Abstract
This study aimed to identify circular RNAs differentially expressed in the islets of type 2 diabetes (T2DM) models and clarify their roles in the control of β-cell functions. Circular RNAs dysregulated in the islets of diabetic db/db mice were identified by high-throughput RNA sequencing. Then, the expression level of the selected circular RNA circ-Tulp4 was confirmed by real-time PCR in the islets of diabetic models and Min6 cells. MTS, EdU, western blot, flow cytometric analysis, and luciferase assay were performed to investigate the impact of circ-Tulp4 on β-cell functions. This study identified thousands of circular RNAs in mouse pancreatic islets. The circ-Tulp4 level significantly decreased in the diabetic models and altered in the Min6 cells under lipotoxic condition. The modulation of circ-Tulp4 level in Min6 cells regulated cell proliferation. Furthermore, an interaction was demonstrated between circ-Tulp4 and miR-7222-3p, which suppressed the expression of cholesterol esterification-related gene, sterol O-acyltransferase 1 (SOAT1). The accumulation of soat1 activated cyclin D1 expression, thus promoting cell cycle progression. These findings showed that circ-Tulp4 regulated β-cell proliferation via miR-7222-3p/soat1/cyclin D1 signaling. Our research suggested that circ-Tulp4 might be a potential therapeutic intervention for T2DM. Besides, soat1 might be important for β-cell adaptation to lipotoxicity.
Highlights
Pancreatic β cells are specialized insulin-secreting cells responsible for the control of blood glucose levels (Ferrannini & Mari 2004). β-Cell mass reduction and/or dysfunction can lead to hyperglycemia and the development of diabetes (Heit et al 2006)
This study proved that circ-Tulp4 promoted β-cell function by sponging miR-7222-3p and regulating the expression of cholesterol esterificationrelated gene, sterol O-acyltransferase 1 (SOAT1) and cyclin D1 signaling
The chromosomal location and the fold changes of these circRNAs were shown in Supplementary Table 2. The expression of these circRNAs in primary islets were validated using specific divergent primers and Sanger sequencing. These results suggested that circRNAs were abundantly expressed in pancreatic islets, and various circRNA levels were dysregulated in diabetic mice models
Summary
Pancreatic β cells are specialized insulin-secreting cells responsible for the control of blood glucose levels (Ferrannini & Mari 2004). β-Cell mass reduction and/or dysfunction can lead to hyperglycemia and the development of diabetes (Heit et al 2006). Pancreatic β cells are specialized insulin-secreting cells responsible for the control of blood glucose levels (Ferrannini & Mari 2004). Β-Cell mass reduction and/or dysfunction can lead to hyperglycemia and the development of diabetes (Heit et al 2006). Type 2 diabetes (T2DM) is characterized by insufficient β-cell function under obesity-induced insulin resistance (Kahn et al 2006). Β cells accelerate their proliferation rates to compensate for the β-cell loss caused by apoptosis Prolonged exposure to high concentrations of glucose and free fatty acids increase β-cell apoptosis and inhibit proliferation, eventually reducing β-cell mass and inducing T2DM manifestation (Busch et al 2005, Prentki & Nolan 2006, Schofield & Sutherland 2012).
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