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研究生:李慧欣
研究生(外文):Hui-Hsin Lee
論文名稱:胰島素阻抗性對周邊組織日變節律相關基因的影響
論文名稱(外文):Peripheral circadian rhythm-related genes expression influenced by insulin resistance
指導教授:謝坤叡
指導教授(外文):Kun-Ruey Shieh
學位類別:碩士
校院名稱:慈濟大學
系所名稱:神經科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
畢業學年度:96
語文別:中文
論文頁數:105
中文關鍵詞:胰島素阻抗性streptozotocinnicotinamideNADH/NAD+ ratio日變節律
外文關鍵詞:circadian rhythminsulin resistancestreptozotocinnicotinamideNADH/NAD+ ratio
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罹患第二型糖尿病的人口在開發中或是已開發國家發展的非常迅速,除了一部分是與遺傳有關之外,大部分的第二型糖尿病主要是由於能量的代謝失調所造成。全球大約80 %的第二型糖尿病患者有肥胖的情形。另一項第二型糖尿病的主要特徵為胰島素阻抗性,這兩項症狀都會增加血漿中游離脂肪酸的含量。當糖解作用進行時,游離脂肪酸進入到肝臟代謝的路徑是與NAD(H)的氧化還原能力有關,特別的是,NAD(H)的氧化還原會影響CLOCK:BMAL1與E-box結合的能力,進而影響日變節律相關基因的產生。因此,日變節律相關基因不僅與生物時鐘有關,可能也在能量代謝中扮演一定的角色。所以我們的實驗主要是探討能量代謝失調 (胰島素阻抗性或第二型糖尿病)與日變節律相關基因之間的關係。 新生SD公鼠在出生後第2天注射streptozotocin (STZ, 60 mg/kg)或是在出生後第21天注射nicotinamide (NA, 270 mg/kg)以及STZ (60 mg/kg)。為了觀察處置後的生理狀態,我們測量體重、血糖以及利用腹腔注射葡萄糖耐受性測試的方式去評估是否呈現胰島素阻抗性。我們分ZT2以及ZT9 (ZT0:代表燈亮開始)兩個不同時間點犧牲,並取肝臟、腎臟待後續實驗所需。 我們發現年輕實驗組大鼠 (4或5個月大)在6週大時的體重都是低於控制組的,不過呈現胰島素阻抗性的PND21-NA-STZ以及PND2-STZ (5個月大)分別在16以及18週大後體重超越控制組。而較老的PND2-STZ (8個月大)這一組其體重在32週大後是明顯高於控制組的。這些實驗組大鼠在離乳後都呈現血糖增加的趨勢,而且形成胰島素阻抗性或是第二型糖尿病。使用定量聚合�○s鎖反應去觀察日變節律相關基因: rClock、rBmal、rPer1、rPe2、rPer3、rCry1、rCry2、rCK1ε、rDbp、rE4BP4在肝臟以及rClock、rBmal、rPer1、rPe2、rPer3、rCry1、rCry2、rCK1ε、rDbp、rE4BP4、rRev-erbα、rRev-erbβ在腎臟的表現。我們發現,大部份的基因都呈現出節律性,只有rClock在肝臟呈現無節律的現象。當大鼠發展出胰島素阻抗性時,大部份的基因表現都是呈現上升的情形。除此之外,我們還也觀察到這些基因的表現似乎呈現提前的相移反應。如果是較老的胰島素阻抗性大鼠 (PND2-STZ 8個月大),其肝臟基因的節律表現會更加明顯,但是我們發現腎臟基因似乎呈現一種趨勢,就是在ZT2的基因表現都是上升的、ZT9的表現都是下降的,依照這些改變的模式,我們發現基因表現的節律性有漸趨喪失的現象。 根據以上結果,我們認為日變節律相關基因可能可視為胰島素阻抗性以及年長的一項生物指標,不過還需要更多的佐證來支持我們的假說。
Population of type 2 diabetes mellitus (T2DM) is increased with high rate in well-developed and developing countries. Except some related to heredity, most of T2DM are related to the imbalance in the ratio of energy income and outcome. About 80 % T2DM patient are obese in worldwide. Another important sign to develop T2DM is insulin resistance (IR). Both obesity and IR increase plasma free fatty acids (FFAs). When glycolysis proceeding, FFAs from circulation enter to mitochondria in liver, and are implicated in the necessary reoxidation of NADH + H+ to NAD+, thereby enabling maintenance of glycolytic flux. Interesting, The DNA-binding activity of the CLOCK:BMAL1 heterodimers, which are translated from ones of circadian rhythm-related genes, is also regulated by the redox state of NAD cofactors. The circadian rhythm-related genes play the important role on not only the biological clock but also the energy metabolism. Therefore, this study was focused on the relationships between energy imbalance (IR or T2DM) and circadian rhythm-related genes expression. The neonatal male Sprague-Dawley rats injected streptozotocin (STZ, 60 mg/kg) on postnatal day 2 (PND2) or injected nicotinamide (NA, 270 mg/kg) and STZ (60 mg/kg) on PND21 were used in this study. For monitoring the physiological responses of treatments, we measured the body weight and plasma glucose level of fasting or glucose treatment by intraperitoneal glucose tolerance test (IPGTT). We sacrificed animals at different time points, ZT2 and ZT9 (ZT0 indicated the time of light-on), and collected liver and kidney for follow-up experiment. We found that the body weights of all the young experimental groups (4 or 5 months old) were lower than the control groups after 6 weeks of age, but increase after 16 and 18 weeks of age on PND21-NA-STZ IR and PND2-STZ (5 months old) group. The body weight of the old PND2-STZ group (8 months old) was significant higher than the control group after 32 weeks of age. The experimental groups displayed gradually increase of fasting glucose level, and exerted the trend of IR even T2DM after treatment. Using the reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) to measure the expression levels of the circadian rhythm-related genes, such as rClock, rBmal1, rPer1, rPer2, rPer3, rCry1, rCry2, rCK1ε, rDbp, and rE4BP4、rRev-erbα、rRev-erbβ in liver and rClock, rBmal1, rPer1, rPer2, rPer3, rCry1, rCry2, rCK1ε, rDbp, and rE4BP4 in kidney, most of genes exhibited the diurnal rhythmicity in all groups. Interestingly, the rClock gene expression did not have this rhythmic pattern in liver. Moreover, the levels of these circadian rhythm-related genes expression were changed and almost showed the increasing following the animals developed the IR. We also found that the levels of these genes expression might present phase advance. If IR combined with an older factor, the changes of genes expression in liver were amplify rhythm. But in kidney, all the genes expression was significant increased at ZT2 and decreased at ZT9. According the above pattern, we found the genes expression rhythm was attenuated. In conclusion, the expression of circadian rhythm-related genes might have the potentials as the indices for IR and elder, but the further studies are needed to make this clearly.
致謝.....................................................Ⅰ
Abstract.................................................Ⅱ
摘要.....................................................Ⅲ
緒論......................................................1
一、 新陳代謝症候群 (metabolic syndrome, MetS)............2
二、 第二型糖尿病及動物模式 (T2DM and animal models)......2
三、 肥胖與脂肪組織 (Obesity and adipose tissue)..........3
四、 Peroxisome proliferators-activated receptors (PPARs).4
五、 發炎反應與胰島素阻抗性 (Inflammation and IR).........4
六、 代謝相關基因 (Metabolism-related genes)..............4
七、 生物時鐘 (Chronobiology / biological clocks).........5
八、 日變節律系統 (Molecular timing system)...............5
九、 日變節律相關基因 (Circadian rhythm-related genes)....6
十、 日變節律相關基因與動物行為...........................7
(Circadian rhythm-related genes and animal behavior)
十一、 日變節律相關基因與疾病 (Circadian rhythm-related
genes and diseases)................................9
十二、 能量代謝與日變節律相關基因的關係...................9
(The relationship between energy metabolism and
circadian rhythm-related genes)
十三、 周邊組織的能量代謝...............................10
(The energy metabolism of liver)
十四、 實驗研究目的 (The objective of experiment)........10
材料與方法...............................................12
一、 材料................................................13
二、 方法................................................13
結果.....................................................16
一、 誘發IR的動物模式 (Induce animal models of IR).......17
二、 生理狀態監控 (Examine physiological responses)......17
三、 IR對肝臟日變節律相關基因的影響......................17
(The influenced of IR in circadian rhythm-related
genes expression of liver)
四、 T2DM對肝臟日變節律相關基因的影響....................18
(The influenced of T2DM in circadian rhythm-related
genes expression of liver)
五、 年長對肝臟日變節律相關基因的影響....................18
(The influenced of elder in circadian rhythm-related
genes expression of liver)
六、 IR合併年長對肝臟日變節律相關基因的影響..............19
(The influenced of IR and elder in circadian rhythm-
related genes expression of liver)
七、 IR對腎臟日變節律相關基因的影響......................19
(The influenced of IR in circadian rhythm-related
genes expression of kidney)
八、 T2DM對腎臟日變節律相關基因的影響....................20
(The influenced of T2DM in circadian rhythm-related
genes expression of kidney)
九、 年長對腎臟日變節律相關基因的影響....................20
(The influenced of elder in circadian rhythm-related
genes expression of kidney)
十、 IR合併年長對腎臟日變節律相關基因的影響..............20
(The influenced of IR and elder in circadian rhythm-
related genes expression of kidney)
討論.....................................................22
一、 IR動物模式的建立...................................23
(The establishment of animal models of IR)
二、 IR對周邊組織日變節律相關基因的影響..................24
(The influenced of IR in peripheral circadian rhythm-
related genes expression)
三、 T2DM對周邊組織日變節律相關基因的影響................25
(The influenced of T2DM in peripheral circadian
rhythm-related genes expression)
四、 年長對周邊組織日變節律相關基因的影響................25
(The influenced of elder in peripheral circadian
rhythm-related genes expression)
五、 IR合併年長對周邊組織日變節律相關基因的影響..........26
(The influenced of IR and elder in peripheral
circadian rhythm-related genes expression)
六、 MetS對肝臟代謝相關基因的影響........................26
(The influenced of MetS in metabolism-related genes
expression of liver)
七、 年長對肝臟代謝相關基因的影響........................27
(The influenced of elder in metabolism -related genes
expression of liver)
八、 研究上的限制 (The limitations of study).............27
九、 MetS與日變節律相關基因之間的連結....................27
(The connection between MetS and circadian rhythm-
related genes)
結論.....................................................28
圖表及說明...............................................30
參考文獻.................................................88
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