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

Research team lead by Prof. Jiarui Wu from SIBCB, Prof. Junying Yuan from Harvard Medical School and Prof. Dawei Ma from Shanghai Institute of Organic Chemistry recently co-identified a small molecular activator of novel protein kinase Cs (nPKCs) for promoting glucose-dependent insulin secretion. Their work was published on Cell Research.

 

By using an image-based screen for small molecules that can affect Golgi morphology, the researchers identified a small molecule, Sioc145, which can enlarge the Golgi compartments and promote protein secretion. More importantly, Sioc145 potentiated insulin secretion in a glucose-dependent manner. The researchers showed that Sioc145 selectively activated 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, promoted insulin secretion independent of glucose concentrations. Furthermore, the scientists demonstrated that Sioc145 and PMA showed differential abilities in depolarizing the cell membrane, and suggested that Sioc145 promoted insulin secretion in the amplifying pathway downstream of KATP channels. In pancreatic islets, the treatment with Sioc145 enhanced the second phase of insulin secretion. Increased insulin granules close to the plasma membrane were also observed after Sioc145 treatment. Finally, the administration of Sioc145 to diabetic GK rats increased their serum insulin levels and improved glucose tolerance. Collectively, these studies identified Sioc145 as a novel glucose-dependent insulinotropic compound via selectively activating nPKCs.