2026-11-092026-11-09https://scholars.csmu.edu.tw/handle/123456789/38627Diabetes mellitus (DM) is a common endocrine disease with unknown etiology. Many factors can lead to DM onset, however, host genetic factors and environmental factors are the focus of discussion. Our previous study showed a significant association between high IL-4 secreting genotypes and type 2 diabetes mellitus (T2DM) as well as that between the IL-4 genotypes and the lower circulatory HDL-C level. Moreover, mice with lower IL-4 secreting ability had better glucose control ability and were more resistant to STZ-induced diabetic onset. The above observations indicated that IL-4 levels might contribute to type 2 diabetic pathogenesis by inducing insulin resistance through participating in the regulation of lipid and glucose metabolism. To our knowledge, this is the first report uncovering the relationship between IL-4 and T2DM. We think this is a good start to further investigate and uncover the interaction of IL-4 and lipid/glucose metabolism in type 2 diabetic pathogenesis. For further elucidation the role(s) of IL-4 in the diabetic pathogenesis as well as the interactions between adipose tissues and immune responses in insulin resistance, the specific aims of this propose project are to examine the putative effect(s) of IL-4, in the presence or absence of insulin treatment under high or low glucose environments, to key morphological features and markers of adipocyte differentiation and lipid/glucose metabolism. First of all, whether the morphological features and the expression profiles of key transcription factors (markers) for adipocyte differentiation are altered by IL-4 administration will be investigated using 3T3-L1 pre-adipocytes as study model. The combined effects of IL-4, insulin and glucose concentrations to the adipose differentiation will also be analyzed. In the second project year, we will further examine the putative regulation of IL-4/insulin to key enzymes involved in the lipid (lipogenesis and lipolysis) and glucose metabolism (glucose uptake) to elucidate the effect or regulation of IL-4 under low and high glucose culture environment and to uncover the regulatory role(s) of IL-4. In addition, the alteration of insulin sensitivity by IL-4 under various conditions will be examined. Moreover, the signal pathways and the mechanism involved in the regulation of IL-4 to the identified candidate proteins will be further investigated. In the third project year, the in vivo regulation of IL-4 to lipid/glucose metabolism and insulin sensitivity will be further confirmed and investigated using IL-4 overexpressed and IL-4-depleted mice as study model. Besides, the blood chemistry parameters regarding lipid/glucose metabolism will also be studied. Through the implementation of the proposal and taken the in vitro and in vivo study results in the entire project together, novel clues and data regarding cross talks among immune responses, lipid/glucose metabolism and insulin resistance in diabetic pathogenesis will be revealed and provided for further elucidating the role of IL-4 played in the mechanism of T2DM pathogenesis. We believe the completion of the in vitro cellular and in vivo animal studies sequentially can not only disclose the involvement of immune response and energy balance in the development of T2DM, but also provide a putative clue for future designing of type 2 diabetic treatment.糖尿病 (DM) 是常見的內分泌疾病，其致病機轉仍然未知。許多因素可能會導致DM，其中以遺傳與環境因子相關的研究最多。本實驗室先前的研究結果(國科會92-94年度補助計畫)顯示，與健康個體比較，第二型糖尿病(T2DM)患者帶有轉錄活性較高之第四型介白素(interleukin-4, IL-4)啟動子基因型，而且週邊血液單核細胞分泌IL-4的能力也比健康個體之單核細胞高；分析IL-4基因型與患者之血液生化檢驗數據相關性時，本實驗室發現轉錄活性較高之IL-4啟動子基因型與高密度脂蛋白膽固醇(high density lipoprotein cholesterol, HDL-C)濃度有顯著相關性。此外，利用streptozotocin誘導動物產生T2DM的研究模式中也發現，分泌高量IL-4之老鼠的確比分泌低量IL-4之老鼠T2DM發病率較高，發病病程較快，葡萄糖耐受性也較差。上述研究結果顯示IL-4可能會透過參與脂肪與葡萄糖代謝，造成胰島素阻抗性而和T2DM發病與病程有關。本研究計畫為上述國科會補助計畫研究成果的延伸，主要目的是以上述研究成果為根基，循序漸進地從細胞模式到實驗動物模式深入探討IL-4對脂肪與葡萄糖代謝的影響與調控，以及糖尿病致病過程中能量代謝、脂肪細胞與免疫系統間之交互作用，了解IL-4與能量代謝在胰島素抗性形成與糖尿病發病過程中的角色。本研究計劃於97年度(第一年)研究期間將首先以能量代謝與儲存之主要細胞，也是胰島素目標細胞之脂肪前驅細胞3T3-L1細胞株為實驗模式，分析活體外(in vitro) IL-4對3T3-L1細胞分化為成熟脂肪細胞過程中之形態變化與主要調控因子的影響，以及在正常血糖濃度與高血糖濃度環境中，IL-4與胰島素對脂肪細胞分化的調控是否具有加成性或拮抗性作用，並分析其調控的路徑與機制。第二年(98年度)研究期間將持續利用3T3-L1細胞探討IL-4對參與脂肪細胞之脂肪與葡萄糖代謝作用主要關鍵酵素的調控，以及在正常血糖濃度與高血糖濃度環境中，IL-4與胰島素對脂肪細胞之新陳代謝與能量平衡是否具有加成性或拮抗性的影響，並分析其調控的路徑與機制。綜合上述研究之數據，將可了解免疫作用、發炎反應與代謝作用三者之交互作用與胰島素阻抗性的關係，以及在糖尿病致病過程中扮演的角色。第三年(99年度)研究期間計畫以小鼠為實驗動物模式，探討並確認活體中(in vivo) IL-4對脂肪與葡萄糖代謝、胰島素抗性以及胰島素訊息傳遞之主要關鍵酵素的調控；進一步了解在糖尿病致病時免疫作用、發炎反應與脂肪細胞之交互作用在胰島素阻抗性形成過程與糖尿病致病機轉中扮演的角色。我們相信本計畫的執行除了有助於進一步釐清糖尿病致病過程中IL-4的角色之外，也可提供有關免疫作用、發炎反應與脂肪細胞之新陳代謝之間相互調控的資訊；因此本研究不但可以幫助我們更了解T2DM的致病機轉，也提供了未來發展新糖尿病療法的嶄新線索。第四型介白素脂肪代謝葡萄糖代謝胰島素阻抗性第二型糖尿病interleukin-4lipid and glucose metabolisminsulin resistancetype 2 diabetes mellitusProject