The protective effects of seleno-L-methionine (SeMet) on oxidative stress in pancreatic islets were investigated with a short-term nicotinamide (NA) and streptozotocin (STZ)-induced diabetic mouse model. ICR mice were intraperitoneally injected twice with 100 mg/kg STZ and 120 mg/kg NA at a 1-d interval and were then orally administered 158 µg Se/kg SeMet with free access to a selenium-deficient diet for 5 weeks. Administration of SeMet significantly improved the levels of glycated hemoglobin (HbA1c), non-fasting and oral glucose tolerance-tested (OGTT) blood glucose, plasma adiponectin and hepatic glycogen that deteriorated by NA/STZ treatment. However, supplementary SeMet did not restore non-fasting plasma insulin levels in NA/STZ treatment group and significantly suppressed OGTT plasma insulin levels in the control group. Although SeMet significantly suppressed 8-hydroxy-2′-deoxyguanosine density in pancreatic islets, SeMet did not restore insulin density. The hepatic and pancreatic mRNA levels of glutathione peroxidase 1 (GPX1) increased by NA/STZ treatment or SeMet administration. These results suggest that although a physiological level of SeMet improves glucose tolerance by exhibiting insulin-mimetic activity in a short-term induced diabetic mouse model under insufficient Se status, the suppression of pancreatic oxidative stress with the induction GPX1 by SeMet supplementation is unlikely to restore insulin storage and secretion.Key words selenium; diabetes; insulin; glutathione peroxidase 1; seleno-L-methionine; oxidative stress Selenium (Se) is one of the essential micronutrients for human and animals and exerts as a key component of selenoproteins to regulate many physiological functions.1) The families of glutathione (GSH) peroxidase (GPX) and thioredoxin reductase (TR) are the well-known Se-dependent antioxidant enzymes.2,3) GPX1 is particularly important because the antioxidant enzyme has the higher affinity than catalase for hydrogen peroxide (H 2 O 2 ) 4) that is formed by superoxide dismutase from superoxide anions 5) or directly generated by oxidative stress in cytoplasm. Therefore, Se deficiency induces some pathological conditions including cancer and cardiovascular disease.6) The patients with Se-deficiency syndrome, Keshan disease cause cardiomyopathy with the pancreatic atrophy and degeneration.7) The fragility for the oxidative stress in pancreas may be responsible for the pathogenesis. 8)The early stages of type 2 diabetes is characterized by postprandial hyperglycemia by insufficient secretion of insulin from pancreatic β-cells and by the poor response on the target organs.9,10) As the etiology of type 2 diabetes is linked to genetic and lifestyle factors, 11,12) the onset is preventable through the improvements of dietary habits and lifestyle.13) However, deteriorations in dietary habits and lifestyle are involved with oxidative stress 14) and thereby connected with the onset of diabetes.15) Increased generation of reactive oxygen species (ROS) promotes a functional disorder in pancreat...

The role of supplementary selenium on the induction of insulin resistance and oxidative stress in a diabetic mouse model was investigated in NSY mice on a high fat diet (HFD) and administered seleno-L-methionine (SeMet)-containing water for 12 weeks. Significant increases in oral glucose tolerance-tested (OGTT), insulin tolerance-tested, and non-fasting blood glucose levels were observed in mice on a HFD, as well as the significant increases in OGTT and non-fasting plasma insulin levels. Mice on a HFD had decreased plasma adiponectin levels and increased free fatty acid (FFA) levels. Supplementary SeMet significantly augmented OGTT blood glucose levels in mice on a HFD and plasma FFA levels in mice on a normal diet. The mRNA levels of six selenoproteins were measured, and glutathione peroxidase (GPx) 1 and selenoprotein P (SelP) were selected as candidates that may be associated with insulin resistance or oxidative stress in the liver. Hepatic GPx1 expression was elevated in mice on a HFD and SeMet supplementation, and SelP expression increased in mice on a HFD. Histopathological observations in hepatic tissues showed hypertrophy of parenchymal cells and significant expression of 4-hydroxy-2-nonenal in mice on a HFD, indicating lipid accumulation and oxidative stress induction. Hepatic protein tyrosine phosphatase activity also increased by a HFD. These results suggest that hepatic lipid accumulation in NSY mice on a HFD promoted oxidative stress and hepatic SelP expression, and supplementary SeMet induced hepatic GPx1 expression.Key words selenium; diabetes; insulin resistance; glutathione peroxidase 1; selenoprotein P; oxidative stress Type 2 diabetes mellitus is a metabolic disease associated with genetic and lifestyle factors 1) caused by the decline in insulin potency in organs, such as liver, muscle, and adipose tissue, and/or reduced insulin secretion from pancreatic β-cells. 2)This disease leads to diabetic peripheral neuropathy, nephropathy, and retinopathy by raising the level of blood glucose, and eventually gangrene, renal failure, and blindness.3) These pathologies are linked on an individual level to obesity and overweight, 4) on a physiological level to insulin resistance, 5) and on a cellular level to oxidative stress. 6) Insulin-resistant diabetes is a state of declined glucose uptake in target tissue cells, which do not properly respond to insulin and do not have a functioning insulin transduction system. 7) Intracellular production of reactive oxygen species (ROS) and redox activation of protein tyrosine phosphatase (PTP) 1B are involved in the decline of insulin signal transduction phosphorylation [8][9][10] and dysfunction in pancreatic β-cells. 11,12) Selenium (Se) is an essential trace element and functions as a key component of critical enzymes for redox homeostasis and protection from oxidative stress, which include the glutathione peroxidase (GPx) family and selenoprotein P (SelP). 13,14) GPx1 is located in the cytosol to remove hydrogen peroxide (H 2 O 2 ), which is generated by intrac...

The consumption of oxidized cooking oils may exacerbate some allergic diseases. A contact hypersensitivity (CHS) mouse model was used to investigate the effects of naturally oxidized olive oil on the expression of inflammatory cytokines after a sensitization and elicitation phase. The mRNA expressions of IL-12, IL-18, and IFN-γ in the ear increased seven days after sensitization. IL-18 and IFN-γ mRNA expressions after elicitation were significantly enhanced by administration of oxidized olive oil, which exacerbated ear swelling and mononuclear cell infiltration from CHS after elicitation. IL-18 expression in the ear of oxidized oiltreated mice was highest before elicitation and decreased with an increase in IFN-γ expression after elicitation. The acceleration of an immune reaction by administration of naturally oxidized olive oil in the CHS mouse model was caused by increased expression of IL-18 in the ear auricles after sensitization, which was followed by a significant increase in IFN-γ expression after elicitation.

The roles of differentiation and cytokine production of helper T and killer T cells by antigen stimulation were investigated to clarify the mechanisms of CHS exacerbation by naturally oxidized olive oil. Mice were orally administered naturally oxidized olive oil once every 2 days for 1 week after sensitization. IL-18 expression in the ear auricle and AP-1 and caspase-1 activity in the splenocytes were measured. The splenic T cell subpopulation and IL-4 and IFN-γ production in each subpopulation were also analysed. IL-18 expression and AP-1 and caspase-1 activity increased in the oxidized olive oil-administered group. CD3 + CD4 + and CD3 + CD8 + cells in splenocytes of OXA-sensitized mice increased from oxidized olive oil administration, and IFN-γ, a Th1 cytokine produced by antigen-stimulated CD3 + CD4 + cells, was increased. These results suggest that excessive consumption of oxidized oils exacerbates the allergic reaction by promoting antigen-specific T cell differentiation and increasing production of inflammatory cytokines.

The excessive ingestion of oxidized dietary oils may exacerbate some allergic diseases. We previously reported that oxidized olive oil exacerbates active cutaneous anaphylaxis (ACA), one of the immediate allergic reactions. This study was conducted to clarify the effects of oxidized olive oil on the T cell response during ACA. BALB/c female mice were orally administered naturally oxidized olive oil once every 2 d for 2 weeks after ovalbumin (OVA)/aluminum hydroxide gel sensitization, after which ACA was elicited by intracutaneous administration of OVA into the ear auricles. Compared with fresh olive oil, oxidized olive oil administration increased the antigen-specific immunoglobulin E (IgE) antibody titer 2 weeks after OVA-sensitization and vascular hyperpermeability increased due to ACA. In the oxidized olive oil-administered mice, the mRNA expression levels of T-helper 2 (Th2) cytokines, interleukin (IL)-4, -5, -6, and -10, in the lymph nodes increased, as did the proportion of cluster designation (CD)3 CD4 cells in the spleen and lymph nodes. In CD3 CD4 cells, the mRNA expression levels of IL-4 and GATA-binding protein 3 (GATA3), the master regulator of Th2, were higher in the oxidized olive oil-group. Antigen-stimulated specific IL-4 production was promoted in CD3 CD4 cells of oxidized olive oil-administered mice. This suggests that oxidized olive oil exacerbates ACA by promoting Th2 dominance in immediate allergic diseases.