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Changes in Ceramide Levels in Various Diseases Are Associated with Oxidative Stress
intoxication, supra-nutritional intake of Se has been reported to cause an increase in the risk of type 2 diabetes. Previous studies suggested that Se-supply activity of excess SeP was related to deterioration of insulin secretion and glucose metabolism. Thus, the inhibition of Se-supply via suppression of SeP binding to cells might improve insulin secretion and glucose metabolism impaired by excess SeP. We established neutralizing antibodies against human SeP. Among them, anti-human SeP monoclonal antibody (mAb) AE2 was identified to have a strong neutralizing activity, and its administration to mice significantly improved glucose intolerance and reduction of insulin secretion, which were induced by intraperitoneal administration of human SeP. In addition, mAb AE2 significantly suppressed SeP-induced impairment of insulin secretion and cell viability of insulinoma MIN6 cells. In this presentation, we will discuss a molecular basis for the development of therapeutic agents for type 2 diabetes by targeting SeP.
doi: 10.1016/j.freeradbiomed.2016.10.460 420 Survival Biomarker 8-OxoGuo Is Not Associated with Insulin or Metformin Treatment in Type 2 Diabetes Patients Laura Kofoed Kjaer1, Vanja Cejvanovic1, Trine Henriksen1, and Henrik Enghusen Poulsen1 1 Q7642 Laboratory of Clinical Pharmacology, Copenhagen, Denmark Objective: In type 2 diabetes (T2D) we have previously shown that urinary markers of RNA oxidation (8-oxo-7,8-dihydroguanosine [8oxoGuo]), but not DNA oxidation (8-oxo-7,8-dihydro-2’deoxyguanosine [8-oxodG]) is associated with increased mortality in patients with newly diagnosed and well-established T2D (Diabetes Care. 2013 Mar;36(3):669–76). Since it is unknown which pharmacological therapy affects 8-oxoGuo and 8-oxodG, we investigated whether insulin or metformin treatment is associated with increased or decreased levels of urinary markers of nucleic oxidation in T2D patients. Research design and methods: Urine samples were analyzed for 8-oxoGuo and 8-oxodG by UPLC-MS/MS in a cohort of 2727 patients with known T2D. Medical information was derived from health examination questionnaires. Associations were tested with T-test and Cox regression models. Results: 701 of the patients received insulin. There was no difference in mean value of 8-oxoGuo between insulin treated patients and controls, but insulin treated patients had lower mean value of 8-oxodG (p<0.001). Insulin treated patients had a 2.45 (1.89-3.16) hazard ratio for overall death in the Cox model (p<0.001). 1430 patients received metformin treatment. There was no difference in mean value of 8-oxoGuo and 8-oxodG in metformin treated patients (p>0.05). Metformin treated patients had 0.58 (0.45-0.75) hazard ratio for overall death in the Cox model (p<0.001). Conclusion: 8-oxoGuo was not associated with neither insulin nor metformin treatment. The increased risk of death shown in T2D patients with high levels of 8-oxoGuo could not be explained by commonly used antidiabetic drugs. Further detailed studies of antidiabetic medications and their effects on oxidative stress are warranted.
doi: 10.1016/j.freeradbiomed.2016.10.461
421 Changes in Ceramide Levels in Various Diseases Are Associated with Oxidative Stress Keiko Kobayashi1, Ikuyo Ichi2, Yukiko Minamiyama1, and Shosuke Kojo3 Kyoto Prefectural University, Japan, 2Ochanomizu University, Tokyo, Japan, 3The Open University of Japan, Japan 1
Ceramide is a bioactive lipid that induces cellular apoptosis, proliferation, and differentiation. Deficiency of acid sphingomyelinase, which synthesizes ceramide, has been reported to result in smaller aortic root lesions in Western diet-fed Ldl-/- mice. Thus, ceramide is predicted to play a role in atherosclerosis pathogenesis. Therefore, using animal models, we investigated whether ceramide levels were affected by oxidative stress in diseases such as atherosclerosis, diabetes, and fulminant hepatitis. The experiments were performed under acute oxidative stress caused by carbon tetrachloride (CCl4) intoxication and chronic oxidative stress in diabetic rats and in aged apolipoprotein E knock out (apoE-/-) mice. Total ceramide concentrations significantly increased in the liver, brain, kidney, and plasma of CCl4-intoxicated rats. This increase was primarily derived from an increase in neutral sphingomyelinase activity in the liver 2 hours after intoxication with CCl4 and was consistent with the decrease in the GSH/GSSG ratio in the liver. In contrast, secretory sphingomyelinase was stimulated during prolonged oxidative stress associated with diabetes and atherosclerosis. After 2 weeks of streptozotocin administration, plasma secretory sphingomyelinase activity was significantly increased, resulting in elevated ceramide concentrations, whereas neutral sphingomyelinase activity was unchanged in the kidney and liver. Plasma ceramide concentrations and secretory sphingomyelinase activity also increased in aged apoE-/- mice. In conclusion, ceramide levels increased in both acute and chronic oxidative stress-related diseases; however, the enzymes responsible for these changes differed. Based on these results, we propose that antioxidants can prevent ceramide production and ameliorate the exacerbation of oxidative stress-related diseases.
doi: 10.1016/j.freeradbiomed.2016.10.462 422 Lipid Peroxidation and Antioxidant Defense System Changes in Mongoloids with Type 1 Diabetes Mellitus Marina A. Darenskaya1, Lyudmila A. Grebenkina1, Maria I. Dolgikh1, Larisa V. Natyaganova1, Svetlana V. Gnusina1, Sergey I. Kolesnikov1, and Lubov I. Kolesnikova1 1 Scientific Centre for Family Health and Human Reproduction Problems, Irkutsk, Russian Federation Background: Numerous studies indicate the activation of free radical processes in different stages and in different types of diabetes. The impact of ethnic factors on the course of the disease is of particular interest. The aim of this study was investigation of the lipid peroxidation content components in Mongoloids with type 1 diabetes mellitus (T1DM). Methods: The study included living in Eastern Siberia Mongoloid patients with T1DM (n = 38, mean age - 34,4 ± 1,9 years, duration of the disease - 12,05 ± 1,51 years). The "T1DM" diagnosis in all patients was confirmed by clinical and laboratory investigations. Severe comorbidities and severe diabetic complications were excluded. The average level of glycated hemoglobin in Mongoloids
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S175
doi: 10.1016/j.freeradbiomed.2016.10.460 420 Survival Biomarker 8-OxoGuo Is Not Associated with Insulin or Metformin Treatment in Type 2 Diabetes Patients Laura Kofoed Kjaer1, Vanja Cejvanovic1, Trine Henriksen1, and Henrik Enghusen Poulsen1 1 Q7642 Laboratory of Clinical Pharmacology, Copenhagen, Denmark Objective: In type 2 diabetes (T2D) we have previously shown that urinary markers of RNA oxidation (8-oxo-7,8-dihydroguanosine [8oxoGuo]), but not DNA oxidation (8-oxo-7,8-dihydro-2’deoxyguanosine [8-oxodG]) is associated with increased mortality in patients with newly diagnosed and well-established T2D (Diabetes Care. 2013 Mar;36(3):669–76). Since it is unknown which pharmacological therapy affects 8-oxoGuo and 8-oxodG, we investigated whether insulin or metformin treatment is associated with increased or decreased levels of urinary markers of nucleic oxidation in T2D patients. Research design and methods: Urine samples were analyzed for 8-oxoGuo and 8-oxodG by UPLC-MS/MS in a cohort of 2727 patients with known T2D. Medical information was derived from health examination questionnaires. Associations were tested with T-test and Cox regression models. Results: 701 of the patients received insulin. There was no difference in mean value of 8-oxoGuo between insulin treated patients and controls, but insulin treated patients had lower mean value of 8-oxodG (p<0.001). Insulin treated patients had a 2.45 (1.89-3.16) hazard ratio for overall death in the Cox model (p<0.001). 1430 patients received metformin treatment. There was no difference in mean value of 8-oxoGuo and 8-oxodG in metformin treated patients (p>0.05). Metformin treated patients had 0.58 (0.45-0.75) hazard ratio for overall death in the Cox model (p<0.001). Conclusion: 8-oxoGuo was not associated with neither insulin nor metformin treatment. The increased risk of death shown in T2D patients with high levels of 8-oxoGuo could not be explained by commonly used antidiabetic drugs. Further detailed studies of antidiabetic medications and their effects on oxidative stress are warranted.
doi: 10.1016/j.freeradbiomed.2016.10.461
421 Changes in Ceramide Levels in Various Diseases Are Associated with Oxidative Stress Keiko Kobayashi1, Ikuyo Ichi2, Yukiko Minamiyama1, and Shosuke Kojo3 Kyoto Prefectural University, Japan, 2Ochanomizu University, Tokyo, Japan, 3The Open University of Japan, Japan 1
Ceramide is a bioactive lipid that induces cellular apoptosis, proliferation, and differentiation. Deficiency of acid sphingomyelinase, which synthesizes ceramide, has been reported to result in smaller aortic root lesions in Western diet-fed Ldl-/- mice. Thus, ceramide is predicted to play a role in atherosclerosis pathogenesis. Therefore, using animal models, we investigated whether ceramide levels were affected by oxidative stress in diseases such as atherosclerosis, diabetes, and fulminant hepatitis. The experiments were performed under acute oxidative stress caused by carbon tetrachloride (CCl4) intoxication and chronic oxidative stress in diabetic rats and in aged apolipoprotein E knock out (apoE-/-) mice. Total ceramide concentrations significantly increased in the liver, brain, kidney, and plasma of CCl4-intoxicated rats. This increase was primarily derived from an increase in neutral sphingomyelinase activity in the liver 2 hours after intoxication with CCl4 and was consistent with the decrease in the GSH/GSSG ratio in the liver. In contrast, secretory sphingomyelinase was stimulated during prolonged oxidative stress associated with diabetes and atherosclerosis. After 2 weeks of streptozotocin administration, plasma secretory sphingomyelinase activity was significantly increased, resulting in elevated ceramide concentrations, whereas neutral sphingomyelinase activity was unchanged in the kidney and liver. Plasma ceramide concentrations and secretory sphingomyelinase activity also increased in aged apoE-/- mice. In conclusion, ceramide levels increased in both acute and chronic oxidative stress-related diseases; however, the enzymes responsible for these changes differed. Based on these results, we propose that antioxidants can prevent ceramide production and ameliorate the exacerbation of oxidative stress-related diseases.
doi: 10.1016/j.freeradbiomed.2016.10.462 422 Lipid Peroxidation and Antioxidant Defense System Changes in Mongoloids with Type 1 Diabetes Mellitus Marina A. Darenskaya1, Lyudmila A. Grebenkina1, Maria I. Dolgikh1, Larisa V. Natyaganova1, Svetlana V. Gnusina1, Sergey I. Kolesnikov1, and Lubov I. Kolesnikova1 1 Scientific Centre for Family Health and Human Reproduction Problems, Irkutsk, Russian Federation Background: Numerous studies indicate the activation of free radical processes in different stages and in different types of diabetes. The impact of ethnic factors on the course of the disease is of particular interest. The aim of this study was investigation of the lipid peroxidation content components in Mongoloids with type 1 diabetes mellitus (T1DM). Methods: The study included living in Eastern Siberia Mongoloid patients with T1DM (n = 38, mean age - 34,4 ± 1,9 years, duration of the disease - 12,05 ± 1,51 years). The "T1DM" diagnosis in all patients was confirmed by clinical and laboratory investigations. Severe comorbidities and severe diabetic complications were excluded. The average level of glycated hemoglobin in Mongoloids
SfRBM / SFRRI 2016
S175