近日，上海生命科学院生化与细胞所吴家睿研究组与哈佛医学院袁钧英研究组及上海有机所马大为研究组共同合作在线发表最新研究成果，报道了一种新的具有葡萄糖浓度依赖的促胰岛素分泌的小分子化合物。
胰岛素分泌缺陷是2型糖尿病发生的重要原因之一。目前临床上使用最广泛的促胰岛素分泌药物属于磺酰脲类化合物，该类药物促进胰岛素分泌的作用不依赖于血糖浓度，在使用过程中经常引发低血糖。因此，开发具有葡萄糖浓度依赖性的促胰岛素分泌药物对治疗2型糖尿病具有重要的临床价值。此外，研究这类化合物的作用机理有助于我们更好地了解胰岛素分泌的调控机制。
关于糖尿病研究近期进展
Diabetes：不用注射胰岛素治疗糖尿病新法
NEJM：糖尿病流行在中国
糖尿病治疗专题专题糖尿病治疗新手段——生物谷专访张涛博士
通过已经建立的化合物筛选新方法，作者发现了一种PKC的新型激动剂Sioc145。Sioc145可增强胰岛瘤细胞系及原代大鼠胰岛的胰岛素分泌水平，重要的是，其促分泌作用具有葡萄糖浓度依赖性。通过对其作用机制的研究，作者揭示出，Sioc145葡萄糖浓度依赖的促分泌作用与其选择性激活nPKCs而不激活cPKCs紧密相关。进一步的实验结果表明，Sioc145本身并不影响细胞膜电位，其促分泌作用是通过增强放大通路来实现的。在2型糖尿病模型GK大鼠中，Sioc145显著提高了血清中的胰岛素浓度，并对糖耐量异常具有一定的改善作用。该研究工作不仅揭示了胰岛素分泌调控的新机制，而且提示Sioc145有可能作为一种新型促胰岛素分泌剂的先导化合物。
该研究工作得到国家973项目、国家自然科学基金委、中科院知识创新工程、科技部及美国衰老研究所的经费资助。(生物谷Bioon.com)
生物谷推荐英文摘要：
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.