臺灣博碩士論文加值系統

中文摘要
心臟血管疾病在糖尿病患者身上是很常見的。除了冠狀動脈疾病和高血壓之外，患者也會出現一種沒有大小血管併發症的糖尿病心臟肌肉病變 (Diabetic cardiomyopathy)。有一些變化卻是糖尿病心臟肌肉病變所特有的：第一型類胰島素生長因子(Insulin-like growth factor 1) 和熱休克蛋白質 (Heat shock protein)的表現就是其中之一。
首先於第一章中，我回顧文獻中關於第一型類胰島素生長因子以及熱休克蛋白質在心臟保護功能的報告。在糖尿病動物的心臟中，第一型類胰島素生長因子接受體的表現明顯地減少；這種變化跟缺血性心臟肌肉病變以及肥厚性心臟肌肉病變的表現正好相反。降低第一型類胰島素生長因子的表現，會降低心臟在缺氧或缺血時自我保護的功能，可能在引起糖尿病心臟肌肉病變中扮演著重要的角色。另外一個特殊的變化是熱休克蛋白質的表現：熱休克蛋白質在細胞內扮演著管家的角色，來調節細胞內訊號的傳遞，進而在心肌缺氧或缺血時保護心臟。
雖然這些發現顯示，第一型類胰島素生長因子和熱休克蛋白質表現的下降可以導致糖尿病心臟肌肉病變的形成，但是糖尿病如何造成這些蛋白質表現下降的機轉並不清楚。在本篇論文中，我提出一個假說「在糖尿病的心臟中，熱休克蛋白質的表現下降，因而造成第一型類胰島素生長因子系統以及其細胞內訊號傳遞的下降，是形成糖尿病心臟肌肉病變的主要原因之一」。為了證明假說，設計了一系列的實驗來評估糖尿病如何地來調控熱休克蛋白質在心臟中的表現，以及第一型類胰島素生長因子在心臟細胞內的訊號傳遞。在第二章中簡單地陳述我的實驗設計。
在第三章中，先探討心臟中熱休克蛋白質60和第一型類胰島素接受體及其細胞內訊號傳遞在糖尿病的變化，進而探討糖尿病是透過什麼機轉來產生這些變化。心臟中熱休克性蛋白質60和第一型類胰島素生長因子接受體，在大白鼠被誘導成糖尿病後的第四天就開始下降。而第一型類胰島素生長因子在心臟細胞內訊號的傳遞也都明顯地減少。將心臟細胞培養在不同濃度的胰島素及葡萄糖中，心臟細胞內熱休克蛋白質60的表現隨著胰島素濃度的升高而增加，但卻不受葡萄糖濃度的影響。我們又分別使用胰島素和Phlorizin來治療糖尿病大白鼠的血糖：經過胰島素的治療，心臟內熱休克蛋白質60和第一型類胰島素接受體的表現都恢復到正常；但是以Phlorizin治療的大白鼠則無法恢復到正常。這些資料顯示，胰島素的缺乏是造成糖尿病心臟中熱休克蛋白質60表現減少最主要的原因。
在第四章中，首先探討心臟中熱休克蛋白質70家族在糖尿病的變化，然後再研究引起這些變化的機轉。在大白鼠被誘導成糖尿病之後，常態型的熱休克蛋白質70就隨著糖尿病的過程而減少。跟熱休克蛋白質60不一樣的地方是：熱休克蛋白質70並不會調節第一型類胰島素生長因子在心臟細胞內訊號的傳遞。在細胞培養中，胰島素的濃度可調控常態型的熱休克蛋白質70的表現，但不會影響誘導型熱休克蛋白質70的表現。糖尿病的大白鼠經過胰島素的治療之後，可以恢復心臟中熱休克蛋白質70的表現；但是經過Phlorizin治療的糖尿病大白鼠，其心臟中熱休克蛋白質的表現仍然比控制組低。我們的資料顯示，心臟中誘導型的熱休克蛋白質70的表現並不受糖尿病的影響；而胰島素可以調節心臟中常態型的熱休克蛋白質70的表現。
綜合以上資料而言，糖尿病是因為胰島素缺乏而造成心臟中熱休克蛋白質60和常態型熱休克蛋白質70的表現減少的原因。而心臟中熱休克蛋白質60減少，進而降低第一型類胰島素生長因子細胞內訊號的傳遞則是形成糖尿病心臟肌肉病變主要的原因之一。

Abnormalities of cardiovascular systems are common in diabetic patients, and the consequences of cardiac disease in diabetes are devastating. In addition to coronary artery disease and hypertension, diabetic patients often have evidence of a cardiomyopathy that may occur without apparent microvascular or macrovascular diseases. Although a number of biochemical and physiological changes had been described in diabetic myocardium, most are not specific to diabetic cardiomyopathy because similar biochemical abnormalities were found in other forms of cardiomyopathy. However, there are few changes appear to be quite specific for diabetic cardiomyopathy. Two of these changes are the expression of IGF-1 receptor and heat shock proteins.
First, I reviewed the cardioprotection effects of IGF-1 and heat shock protein in the chapter one. In this chapter we also explored the changes of IGF-1 and heat shock protein during the diabetic status. The expression of IGF-1 receptor in myocardium is reduced in animal models of diabetes. This is different from ischemic cardiomyopathy and hypertrophic cardiomyopathy, which are associated with increased IGF-1 receptor expression in myocardium. IGF-1 receptor signaling protects myocardium from injuries through suppression of oxidative stress, inhibition of cardiac muscle apoptosis, enhancement of contractile function, and modulation of cardiac specific genes. Reduced expression of IGF-1 receptor can lead to decreased myocardial protection during myocardial ischemia and thus may play a fundamental role during the development of diabetic cardiomyopathy. The other specific changes are heat shock protein. Hsps are chaperone molecules that may modulate intracellular signaling and play cardiac protective roles during myocardial injuries. Recent data have shown antiapoptotic effects of Hsp60 in cardiac muscle and the expression of various heat shock proteins typically increases upon myocardial stress. The 70 kD family of heat shock proteins is involved in the cellular protection during stress in various tissues, and the expression of Hsp70 was dramatically induced after myocardial ischemic injuries.
Although these findings suggest that reduced Hsp and IGF-1 is a new paradigm contributing to the development of diabetic cardiomyopathy, the mechanism through which diabetes downregulates cardiac Hsp and IGF-1 is not known. In this thesis, I address the hypothesis that reduced heat shock protein expression in diabetic myocardium contributes to the development of diabetic cardiomyopathy, and that the protective effect of Hsp on cardiac muscle involves modulating of IGF-1 receptor signaling. I described these experiments in chapter 2, which were carried out to determine how diabetes alters myocardial Hsp and IGF-1 receptor signaling and to dissect the independent effects of hyperglycemia and insulin deficiency on Hsp in cardiac muscle.
In chapter 3, we investigated the changes of Hsp60 and IGF-1 receptor signaling in the diabetic myocardium and studied how diabetes modulates Hsp60 and IGF-1 receptor in diabetic myocardium. In the streptozotocin (STZ)-induced diabetic rat, downregulation of Hsp60 and IGF-1 receptor occurred 4 days after induction of diabetes. IGF-1 activation of IGF-1 receptor, Mek, and Akt were reduced accordingly in the diabetic myocardium. Incubating cardiomyocytes with insulin was associated with dose-dependent increase of Hsp60 protein. In contrast, the abundance of Hsp60 was not affected by high concentration of glucose in these cells. We used insulin or phlorizin to normalize blood glucose in diabetic rats. In the phlorizin-treated diabetic rats, myocardial Hsp60 was lower than that of the normal controls. In contrast, insulin treatment normalized myocardial Hsp60 in the diabetic rats. These findings suggest that insulin deficiency is a novel mechanism that leads to downregulation of Hsp60 in diabetic muscle tissues.
The study described in chapter 4 was carried out to define the changes of 70 kD heat shock protein family in the myocardium of streptozotocin-diabetes rats, and to explore the mechanisms through which diabetes alters the abundance of Hsp70/Hsc70 in cardiac muscle. In the diabetic myocardium, the abundance of Hsc70 was significantly reduced in diabetic myocardium and the abundance of Hsp70 was low in cardiac muscle and was not visibly induced in the diabetic myocardium. Unlike Hsp60, Hsp70 did not augment IGF-1 receptor signaling in cardiac muscle cells. In cultured cardiomyocytes, insulin directly increased the abundance of Hsc70 whereas insulin could not modulate Hsp70. Treating diabetic rats with insulin restored myocardial Hsc70 level, but phlorizin treatment failed to restore myocardial Hsc70. These in vivo studies confirmed that down-regulation of Hsc70 in diabetic myocardium was secondary to insulin deficiency. Our data showed that, in contrary to other forms of cardiomyopathy, the inducible Hsp70 was not induced in diabetic myocardium while insulin played a major role in maintaining adequate expression of Hsc70 in cardiac muscle.
In conclusion, insulin deficiency is a novel mechanism that leads to downregulation of Hsp60 in diabetic muscle tissues. The development of diabetic cardiomyopathy might have involved downregulation of Hsp60 and subsequent reduction of IGF-1 receptor signaling. Our data also showed that the inducible Hsp70 was not induced in diabetes myocardium while insulin played a major role in maintaining adequate expression of Hsc70 in cardiac muscle.

致 謝 2
中文摘要 3 – 4
英文摘要 5 – 7
中英文對照及縮寫表 8 – 12
第一章 糖尿病的心臟肌肉病變和熱休克蛋白質以及第一型類胰島素生長因子的關係 13–24
第二章 實驗設計及初步的資料 25–36
第三章 糖尿病心臟因為胰島素的缺乏而導致熱休克蛋白質60的減少進而影響第一型類胰島素生長因子在細胞內的訊號傳遞 37–63
第四章 糖尿病心臟的熱休克蛋白質70的減少是因為胰島素的缺乏所引起 64–91
第五章 結論及未來研究的方向 92–99
參考文獻 100–115
發表之論文相關著作 116

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