近日,，上海生命科學院生化與細胞所吳家睿研究組與哈佛醫(yī)學院袁鈞英研究組及上海有機所馬大為研究組共同合作在線發(fā)表最新研究成果,，報道了一種新的具有葡萄糖濃度依賴的促胰島素分泌的小分子化合物。
胰島素分泌缺陷是2型糖尿病發(fā)生的重要原因之一,。目前臨床上使用最廣泛的促胰島素分泌藥物屬于磺酰脲類化合物,，該類藥物促進胰島素分泌的作用不依賴于血糖濃度，在使用過程中經常引發(fā)低血糖,。因此,，開發(fā)具有葡萄糖濃度依賴性的促胰島素分泌藥物對治療2型糖尿病具有重要的臨床價值。此外,，研究這類化合物的作用機理有助于我們更好地了解胰島素分泌的調控機制,。
關于糖尿病研究近期進展
糖尿病治療新手段——生物谷專訪張濤博士
Diabetes：不用注射胰島素治療糖尿病新法
NEJM：糖尿病流行在中國
糖尿病治療專題專題
通過已經建立的化合物篩選新方法，作者發(fā)現(xiàn)了一種PKC的新型激動劑Sioc145,。Sioc145可增強胰島瘤細胞系及原代大鼠胰島的胰島素分泌水平,，重要的是，其促分泌作用具有葡萄糖濃度依賴性,。通過對其作用機制的研究,，作者揭示出，Sioc145葡萄糖濃度依賴的促分泌作用與其選擇性激活nPKCs而不激活cPKCs緊密相關,。進一步的實驗結果表明,，Sioc145本身并不影響細胞膜電位，其促分泌作用是通過增強放大通路來實現(xiàn)的,。在2型糖尿病模型GK大鼠中,，Sioc145顯著提高了血清中的胰島素濃度，并對糖耐量異常具有一定的改善作用,。該研究工作不僅揭示了胰島素分泌調控的新機制,，而且提示Sioc145有可能作為一種新型促胰島素分泌劑的先導化合物。
該研究工作得到國家973項目,、國家自然科學基金委,、中科院知識創(chuàng)新工程、科技部及美國衰老研究所的經費資助,。(生物谷Bioon.com)
生物谷推薦英文摘要：
Cell Research (2010): 1-12
Identification of a small molecule activator of novel PKCs for promoting glucose-dependent insulin secretion
Shuai Han1,*, Heling Pan2,*, Jianhua Zhang1, Li Tan2, Dawei Ma2, Junying Yuan3 and Jia-Rui Wu1,4
1Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
2Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
33Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
44Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China, Hefei, 230027, China
Using an image-based screen for small molecules that can affect Golgi morphology, we identify a small molecule, Sioc145, which can enlarge the Golgi compartments and promote protein secretion. More importantly, Sioc145 potentiates insulin secretion in a glucose-dependent manner. We show that Sioc145 selectively activates novel protein kinase Cs (nPKCs; δ and ε) but not conventional PKCs (cPKCs; α, βI and βII) in INS-1E insulinoma cells. In contrast, PMA, a non-selective activator of cPKCs and nPKCs, promotes insulin secretion independent of glucose concentrations. Furthermore, we demonstrate that Sioc145 and PMA show differential abilities in depolarizing the cell membrane, and suggest that Sioc145 promotes insulin secretion in the amplifying pathway downstream of KATP channels. In pancreatic islets, the treatment with Sioc145 enhances the second phase of insulin secretion. Increased insulin granules close to the plasma membrane are observed after Sioc145 treatment. Finally, the administration of Sioc145 to diabetic GK rats increases their serum insulin levels and improves glucose tolerance. Collectively, our studies identify Sioc145 as a novel glucose-dependent insulinotropic compound via selectively activating nPKCs.
