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研究生:林唐玉
研究生(外文):Tang-Yu Lin
論文名稱:糖尿病狀態對於甲基代謝路徑影響之相關研究
論文名稱(外文):Effects of diabetic status on methyl group metabolism
指導教授:蔣恩沛
指導教授(外文):En-Pei Chiang
口試委員:曾志正唐烽堯
口試日期:2011-07-30
學位類別:碩士
校院名稱:國立中興大學
系所名稱:食品暨應用生物科技學系所
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:英文
論文頁數:62
中文關鍵詞:硫-腺核苷硫-腺核苷硫-腺核苷硫-腺核苷
外文關鍵詞:diabeteshomocysteineS-adenosylmethionine
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Abstract
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.


Catalog
中文摘要.............................i
Abstract.............................ii
Catalog..............................iv
List of abbreviations................vi
Introduction.........................1
Materials and Methods................5
Result...............................12
Discussion...........................17
Reference List.......................24

Table 1. Body weight, organ weight and food intake in (A) STZ and (B) db/db diabetic mice...........................33
Table 2. Plasma homocysteine, cysteine, GSH, and CysGly concentrations in (A) STZ and (B) db/db diabetic mice.....34
Table 3. Transsulfuration fluxes in (A) plasma, (B) bone marrow, (C) liver, and (D) kidney of diabetic mice........35
Table 4. AdoMet, adoHcy, ratio of adoMet/adoHcy and MAT activity in (A) liver, (B) kidney, (C) whole blood........37
Table 5. Hepatic SAH-hydrolase activity in (A) STZ and (B) db/db diabetic mice.......................................40
Table 6. Remethylation fluxes in (A) plasma, protein and cytoplasma of (B) bone marrow, (C) liver, and (D) kidney....................................................41
Table 7. DNMT activity and 5MdC (%) content in liver and kidney of (A) STZ and (B) db/db diabetic mice.............48
Table 8. Correlation matrix of variables measured in diabetic mice models......................................49
Figure 1. Phenotypic data and metabolic profile in diabetic models....................................................50
Figure 2. Glucose tolerance ability of (A) STZ and (B) db/db diabetic mice models................................55
Figure 3. Plasma homocysteine levels of (A) STZ and (B) db/db diabetic mice models before and after methionine loading test..............................................56
Figure 4. Hepatic protein abundance in (A) STZ and (B) db/db diabetic mice models................................57
Figure 5. Summary impacts of diabetic status on methyl group metabolism in (A) liver and (B) kidney of STZ-treated mice......................................................59
Figure 6. Summary impacts of diabetic status on methyl group metabolism in (A) liver and (B) kidney of db/db mice......................................................61





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