| Antioxidant micronutrients (AM) consist of some micronutrients, vitamins and other compounds, such as selenium (Se), vanadium (V), chromium (Cr), vitamin E (VE), vitamin C (VC), lipoic acid and niacinamide, which function as scavengers of free radicals and inhibitors of oxidative stress. AM maintain the dynamic balance between production and elimination of free radicals through different mechanisms. The characters of trace and high efficiency make them become the necessary micronutrients that keep some biological functions. Type 1 diabtetes was known to result from an immunological destruction of the insulin-producing islet βcells. An interplay between genetic susceptibility (polygenic) and a triggering enviromental agent was thought to provide the fundamental elements for disease formation. The natural weaks exist in the antioxidant defences of pancreas: extreme low content of key enzymes in endogenous antioxidant defences but prosperous endoplasmic reticulum in pancreatic islet βcells, which becomes the main target that free radicals attack. Numerous studies suggest that damage from free radicals participate in the destroy of pancratic islet βcells and many factors involved in the pathogenesis of diabetes mellitus can promote the production of free radicals. ROS can induce lipid peroxidation with their strong oxidative ability. Through reacting with lipid, protein and nucleic acid, oxygen free radicals can damage the integrity of cell membrane, degenerate proteins, inactivate enzymes, damage DNA and destroy the stability of inner environment. Some achievements of studies on effects of AM on treatment of diabetes have been obtained, hereto the main machanisms include: (1) Display the insulin-like function: including Se, V and Cr. Se participates in the tyrosine phosphorylation of two proteins involved in the signal conduction of insulin. V could increase mRNA expression of glucose transpoter 4 (GLUT4) in the tissues that are sensitive to insulin, and promote the transfer of GLUT1 and GLUT4 from inside cell to cell membrane. As one component of glucose tolerance factor (GTF), Cr3+ could enhance glucose utilization by cells, accelerate the oxidation and phosphorylation of glucose, promote composition of hepatin and improve insulin stability, as a result blood glucose level could be decreased. (2) Protect pancreatic islet βcells: including Se, VE, VC, lipoic acid and niacinamide. As the active center component of GSH-Px, Se supplementation could increase GSH-Px activity and heighten the removal of free radicals. VE locates in double layer phosphatide molecules of biological membrane, forming the first defence of membrane antioxidation and maintaining the integrity of endoplasmic reticulum in islet βcells. VC exists in aqueous phase locating inside and outside cell, possessing the function of preventing production of free radicals and lipid peroxidation. Niacinamide can directly scavenge free radicals and improve transcription and expression of insulin regenerating gene (Reg I). As a brand new antioxidant, lipoic acid is an important component of antioxidant defences. (3) Attenuate autoimmune damage: Supplementation of combined Se, V, Cr and VE could both upregulate expression of IL-4 and IL-10 that have protective effects on islet and downregulate expression of TNF-αand IFN-γthat have pathogenic effects on βcells. (4) Postpone onset of diabetic complications: including Se, VE, VC, lipoic acid and niacinamide, mainly due to their function of eliminating free radicals directly or indirectly.At present the cellular and molecular mechanisms involved in protective effects of AM on islet cells are still unclear, no systemic study of morphology on it has been reported. In this study, we added VC, lipoic acid and niacinamide into the previous combined antioxidant micronutrients (Se, V, Cr and VE). Systemic study of morphology on effects of AM on islet cells was performed. The influence of AM both on the expression of IL-2, IL-4, IL-6, IL-10, IL-12, TNF-αand IFN-γin peripheral blood and on the oxidative stress in important organs such as heart, brain, kidney and liver was determined. We also investigated the regulatory effects of AM on insulin expression at both transcription and translation level. Through elucidating these molecular mechanisms, we hope to provide academic basis for application of AM on clinic treatment of diabetes. The following results have been obtained in this study: 1, Supplementation of AM could attenuate islet atrophy and efficiently protect residual functional βcells of IDDM mice. Image quantitative analysis on HE staining sections of mice pancreas tissues showed that AM could improve the ratio between islet area and pancreas area and regulate islet figure factor, suggesting that AM could decrease pancreatic islet destruction. Quantitative analysis on insulin immunohistochemistry showed that AM could significantly increase the ratio between the insulin expression positive area and pancreas area, suggesting AM could efficiently protect functional βcells. 2, Supplementation of AM could increase the stability of islet endoplasmic reticulum. The effects of AM on untrastructure of βcells of IDDM mice were observed by using transmission electron microscope. Results showed that AM could effectively protect the structure of endoplasmic reticulum inside βcells of IDDM mice, exhibiting as the increase of endocrine granules and their relatively normal structure. 3, Supplementation of combined AM could downregulate expression of Th1 cytokines in lymphocytes of peripheral blood and spleen of IDDM mice.The influence of AM on expression of part of Th1 cytokines in peripheral blood lymphocytes was observed by using flow cytometer. Results indicated that AM could downreglate expression of pathogenic cytokines, including TNF-α, IFN-γand IL-12 in peripheral blood lymphocytes and TNF-αin spleen, which is a molecular target involved in protective effects of AM against autoimmune destruction of pancreatic islets. 4, Supplementation of combined AM could upregulate expression of Th2 cytokines in lymphocytes of peripheral blood and spleen of IDDM mice. Results showed that AM increased IL-10 expression in peripheral blood lymphocytes and IL-4 expression in spleen, which is another molecular target involved in protective effects of AM against autoimmune destruction of pancreatic islets. 5, Supplementation of combined AM could attenuate oxidative stress in important organs such as heart, brain, kidney and liver of IDDM mice. The influence of AM on oxidative stress in important organs such as heart, brain, kidney and liver of IDDM mice was observed in this study. Results showed that AM decreased MDA content in heart, brain, kidney and liver of IDDM mice, then oxidative pressure in important organs could be released. At the same time AM significantly improved GSH-Px activity in heart, brain, kidney and liver as well as SOD activity in heart, kidney and liver, which ameliorated antioxidant defensive ability of these important organs, therefore the onset of chronic diabetic complications could be prevented or delayed. It also provided a stable inner environment for relative hormones in glucose metabolism to function normally. 6, Supplementation of combined AM could enhance transcription of insulin mRNA in islet βcells of IDDM mice. The influence of AM on transcription of insulin mRNA in islet βcells of IDDM mice was observed by using quantitative analysis on in-situ hybridization of insulin mRNA as well as semiquantitative RT-PCR. Results showed that AM could increase...
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