Nrf2 in Type 2 diabetes and diabetic complications: Yin and Yang
Graphical abstract
Introduction
The prevalence of Type 2 diabetes (T2D) is increasing at an alarming rate and has become a public health problem on a global scale ∗1, 2. Two major pathophysiologic abnormalities, including insulin resistance and pancreatic β-cell dysfunction, underlie most cases of T2D 3, ∗4. Normal β-cells can compensate for insulin resistance by increasing insulin secretion and production and/or β-cell mass [5]. Insufficient compensation ultimately leads to the onset of glucose intolerance and T2D [6]. Diabetic complications can result from long-term diabetic conditions due to a defect in the balancing of metabolites such as carbohydrates and lipids, which eventually leads to problems in the microvascular and cardiovascular systems ∗7, 8, ∗∗9, ∗∗10. Although the precise mechanisms for various diabetic complications are still unclear, oxidative stress is undisputedly identified as a major pathogenic factor. In terms of pathogenesis, T2D and diabetic complications are distinct disorders. However, amidst the various mechanisms proposed for insulin resistance and β-cell dysfunction and their roles in the progression to overt diabetes, oxidative stress has also been condemned as one of the prime culprits 6, 11, 12, ∗13, ∗14, ∗15, 16.
In contrast to the prevailing view that reactive oxygen species (ROS) are an evil causing a variety of chronic disorders, growing evidence indicates that ROS can function as a secondary messenger, serving an intracellular signaling role [17]. Accordingly, Watson carefully reviewed the emerging data on the hindrance of antioxidant supplements to the health-promoting effects of physical exercise and hypothesized that T2D is a redox disease that may be accelerated or caused by insufficient supplies of oxidative potential or key ROS [18]. In keeping with the idea, Naviaux has also proposed that ROS and oxidative changes in chronic diseases, including T2D, are the biochemical symptoms of the disease rather than the cause [19]. Thus, ROS may play distinct roles in the development of T2D and diabetic complications. Considering that endogenous redox homeostasis, which is coordinately maintained by metabolic conditions, is essential for normal cell growth and function, the precise roles of ROS and antioxidants in the development of T2D and its complications need to be carefully revisited.
Nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2), a basic leucine zipper protein, is expressed ubiquitously and serves as a master regulator in both constitutive and inducible expression of antioxidant response element (ARE)-dependent genes, which include many antioxidant and phase 2 detoxification enzymes [20]. Therefore, activation of Nrf2 is generally believed to be an efficient approach to enhance antioxidant defense and prevent oxidative stress [21]. In contrast, deficiency or inhibition of Nrf2 may result in sensitization to oxidative damage leading to a variety of disorders. In consistence with the scientific literature that is heaped with extensive experimental evidence suggesting apparent benefits of antioxidant therapy and the conventional wisdom that antioxidants may do everything from preventing the development of T2D to treating its complications, Nrf2 is logically believed as a therapeutic target. Against this backdrop, it is surprising that multiple randomized clinical trials failed to show benefit effects of antioxidants, and some even observed increased risk of T2D ∗14, 22, 23, 24, ∗25.
In this mini review, we provide an overview on the distinct roles of ROS, antioxidant and Nrf2 in the development of insulin resistance, β-cell dysfunction, and diabetic complications. While highlighting the potential beneficial effects of antioxidants and Nrf2 inducers in treating diabetic complications, we also assert that persistent elevation of ROS-scavenging activity by supplying either exogenous antioxidants or Nrf2 inducers may aggravate the pathogenesis of β-cell dysfunction and/or insulin resistance in the early stage of T2D. We try to give a mechanistic explanation on the current dilemma of why antioxidant therapy has not worked as expected, and suggest alternative strategy to prevent T2D and relieve associated complications.
Section snippets
ROS, antioxidant and Nrf2 in the development of T2D
Although persistent elevation of ROS, also generally defined as oxidative stress, is deleterious to biological systems [26], transient elevation of ROS in response to extrinsic and intrinsic signals is essential for physiological regulation in cells 17, ∗27. ROS may function as important intracellular signaling molecules involved in cellular responses to a variety of physiological stimuli, including insulin signaling in the fat, liver and skeletal muscle, and glucose sensing in the hypothalamus
ROS, antioxidant and Nrf2 in diabetic complications
Current understanding on the mechanisms of diabetic complications has been systematically reviewed [10] and highlighted [9] previously. It is evident that hyperglycemia is a key initiating factor in the pathogenesis of diabetic complications [9]. In addition, insulin resistance and subsequent hyperinsulinemia and persistent insulin signaling in relevant tissues also contribute to the development [10]. Clearly, effective management of metabolic perturbations, such as glycemic control, are
Future perspectives
As a systemic disorder that is manifested in many different organs, T2D is a too broad term to define the metabolic syndrome. Considering that ROS, antioxidant and Nrf2 play paradoxical Yin- and Yang-roles in different stage of T2D and diabetic complications, we attempted to classify T2D, as shown in Figure 2, into three stages based on the status of redox homeostasis and ROS signaling. Such a classification may provide a general advice on the applicability of various antioxidant therapies to
Acknowledgements
This research was supported in part by Chinese Nature Science Foundation 81573106 (J.P.), 81402635 (J.F.), 81402661 (Y.H.) and the Startup Funding of China Medical University (J.P.) and Liaoning Pandeng Scholar (J.P.). The content is solely the responsibility of the authors. All authors have agreed to its content.
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