Abstract
Elevated extracellular free fatty acids (FFAs) can induce pancreatic beta cell apoptosis, thereby contributing to the pathogenesis of type 2 diabetes mellitus (T2D). Mitochondrial dysfunction has been implicated in FFA-induced beta cell apoptosis. However, molecular mechanisms linking mitochondrial dysfunction and FFA-induced beta cell apoptosis are not clear. Dynamin-related protein 1 (DRP-1) is a mitochondrial fission modulator. In this study, we investigated its role in FFA-induced INS-1 beta cell apoptosis. DRP-1 protein was promptly induced in INS-1 cells and rat islets after stimulation by FFAs, and this DRP-1 upregulation was accompanied by increased INS-1 cell apoptosis. Induction of DRP-1 expression significantly promoted FFA-induced apoptosis in DRP-1 WT (DRP-1 wild type) inducible INS-1-derived cell line, but not in DRP-1K38A (a dominant negative mutant of DRP-1) inducible INS-1-derived cell line. To validate these in vitro results, we transplanted DRP-1 WT or DRP-1 K38A cells into renal capsules of streptozotocin (STZ)-treated diabetic mice to study the apoptosis in xenografts. Consistent with the in vitro results, the over-expression of DRP-1 led to aggravated INS-1-derived cell apoptosis triggered by FFAs. In contrast, dominant-negative suppression of DRP-1 function as represented by DRP-1 K38A significantly prevented FFA-induced apoptosis in xenografts. It was further demonstrated that mitochondrial membrane potential decreased, while cytochrome c release, caspase-3 activation, and generation of reactive oxygen species (ROS) were enhanced by the induction of DRP-1WT, but prevented by DRP-1 K38A in INS-1-derived cells under FFA stimulation. These results indicated that DRP-1 mediates FFA-induced INS-1-derived cell apoptosis, suggesting that suppression of DRP-1 is a potentially useful therapeutic strategy for protecting against beta cell loss that leads to type 2 diabetes.
Highlights
Type 2 diabetes (T2D) is associated with dyslipidemia, hyperglycemia, insulin resistance, and defects in insulin secretion from pancreatic beta cells [1]
We initially examined the effects of saturated free fatty acids (FFAs) palmitate on the apoptosis in the rat pancreatic beta cell line, INS-1
dynamin-related protein 1 (DRP-1) was upregulated in beta cells upon stimulation by FFAs, and such an upregulation correlated with aggravated cell apoptosis
Summary
Type 2 diabetes (T2D) is associated with dyslipidemia, hyperglycemia, insulin resistance, and defects in insulin secretion from pancreatic beta cells [1]. It is becoming clear that increased beta cell apoptosis is associated with diabetes in humans and animal models [2,3,4,5]. Mitochondrial dysfunction has been implicated in FFA-induced beta cell apoptosis. Molecular mechanisms linking mitochondrial dysfunction and FFA-induced beta cell apoptosis are not clear [12,13,14]. Our previous studies found that hyperglycemia increased the expression of DRP-1 and yielded DRP-1-induced mitochondrial fission to cause mitochondrial fragmentation and apoptosis in INS-1-derived cells, while DRP1 dominant-negative mutant impeded fission and apoptosis [17]. To our knowledge, the effects of DRP-1 on FFA-induced beta cell apoptosis have not been explored so far
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.
