Abstract
Chronic exposure to free fatty acids (FFAs) may induce β cell apoptosis in type 2 diabetes. However, the precise mechanism by which FFAs trigger β cell apoptosis is still unclear. Tribbles homolog 3 (TRB3) is a pseudokinase inhibiting Akt, a key mediator of insulin signaling, and contributes to insulin resistance in insulin target tissues. This paper outlined the role of TRB3 in FFAs-induced INS-1 β cell apoptosis. TRB3 was promptly induced in INS-1 cells after stimulation by FFAs, and this was accompanied by enhanced INS-1 cell apoptosis. The overexpression of TRB3 led to exacerbated apoptosis triggered by FFAs in INS-1-derived cell line and the subrenal capsular transplantation animal model. In contrast, cell apoptosis induced by FFAs was attenuated when TRB3 was knocked down. Moreover, we observed that activation and nuclear accumulation of protein kinase C (PKC) δ was enhanced by upregulation of TRB3. Preventing PKCδ nuclear translocation and PKCδ selective antagonist both significantly lessened the pro-apoptotic effect. These findings suggest that TRB3 was involved in lipoapoptosis of INS-1 β cell, and thus could be an attractive pharmacological target in the prevention and treatment of T2DM.
Highlights
Beta cell dysfunction is one of major characteristics in the pathogenesis of type 2 diabetes [1]
Numerous in vivo and in vitro studies have demonstrated the destructive effects of chronic exposure of free fatty acids (FFAs) on b cell survival T2DM is characterized by peripheral insulin resistance and pancreatic b cell dysfunction resulting in defective glucose-induced insulin secretion and b cell dysfunction and loss through apoptosis [3,4,26] which is thought to largely contribute to development and progression of T2DM
This study was designed to identify the mechanisms of lipotoxicity in diabetes and to test the hypothesis that Tribbles homolog 3 (TRB3) may play a critical role in apoptosis of b cells induced by FFAs
Summary
Beta cell dysfunction is one of major characteristics in the pathogenesis of type 2 diabetes [1]. Many studies have validated that FFAs induce b cell dysfunction and apoptosis [3,4]. The mechanisms underlying FFAs-induced b cell apoptosis and dysfunction are not well understood. The Tribbles family as an inhibitor of mitosis was first described in Drosophila, and has been shown to regulate cell morphogenesis, proliferation and migration [5,6,7]. A few studies have suggested a close association of TRB3 with pancreatic b cell apoptosis, the potential significance of the regulation of TRB3 function to FFAs-induced b cell apoptosis deserves further investigation. The present study was designed to identify the importance of TRB3 in lipotoxicity -induced b cell apoptosis and to investigate the relevant mechanisms underlying TRB3’s activity in b cells
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.
