糖尿病大血管與小血管病變之危險因子探討與治療

Evaluation and Treatment of Risk Factors that Affect Diabetic Macro-vascular and Micro-vascular Complications

李美月(Mei-Yueh Lee)

指導教授 ： 辛錫璋

高雄醫學大學/醫學院/臨床醫學研究所博士班/博士(2019年)

摘要

糖尿病是一種與小血管和大血管併發症密切相關的疾病，包括視網膜病變，腎病變，神經病變（小血管病變）和缺血性心臟病，周邊血管疾病和腦血管疾病（大血管），導致大約三分之一到一半糖尿病患者器官和組織損傷。
最近的研究證據證明，與第2型糖尿病患者的平均HbA1c相比，血糖變異性可能是個更可靠的血糖控制指標。研究還顯示，HbA1c變異性與大血管併發症有關，特別是與第2型糖尿病患者的心血管事件有關，但尚未提到於哪一個糖尿病腎臟病階段有關。
大血管疾病的中心病理機制是動脈粥樣硬化，其導致整個身體的動脈壁變窄。動脈粥樣硬化被認為是由周邊或冠狀血管系統中的慢性發炎和動脈壁損傷引起有關。醛糖還原酶可能參與糖尿病併發症的發展，但可能與小血管併發症有關。山梨糖醇囤積的滲透壓被認為是糖尿病小血管併發症（包括糖尿病視網膜病變）發展的潛在機制。其他因素如晚期糖基化終產物（AGEs），氧化應激，生長因子，包括血管內皮生長因子（VEGF），生長激素和β轉化生長因子，也被認為在糖尿病視網膜病變的發展中起重要作用。然而，這些因素並未提起會引起大血管併發症。大血管併發症之周邊血管疾病與小血管併發症之糖尿病視網膜病變的交叉作用引起了我們的興趣。
大血管和小血管併發症的主要危險因素是血脂異常。對於內皮損傷和發炎症，來自LDL顆粒的氧化脂質在動脈的內皮壁中累積，導致一連串反應，該過程的最終結果是形成具有纖維帽的富含脂質的動脈粥樣硬化病變。該病變的破裂導致急性血管梗塞。增加的凝固性和纖維蛋白溶解受損的組合可能進一步增加第2型糖尿病中血管閉塞和心血管事件的風險。探討其他脂蛋白異常如三酸甘油酯，高密度脂蛋白以及其比例對於預防大血管和小血管併發症也很重要。
預防大血管和小血管併發症重要。
雖然預防大血管和小血管併發症很重要，但早期發現和治療第2型糖尿病的高危險群也是改善糖尿病照護的策略。慢性C型肝炎感染也與胰島素阻抗甚至糖尿病的高患病率有關。Liraglutide是一種長效胰高血糖素樣肽-1（GLP-1）作用劑，用於治療第2型糖尿病。在胰島素阻抗的狀態下，Liraglutide顯示出改善肝臟和肌肉中的胰島素阻抗性並改善脂肪肝。因此，進行Liraglutide是否可透過改善胰島素阻抗來抑制C型肝炎病毒複製研究的可行度是很高的。

關鍵字

糖尿病大小血管病變

並列摘要

Diabetes is a disease that is strongly associated with both microvascular and macrovascular complications, including retinopathy, nephropathy, and neuropathy (microvascular) and ischemic heart disease, peripheral vascular disease, and cerebrovascular disease (macrovascular), resulting in organ and tissue damage in approximately one third to one half of people with diabetes.
Emerging evidence suggests that glycemic variability may be a more reliable measure of glycemic control than mean HbA1c in type 2 diabetes mellitus. Studies also shown HbA1c variability is associated with macrovascular complications especially with cardiovascular events in type 2 diabetic patients, but not in different stages of diabetic kidney disease.
The central pathological mechanism in macrovascular disease is the process of atherosclerosis, which leads to narrowing of arterial walls throughout the body. Atherosclerosis is thought to result from chronic inflammation and injury to the arterial wall in the peripheral or coronary vascular system. Aldose reductase may participate in the development of diabetes complications, but in microvascular complications. Osmotic stress from sorbitol accumulation has been postulated as an underlying mechanism in the development of diabetic microvascular complications, including diabetic retinopathy. Other factors like advanced glycosylated end products (AGEs), oxidative stress, growth factors, including vascular endothelial growth factor (VEGF), growth hormone, and transforming growth factor β, have also been postulated to play important roles in the development of diabetic retinopathy. However, these factors were not known to cause macrovascular complications. The cross interaction of macrovascular complication peripheral vascular disease to microvascular complication diabetic retinopathy gains our interest.
The primary risk factor of both macrovascular and microvascular complications was dyslipidemia. In response to endothelial injury and inflammation, oxidized lipids from LDL particles accumulate in the endothelial wall of arteries leading to a chain reaction with net result of the process is the formation of a lipid-rich atherosclerotic lesion with a fibrous cap. Rupture of this lesion leads to acute vascular infarction.
The combination of increased coagulability and impaired fibrinolysis likely further increases the risk of vascular occlusion and cardiovascular events in type 2 diabetes. Identifying other lipoprotein impairment like triglycerides, high density lipoproteins and its ratio may also important in preventing macrovascular and microvascular complications.
Although preventing macrovascular and microvascular complications were important, early detection and treatment of high risk for type 2 diabetes mellitus is also a strategy to improve care of type 2 diabetes. Chronic Hepatitis C infection has also been associated with high prevalence rates of insulin resistance and even diabetes mellitus. Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, was developed for the treatment of type 2 diabetes. In an insulin-resistant state, liraglutide was shown to improve insulin resistance in the liver and muscles and to improve fatty liver. Therefore, investigation on whether liraglutide can inhibit hepatitis C virus replication to improve insulin resistance can be conducted.

並列關鍵字

Diabetic macrovascular and microvascular complications

參考文獻

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