Volume 21, No 4, Apr 2011

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 21 Issue 4, April 2011: 588-599

ORIGINAL ARTICLES

Identification of a small molecule activator of novel PKCs for promoting glucose-dependent insulin secretion

Shuai Han^1,*, Heling Pan^2,*, Jianhua Zhang¹, Li Tan², Dawei Ma², Junying Yuan³ and Jia-Rui Wu^1,4

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 Correspondence: Jia-Rui Wu, Junying Yuan,(wujr@sibs.ac.cn; jyuan@hms.harvard.edu)

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 K_ATP 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.

Cell Research (2011) 21:588-599. doi:10.1038/cr.2010.137; published online 28 September 2010

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