Abstract
"第2型糖尿病是造成全球死亡率和器官失能的主要原因,而胰島素抵抗是其主要病理特徵。 目前,全球糖尿病患者達到4.3億人,台灣達到220萬人。骨骼肌負責約90%的胰島素刺激的葡萄糖攝取,且骨骼肌中的胰島素抵抗性是第2型糖尿病最早發生之前的病理特徵。 然而,但目前如何改善骨骼肌胰島素抵抗性的療法卻付之闕如。
胰島素在骨骼肌可以促進葡萄糖之攝取作用,在骨骼肌中胰島素會觸發葡萄糖轉運蛋白GLUT4從儲存囊泡轉移到細胞膜,從而由血液攝取葡萄糖至細胞內來降低血糖。如眾所周知,胰島素會增加胞吐作用,促進GLUT4轉移到細胞膜。 但是,關於GLUT4內吞回收作用的調控卻知之甚少。
GSK3是一種普遍表達的絲氨酸/酥氨酸激酶,最初被發現為肝醣合成的主要調節分子。 GSK3包含兩個異構型GSK3α和GSK3β。 最近的研究發現, 這兩個GSK3異構型作用並不完全相同。 先前對GSK3的研究主要集中在GSK3β,而GSK3α的研究甚少。 然而最近越來越多的證據證明GSK3α對於糖尿病,心血管疾病和神經退行性疾病具有重要作用。哈佛大學研究團隊最近發現,從第2型糖尿病病患誘導分化出的骨骼肌, 在胰島素刺激後有較低的GSK3α和GSK3β磷酸化比值,顯示GSK3α活性對骨骼肌的胰島素抵抗有重要的影響。
我們初步研究發現,胰島素不僅通過調節胞吐機制,而且還通過內吞過程來調節GLUT4在肌肉細胞內的分佈。 我們的初步研究表明,胰島素-AKT信息傳遞途徑可通過抑制GSK3α的活性來減少GLUT4的內吞作用。 活化GSK3α會導致dynamin-2的活性加強,而dynamin-2是GLUT4內吞作用的關鍵蛋白,這顯示GSK3α是骨骼肌中調節胰島素所刺激的葡萄糖攝取的關鍵。 最近,GSK3α專一特異性的抑制劑已經陸續被開發出來,如BRD0705和G28_14,為開發改善骨骼肌胰島素抵抗的治療提供了機會。此外,我們將使用GSK3α抑制多胜肽來驗證結果。 我們提出了一項三年的研究計畫:
1.進一步闡明GSK3α活性對骨骼肌細胞胰島素阻抗性的影響。
2.探討GSK3α基因剔除小鼠骨骼肌的胰島素敏感性。
3.研究GSK3α小分子抑制劑與抑制胜肽對第2型糖尿病小鼠模型的治療效果。
我們相信這項研究將發現治療第2型糖尿病的嶄新方法。"
"Type 2 diabetes is one of the major cause of morbidity and mortality worldwide with insulin resistance as the main pathological feature. The number of patients with diabetes mellitus now reaches 430 million globally and 2.2 million in Taiwan. Skeletal muscle is responsible for ~90 % uptake of insulin-stimulated glucose uptake. Insulin resistance in skeletal muscle is the earliest features to be detected which precedes the development of type 2 diabetes. However, it remains unknown how to mitigate the insulin resistance in skeletal muscle.
Skeletal muscle responds to insulin-mediated glucose uptake through triggering the translocation of a glucose transporter, GLUT4 from the storage vesicle to plasma membrane. The translocation of GLUT4 to plasma membrane leads to uptake of glucose from the blood and lower blood glucose. It is well-established that insulin increase exocyst complex to facilitate GLUT4 exocytosis. However, less is known about the regulation of GLUT4 endocytosis.
GSK3 is a ubiquitously expressed serine/threonine kinase first identified as the main regulators of glycogen synthesis. GSK3 comprises two isoforms, GSK3α and GSK3β. It has now clarified that these two GSK3 isoforms are not identical but display both isoform-specific as well as overlapping functions. Previous studies of GSK3 largely focused on β isoform thus leave GSK3α overshadowed. Emerging evidence now demonstrate significant roles of GSK3α in the pathogenesis of diabetes, cardiovascular disease and neurodegenerative disorders. Furthermore, R. Kahn and colleagues have recently reported that the skeletal muscle cells derived from type 2 diabetic patient iPSC showed reduced insulin-stimulated phosphorylation of GSK3α:GSK3β ratio, implying GSK3α isoform activity is of particular importance of insulin action in diabetic skeletal muscle. This finding stresses the importance of GSK3 subtype.
We discovered that insulin signaling determines the subcellular distribution of GLUT4 not only through regulating the exocytosis machineries, but also the endocytic processes. Our preliminary data shows that insulin-AKT pathway reduces GLUT4 endocytosis by inhibiting the activity of GSK3α. GSK3α inhibition leads to attenuated activity of dynamin-2, a critical protein for GLUT4 endocytosis (Fig 1). With these pilot discoveries, we hypothesize that GSK3α is the critical and specific GSK3 isoform in regulating insulin resistance of skeletal muscle. Recently, small-molecule GSK3α-specific inhibitors such as BRD0705 and G28_14 have been developed, providing an opportunity to develop therapeutic strategy for treating insulin resistance. Furthermore, we will use GSK3 inhibitory polypeptide to verify out results. Here we proposed a three-year integrated project to accomplish following goals:
1. To further investigate the effect of GSK3α activity on insulin resistance in skeletal muscle.
2. To examine the insulin sensitivity of skeletal muscles of GSK3 knockout mice.
3. To examine the effect of GSK3 small-molecule inhibitors and inhibitory polypeptide on the insulin resistance in type 2 diabetic mice model.
We believe this study will lead to the brand new approach to treat type 2 diabetes."
Keyword(s)
GSK3α
葡萄糖轉運蛋白GLUT4
骨骼肌
內吞過程
胰島素阻抗
GSK3α抑制劑
GSK3α
GLUT4
skeletal muscle
endocytosis
insulin resistance
GSK3α inhibitor