We recently reported that cluster determinant 36 (CD36), a fatty acid transporter, plays a pivotal role in glucotoxicity-induced β-cell dysfunction. However, little is known about how glucotoxicity influences CD36 expression. Emerging evidence suggests that the small GTPase Rac1 is involved in the pathogenesis of beta cell dysfunction in type 2 diabetes (T2D). The primary objective of the current study was to determine the role of Rac1 in CD36 activation and its impact on β-cell dysfunction in diabetes mellitus. To address this question, we subjected INS-1 cells and human beta cells (1.1B4) to high glucose conditions (30 mM) in the presence or absence of Rac1 inhibition either by NSC23766 (Rac1 GTPase inhibitor) or small interfering RNA. High glucose exposure in INS-1 and human beta cells (1.1b4) resulted in the activation of Rac1 and induced cell apoptosis. Rac1 activation mediates NADPH oxidase (NOX) activation leading to elevated ROS production in both cells. Activation of the Rac1-NOX complex by high glucose levels enhanced CD36 expression in INS-1 and human 1.1b4 beta cell membrane fractions. The inhibition of Rac1 by NSC23766 inhibited NADPH oxidase activity and ROS generation induced by high glucose concentrations in INS-1 & human 1.1b4 beta cells. Inhibition of Rac1-NOX complex activation by NSC23766 significantly reduced CD36 expression in INS-1 and human 1.1b4 beta cell membrane fractions. In addition, Rac1 inhibition by NSC23766 significantly reduced high glucose-induced mitochondrial dysfunction. Furthermore, NADPH oxidase inhibition by VAS2870 also attenuated high glucose-induced ROS generation and cell apoptosis. These results suggest that Rac1-NADPH oxidase dependent CD36 expression contributes to high glucose-induced beta cell dysfunction and cell death.
Rac1- NADPH oxidase induces CD36 expression under high glucose. High glucose induced Rac1-NADPH oxidase complex induced CD36 trafficking to the plasma membrane. Increased plasma membrane expression of CD36 may increase influx of free fatty acids into the cell and increase the dysfunction of beta cells. High levels of ROS enhance the oxidative damage and exacerbate the beta cell apoptosis by mitochondrial dysfunction.
High glucose induce β-cell damage by Rac1 and NADPH oxidase activation.
High glucose induced Rac1-NADPH oxidase mediate CD36 expression and mitochondrial dysfunction.
Inhibition of Rac1 suppressed high glucose induced NADPH oxidase activity and downregulated CD36 expression.
Inhibition of Rac1 or NADPH oxidase prevent high glucose induced mitochondrial dysfunction and β-cell apoptosis.