Effects of diabetic status on methyl group metabolism
| Autor: | Tang-Yu Lin, 林唐玉 |
|---|---|
| Rok vydání: | 2011 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 99 Background. Defection in insulin secretion or insulin action divided diabetes into two group: Type I and Type II diabetes. Type I diabetes, accompanying hyperglycemia and hypoinsulinia. Type II diabetes was commonly associating with obesity, hyperglycemia and hyperinsulinia. The previous study has reported that diabetes might disrupt methyl group metabolism. The goal of this study was to determine the alterations in methyl group metabolism causing by the conditions of diabetes; and further, influence the status of genomic methylation. Methods. We study two main types of diabetes separately, STZ-treated mice as Type I diabetic model and db/db transgenic mice as Type II diabetic model. We performed a methionine-load test to estimate the influence of diabetes on homocysteine metabolism. The metabolites involved in transsulfuration: homocysteine, cysteine, Cys-Gly and total GSH concentrations in plasma were analyzed. AdoMet, AdoHcy, enzyme activity of MAT and SAHH were determined. To investigate status of global DNA methylation, percentage of methylated cytidine, DNMT activity and abundance of protein associated with DNA methylation were determined. The impact of diabetes on pathway fluxes of one-carbon metabolism was illustrated by stable isopotic tracers. Results. We examined the impact of Type I and Type II diabetes on homocysteine production and found that plasma homocysteine and cysteine concentrations were lower in the both diabetic groups at all time points. The transsulfuration fluxes were increased in both mice model. However, GSH and Cys-Gly concentrations were increased in Type I diabetes alone. In Type I diabetes, there was no significant change in hepatic concentration of adoMet and adoHcy, whereas adoMet was elevated and adoHcy was reduced in Type II diabetes at 42 wk. Hepatic MAT activity was lower but MAT abundance was elevated in Type I diabetes and Type II diabetes at 28 wk. Hepatic adoMet/adoHcy ratio did not differ in diabetic mice compared with the controls. However, the remethylation fluxes in both mice model were increased. In addition, hepatic DNMT activity, DNMT1 and DNMT3a abundance were lower in Type I diabetic mice than in control mice with the decreased content of 5MdC. Moreover, hepatic DNMT activity, DNMT1 and DNMT3a abundance were elevated in Type II diabetes at all time point, ultimately resulting in the rising content of 5MdC in DNA. Conclusion. During the Type I diabetes status, methyl group metabolism was disturbed with genomic hypomethylation in the mice liver. Compare with Type I diabetes, Type II diabetes have the equivalent alterations in transmethylation and homocysteine production, whereas have distinct impact on DNA methylation that the 5MdC was increased. We suggest that must be different factors affect the DNA methylation status and related reactions within two models. The related further studies are underway. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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