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      Rac1-NADPH oxidase signaling promotes CD36 activation under glucotoxic conditions in pancreatic beta cells

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          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 (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.

          Graphcal abstract

          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.

          Highlights

          • 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.

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          Most cited references30

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          Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity.

          It is now widely accepted, given the current weight of experimental evidence, that reactive oxygen species (ROS) contribute to cell and tissue dysfunction and damage caused by glucolipotoxicity in diabetes. The source of ROS in the insulin secreting pancreatic beta-cells and in the cells which are targets for insulin action has been considered to be the mitochondrial electron transport chain. While this source is undoubtably important, we provide additional information and evidence for NADPH oxidase-dependent generation of ROS both in pancreatic beta-cells and in insulin sensitive cells. While mitochondrial ROS generation may be important for regulation of mitochondrial uncoupling protein (UCP) activity and thus disruption of cellular energy metabolism, the NADPH oxidase associated ROS may alter parameters of signal transduction, insulin secretion, insulin action and cell proliferation or cell death. Thus NADPH oxidase may be a useful target for intervention strategies based on reversing the negative impact of glucolipotoxicity in diabetes.
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            Regulation of NADPH oxidases: the role of Rac proteins.

            The role for reactive oxygen species (ROS) in cellular (patho)physiology, in particular in signal transduction, is increasingly recognized. The family of NADPH oxidases (NOXes) plays an important role in the production of ROS in response to receptor agonists such as growth factors or inflammatory cytokines that signal through the Rho-like small GTPases Rac1 or Rac2. The phagocyte oxidase (gp91phox/NOX2) is the best characterized family member, and its mode of activation is relatively well understood. Recent work has uncovered novel and increasingly complex modes of control of the NOX2-related proteins. Some of these, including NOX2, have been implicated in various aspects of (cardio)vascular disease, including vascular smooth muscle and endothelial cell hypertrophy and proliferation, inflammation, and atherosclerosis. This review focuses on the role of the Rac1 and Rac2 GTPases in the activation of the various NOX family members.
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              Pathogenesis of type 2 diabetes mellitus.

              The pathological sequence for type 2 diabetes is complex and entails many different elements that act in concert to cause that disease. This review proposes a sequence of events and how they interact by a careful analysis of the human and animal model literature. A genetic predisposition must exist, although to date very little is known about specific genetic defects in this disease. Whether the diabetes phenotype will occur depends on many environmental factors that share an ability to stress the glucose homeostasis system, with the current explosion of obesity and sedentary lifestyle being a major cause of the worldwide diabetes epidemic. We also propose that a lowered beta-cell mass either through genetic and/or beta-cell cytotoxic factors predisposes for glucose intolerance. As the blood glucose level rises even a small amount above normal, then acquired defects in the glucose homeostasis system occur--initially to impair the beta cell's glucose responsiveness to meals by impairing the first phase insulin response--and cause the blood glucose level to rise into the range of impaired glucose tolerance (IGT). This rise in blood glucose, now perhaps in concert with the excess fatty acids that are a typical feature of obesity and insulin resistance, cause additional deterioration in beta-cell function along with further insulin resistance, and the blood glucose levels rise to full-blown diabetes. This sequence also provides insight into how to better prevent or treat type 2 diabetes, by studying the molecular basis for the early defects, and developing targeted therapies against them.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                23 November 2016
                April 2017
                23 November 2016
                : 11
                : 126-134
                Affiliations
                [a ]Institute of Medical Science, Daegu, Republic of Korea
                [b ]Department of Internal Medicine,Yeungnam University College of Medicine, Daegu, Republic of Korea
                [c ]Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea
                Author notes
                [* ]Corresponding author.
                [** ]Corresponding author at: Department of Internal Medicine, Yeungnma University College of Medicine, 170 Hyunchung-ro, Namgu, Daegu 705-703, Republic of Korea. kcwon@ 123456med.yu.ac.kr
                [1]

                Both authors equally contributed as first authors.

                Article
                S2213-2317(16)30172-0
                10.1016/j.redox.2016.11.009
                5133656
                27912197
                c0311c0f-e012-4f00-bcf2-4e5504416607
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 10 September 2016
                : 9 November 2016
                : 10 November 2016
                Categories
                Research Paper

                rac1,nadph oxidase,beta-cell dysfunction,cd36,oxidative stress

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