Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway
Introduction
Selenium (Se), an essential trace element in human nutrition, is closely associated with human health through incorporation into selenoproteins which possess a wide range of important biological functions. In mammals, Se deficiency may lead to various diseases including cardiomyopathy of Keshan disease, pancreas atrophy, liver necrosis, reproductive disorders and growth retardation (Ge and Yang, 1993, Moir and Masters, 1979, Reilly, 1996). In contrast, a considerable number of studies have suggested beneficial effects of selenium supplementation on some diseases, such as cancer, and cardiovascular and neurodegenerative diseases related to chronic oxidative stress.
The main source of Se in the human diet is organic Se in the form of selenomethionine, selenocysteine and derivatives thereof, mainly as integral constituents of animal and plant proteins. Although inorganic Se (selenite and selenate) does not represent main natural food constituents, selenite has been found in a variety of foods in detectable amounts, such as wheat grain, rice, garlic (Allium sativum), Chives (Allium schoenoprasum) leaves, cooked cod, several species of marine and freshwater fish, several marine animal organisms (mollusks, crustaceans and pods), as well as Se-yeast (Rayman et al., 2008). Furthermore, selenite has also been widely used as components of certain food stuffs or dietary supplements, during individually conducted supplementation efforts or within experimental or clinical trials (Burk et al., 2006, Finley, 1999, Persson-Moschos et al., 1998, Van Dael et al., 2001, Xia et al., 2005). In this context, selenite is commonly used in multivitamin/mineral preparations, protein mixes, infant formulas, and weight-loss products (Schrauzer, 2001). Also, selenite is usually the preferred choice when fast supplementation effects are desired as, e.g., in the case of adjuvant treatment of Se-deficient sepsis patients in intensive care units (Angstwurm et al., 2007). Strikingly, several large-scale prospective studies in China in 1960–70 showed that oral administration of sodium selenite tablets or sodium selenite fortified salt effectively prevented Keshan disease, and mitigated the clinical manifestations in patients with the disease (Chen, 2012, Keshan Disease Research Group, 1979b). In response to these studies, the Ministry of Health of China implemented nutritional policies promoting oral selenite supplementation, which virtually eliminated Keshan disease in areas where it was endemic (Chen, 2012, Keshan Disease Research Group, 1979a). At present, sodium selenite has also been approved by China Food and Drug Administration (CFDA) as one of the available Se compounds used for nutritional selenium supplementation. According to CFDA guidelines, selenium can be supplemented in Se-deficient individuals with amounts of 15–100 μg/day for nutritional supplementation.
Diabetes mellitus is one of the most costly chronic diseases with an estimated worldwide prevalence of 387 million in 2014, which is expected to rise to 592 million by 2035 according to the International Diabetes Federation (Donath, 2014). Depending on the cause of the disease, four general forms of diabetes are distinguished: type 1 diabetes, type 2 diabetes (T2D), gestational diabetes and maturity onset diabetes of the young (MODY). Type 2 diabetes, accounting for 90% of diabetes, is characterized by peripheral insulin resistance with an insulin-secretory defect that varies in severity. It has been well recognized that oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes (Evans et al., 2002, Houstis et al., 2006). Accordingly, in recent years a large number of studies have been carried out focusing on the preventive and healing role of antioxidants, including selenium, in diabetes and in secondary diabetic complications. In earlier studies, inorganic Se compounds including selenate and selenite have even been considered as potential therapeutic agents for diabetes, since they have been proved to possess insulin-mimetic properties in isolated adipocytes (Ezaki, 1990) and in streptozotocin (STZ)-induced type 1 diabetic rodents (Becker et al., 1996, McNeill et al., 1991, Zeng et al., 2009), and exert antioxidant activities in diabetic animal models (Ayaz et al., 2006, Mukherjee et al., 1998, Sheng et al., 2005). However, the doses of selenate and selenite responsible for the potential hypoglycemic effects are generally very high, and thus potential toxicity associated with such doses has compromised their therapeutic value (Mueller et al., 2009, Zhou et al., 2013).
In recent years, emerging evidence from human trial and animal studies suggests a positive correlation between high Se intake or plasma Se levels and diabetes (Rayman and Stranges, 2013, Zhou et al., 2013, Steinbrenner, 2013). It is noteworthy that elevating dietary Se intake (0.4 to 3.0 mg/kg diet) above the nutrient requirement led to insulin resistance and/or T2D-like phenotypes in mice, rats, and pigs, which had been initially normal glucose-tolerant before high-Se intake (Labunskyy et al., 2011, Liu et al., 2012, Pinto et al., 2012, Zeng et al., 2012). On the other hand, at present it remains largely unknown how Se supplementation might influence glucose metabolism in type 2 diabetes. In this regard, Mueller et al. (2003) reported that selenite, but not selenate, aggravated the diabetic status in db/db mice, a genetic mouse model of T2D. More recently, Faghihi et al. (2014) for the first time reported that Se supplementation (200 μg Se/d as sodium selenite administered orally for 3 months) in type 2 diabetics was associated with adverse effects on blood glucose homeostasis when compared to the placebo group. Collectively, these findings suggest a potential pro-diabetic effect of selenite in animal models or patients of T2D. To date, however, the molecular mechanisms underlying this pro-diabetic effect of selenite remain elusive. In this study, we investigated the effects and the underlying mechanisms of selenite treatment on glucose metabolism and insulin sensitivity in a nongenetic mouse model of T2D.
Section snippets
Reagents and antibodies
Bovine serum albumin (BSA), sodium selenite and STZ were purchased from Sigma Co. Protease inhibitor cocktail was obtained from Calbiochem. Anti-insulin receptor β subunit (IRβ) antibody, anti-insulin receptor substrate-1 (IRS-1) antibody, anti-phospho-IRβ (Tyr1146) antibody, anti-phospho-IRS-1 (Ser307) antibody, anti-Akt antibody, anti-phospho-Akt (Ser473) antibody, anti-FoxO1 antibody, anti-phospho-FoxO1 (Thr24) antibody, anti-c-Jun N-terminal kinase (JNK) antibody, anti-phospho-JNK
Selenite elevates FPI levels and insulin resistance index in a nongenetic mouse model of T2D
To study the metabolic effects of selenite treatment on type 2 diabetic mice, we first generated a nongenetic mouse model of T2D. The mice were fed a 60% HFD for 6 weeks, and β cell function was impaired by administration of a moderate dose of STZ. This model closely simulates the metabolic abnormalities of the human T2D and is also cost-effective when compared with the genetic T2D animal models currently available. This approach has been successful in developing a nongenetic mouse model of T2D
Discussion
To date, available data regarding the role of Se in diabetes are inconsistent, and in particular, the relationship between selenium and type 2 diabetes is complex. Among the factors influencing the effect of Se supplementation on glucose metabolism in T2D, the chemical form and doses of Se compounds are of particular importance. In this regard, while selenate has been shown to have antidiabetic and insulin-mimetic effects in T2D animal models (Mueller and Pallauf, 2006, Mueller et al., 2003,
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Transparency document
Acknowledgments
The research was supported by grants from the National Natural Science Foundation of China (Nos. 31270870 and 21001045). We thank the staff from Analytical and Testing Center of Huazhong University of Science and Technology for their assistances in real-time PCR experiments.
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