findings indicate that SIK1 may be associated with the pathogenesis of T2DM and NAFLD.




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