title: Rac1-NADPH oxidase signaling promotes CD36 activation under glucotoxic conditions in pancreatic beta cells.
abstract: 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 (30mM) 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.
authors.affiliation: Institute of Medical Science, Daegu, Republic of Korea.
authors.forename: Suma
authors.initials: S
authors.lastname: Elumalai
authors.affiliation: Institute of Medical Science, Daegu, Republic of Korea.
authors.forename: Udayakumar
authors.initials: U
authors.lastname: Karunakaran
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: In Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine,Yeungnam University College of Medicine, Daegu, Republic of Korea.
authors.forename: Jun Sung
authors.initials: JS
authors.lastname: Moon
authors.affiliation: Institute of Medical Science, Daegu, Republic of Korea; Department of Internal Medicine,Yeungnam University College of Medicine, Daegu, Republic of Korea. Electronic address: kcwon@med.yu.ac.kr.
authors.forename: Kyu Chang
authors.initials: KC
authors.lastname: Won
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000634:Aminoquinolines; D018955:CD36 Antigens; D008562:Membrane Glycoproteins; C487513:NSC 23766; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D005947:Glucose
keywords: Beta-cell dysfunction; CD36; NADPH oxidase; Oxidative stress; Rac1