Oxidative stress and diabetes: What can we learn about insulin resistance from antioxidant mutant mouse models?

Styskal, JennaLynn; Remmen, Holly Van; Richardson, Arlan; Salmon, Adam B.

doi:10.1016/j.freeradbiomed.2011.10.441

Cited by 258 publications

(223 citation statements)

References 189 publications

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“…Oxidative stress is considered one of the main mechanisms in the pathogenesis of diabetes and IR (1). Among the antioxidant enzymes that are able to regulate ROSmediated injuries, PRDX6 belongs to a relative new family of proteins that is widely distributed in the tissues of the body (5).…”

Section: Discussionmentioning

confidence: 99%

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Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

Pacifici

Arriga

Sorice³

et al. 2014

Diabetes

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Enhanced oxidative stress contributes to the pathogenesis of diabetes and its complications. Peroxiredoxin 6 (PRDX6) is a key regulator of cellular redox balance, with the peculiar ability to neutralize peroxides, peroxynitrite, and phospholipid hydroperoxides. In the current study, we aimed to define the role of PRDX6 in the pathophysiology of type 2 diabetes (T2D) using PRDX6 knockout (2/2) mice. Glucose and insulin responses were evaluated respectively by intraperitoneal glucose and insulin tolerance tests. Peripheral insulin sensitivity was analyzed by euglycemic-hyperinsulinemic clamp, and molecular tools were used to investigate insulin signaling. Moreover, inflammatory and lipid parameters were evaluated. We demonstrated that PRDX6 2/2 mice developed a phenotype similar to early-stage T2D caused by both reduced glucose-dependent insulin secretion and increased insulin resistance. Impaired insulin signaling was present in PRDX6 2/2 mice, leading to reduction of muscle glucose uptake. Morphological and ultrastructural changes were observed in islets of Langerhans and livers of mutant animals, as well as altered plasma lipid profiles and inflammatory parameters. In conclusion, we demonstrated that PRDX6 is a key mediator of overt hyperglycemia in T2D glucose metabolism, opening new perspectives for targeted therapeutic strategies in diabetes care.A large body of evidence supports a pivotal role for oxidative stress in the etiopathogenesis of insulin resistance (IR) and diabetes (1). Oxidative stress is characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense systems. Among all body tissues, pancreatic b-cells are very sensitive to oxidative stress because of their low expression of antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (2). Moreover, hyperglycemia by itself induces IR, increasing oxidative stress injuries, which lead to overt type 2 diabetes (T2D) (3). Interestingly, a relatively new family of antioxidant proteins, the peroxiredoxins (PRDXs), is more highly expressed in pancreatic b-cells (4). Among the six members of this non-seleno peroxidase family, PRDX6 is present in the cytoplasm and is unique because it has peroxidase and also phospholipase A 2 activity (5). Several findings demonstrate the importance of PRDX6 in maintaining redox homeostasis, as follows: lack of PRDX6, in fact, increases the susceptibility to oxidative stress in different tissues (6,7). Nevertheless, data on the relationship between PRDX6 and the pathogenesis of IR and T2D are not available (8). Therefore, we hypothesized that, in terms of physiological status, PRDX6 may play a role in the etiology of IR and diabetes conditions through tissue redox levels. In the current study, we tested our hypothesis in a model of PRDX6 knockout mice (PRDX6 2/2). RESEARCH DESIGN AND METHODS Animal ModelsC57BL/6J wild-type (WT) mice weighing 18-20 g were obtained from The Jackson Laboratory (Bar Harbor, ME), while PRDX6 2/2 mice of mixed background (C57BL6/129SvJ)...

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Section: Discussionmentioning

confidence: 99%

“…A large body of evidence supports a pivotal role for oxidative stress in the etiopathogenesis of insulin resistance (IR) and diabetes (1). Oxidative stress is characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense systems.…”

mentioning

confidence: 99%

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

Pacifici

Arriga

Sorice³

et al. 2014

Diabetes

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“…Chronic hyperglycemia/hyperlipidemia may be the driving force that leads to increased ROS production, and ROS are known to damage components of the cellular machinery, including DNA, proteins and lipids. Besides damaging islet cells, it is likely that oxidative stress is contributing to the development of peripheral insulin resistance, and to many of the vascular complications occurring in the late stages of the disease [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice

Anvari

Wikström

Walum

et al. 2015

Free Radical Research

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The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice.. (11) http://dx.doi.org/10. 3109/10715762.2015.1067697 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. EA and PW performed the experiments. PW, EW and NW designed the experiments, analyzed the results and wrote the manuscript. Free radical research, 49 2 ABSTRACTIn Type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) over-activity. Five different NOX enzymes (NOX1-5) have been characterized, among which NOX1 and NOX2 have been proposed to negatively affect beta-cells, but the putative role of NOX4 in type 2 diabetes-associated beta-cell dysfunction and glucose intolerance is largely unknown. Therefore, we presently investigated the importance of NOX4 for high-fat diet (HFD)-induced glucose intolerance using male C57BL/6 mice using the new NOX4 inhibitor GLX351322, which has relative NOX4 selectivity over NOX2. In HFD-treated male C57BL/6 mice a two-week treatment with GLX351322 counteracted non-fasting hyperglycemia and impaired glucose tolerance. This effect occurred without any change in peripheral insulin sensitivity. To ascertain that NOX4 also plays a role for the function of human beta-cells, we observed that glucose-and sodium palmitate-induced insulin release from human islets in vitro was increased in response to NOX4 inhibitors. In longterm experiments (1-3 days), high glucose-induced human islet cell ROS production and death were prevented by GLX351322. We propose that whilst short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4-activity, e.g. during conditions of high-fat feeding, promotes ROSmediated beta-cell dysfunction. Thus, selective NOX-inhibition may be a therapeutic strategy in Type 2 diabetes.3

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“…1 Diabetes mellitus is describe as metabolic syndrome that is also associated with overproduction of reactive oxygen species (ROS). 27 Free radical formation has been reported to be a direct consequence of hyperglycemia. 28 Expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and catalase, and antioxidant capacity of the liver, kidney, skeletal muscle and adipose tissue is known to be in the lowest level in pancreatic islet cells compared to other tissues such as the liver, kidney, skeletal muscle and adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Bryonia multiflora Extract on Pancreatic Beta Cells, Liver and Kidney of Streptozotocin-Induced Diabetic Rats: Histopathological and Immunohistochemical Investigations

Uyar¹,

Yaman²,

Keleş³

et al. 2017

IJPER

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Objective: In this study, the ameliorative potential and antioxidant capacity of treated with different doses of Bryonia multiflora extract (BE) was investigated using histopathological and immunohistochemical changes in pancreatic beta cells, liver and kidney tissues of streptozotocin (STZ)-induced diabetic rats. Material and Methods: A total of forty-two healthy adult Wistar albino male rats were divided randomly into six groups as Control (C); Diabetes mellitus (DM); DM+Akarboz 20 mg/kg; DM+100 mg/kg BE extract (BE1); DM+200 mg/kg BE extract (BE2); DM+400 mg/kg BE extract (BE3). Experimental diabetes was established by a single-dose [45 mg/kg, intra-peritoneal (i.p)] STZ injection. Essential dosages of BE extracts and Akarboz were applied with gastric gavage for 21 day. Blood glucose levels were recorded throughout the all experiment period. Results: Histopathological studies showed that hepatorenal and pancreatic protection by depending on the dose level of BE extracts was further supported by the almost normal histology in DM+ BE extract-treated group as compared to the degenerative changes such as disorder of architectural structure, inflammatory cell infiltration, hydropic degeneration and necrosis in pancreas, liver and kidney tissues of STZ-treated rats. Immunohistochemical investigation revealed that STZ-induced degenerative changes in beta-cells in the pancreas of the diabetic rats has reduced insulin immunoreactivity. On the other hand, insulin immunoreactivity in the β cells of pancreas of BE -treated diabetic rats has significantly increased. Additionally, Glutathione peroxidase 1 (GPx1) immunoreactivity was lower in the tissues of diabetic rats (DM group) compared to the other groups. Conclusion: In conclusion, BE extract has a protective effect on tissue damage probably due to its antioxidant activity and possess the ability to regenerate β-cell in STZ-induced diabetic rats.

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Oxidative stress and diabetes: What can we learn about insulin resistance from antioxidant mutant mouse models?

Cited by 258 publications

References 189 publications

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice

Protective Effects of Bryonia multiflora Extract on Pancreatic Beta Cells, Liver and Kidney of Streptozotocin-Induced Diabetic Rats: Histopathological and Immunohistochemical Investigations

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