Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

Abstract

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)...

Differential proteomic analysis of white adipose tissues from T2D KKAy mice by LC‐ESI‐QTOF

“…Evidence has shown opposite changes of two peroxiredoxin family members in islet cells of insulin resistant mice. Where PRDX3 was reduced, which is consistent with the protective role of this protein, but PRDX6 was increased . Here, it is possible that PRDX1 was up‐regulated by other stimulatory molecules to maintain a redox state of mitochondrial and protect the development of overt diabetes .…”

Compensatory Islet Response to Insulin Resistance Revealed by Quantitative Proteomics

“…However, islet cells showed increased PRDX6, another antioxidant member of the Peroxiredoxin family known (as for PRDX3) to be down-regulated by inflammation 38b,39 . It is possible that PRDX6 is upregulated by other stimulatory molecules to restore a mitochondrial redox state and protect the mice from developing overt diabetes 40 .…”

Delivery of a protein transduction domain-mediated Prdx6 protein ameliorates oxidative stress-induced injury in human and mouse neuronal cells

“…Importantly, Prdx6 expression, localization, and protective function have also been shown in mitochondria (20), endoplasmic reticulum (ER) and lysosomal organelles (58,59), and plasma membrane (1). Loss of Prdx6 causes etiopathogenesis in many type of tissues and organisms, leading to such conditions as diabetes and neuronal cell degeneration, while introduction of Prdx6 reverses or delays the process (20,43,47,57). In the current study, we demonstrated that human and mouse neuronal cells, HCN-2 and HT22, are susceptible to oxidative stress from paraquat, glutamate, or H 2 O 2 .…”