Abstract
RNA-binding proteins (RBPs) lie at the center of posttranscriptional regulation and the dysregulation of RBPs contributes to diabetes. Therefore, the modulation of RBPs is anticipated to become a potential therapeutic approach to diabetes. CYC27 is a synthetic derivative of marine bromophenol BDB, which is isolated from red alga Rhodomela confervoides. In this study, we found that CYC27 significantly lowered the blood glucose levels of diabetic BKS db mice. Moreover, CYC27 effectively ameliorated dyslipidemia in BKS db mice by reducing their total serum cholesterol (TC) and triglyceride (TG) levels. Furthermore, CYC27 was an insulin-sensitizing agent with increased insulin-stimulated phosphorylation of insulin receptors and relevant downstream factors. Finally, to systemically study the mechanisms of CYC27, label-free quantitative phosphoproteomic analysis was performed to investigate global changes in phosphorylation. Enriched GO annotation showed that most regulated phosphoproteins were related to RNA splicing and RNA processing. Enriched KEGG analysis showed that a spliceosome-associated pathway was the predominant pathway after CYC27 treatment. Protein-protein interaction (PPI) analysis showed that CYC27 modulated the process of mRNA splicing via phosphorylation of the relevant RBPs, including upregulated Cstf3 and Srrt. Our results suggested that CYC27 treatment exerted promising anti-diabetic effects by sensitizing the insulin signaling pathways and modulating RNA splicing-associated RBPs.
Highlights
IntroductionThe IDF Diabetes Atlas, eighth edition, shows that, globally, adult diabetes has increased from 151 million cases in 2000 to 425 million in 2017; this is an increase of nearly two times, meaning that one in every 11 adults has diabetes
Type 2 diabetes mellitus (T2DM), which accounts for 90–95% of all diabetes cases, is characterized by insulin resistance and/or impaired insulin secretion, resulting in hyperglycemia [1]
A seven week administration with CYC27 and Rosiglitazone showed a significant reduction in blood glucose levels compared with the levels of the vehicle-treated showed a significant reduction in blood glucose levels compared with the levels of the vehicle-treated diabetic mice (p < 0.01, Figure 2A,B)
Summary
The IDF Diabetes Atlas, eighth edition, shows that, globally, adult diabetes has increased from 151 million cases in 2000 to 425 million in 2017; this is an increase of nearly two times, meaning that one in every 11 adults has diabetes. Type 2 diabetes mellitus (T2DM), which accounts for 90–95% of all diabetes cases, is characterized by insulin resistance and/or impaired insulin secretion, resulting in hyperglycemia [1]. The FDA has approved 12 classes of drugs to control the blood glucose levels of T2DM patients, including sulfonylureas, biguanide and α-glucosidase inhibitors [2]. These agents each have their limitations and defects
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