Identification of a small molecule activator of novel PKCs for promoting glucose-dependent insulin secretion.
Cell Res
; 21(4): 588-99, 2011 Apr.
Article
em En
| MEDLINE
| ID: mdl-20877311
ABSTRACT
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 É) but not conventional PKCs (cPKCs; α, ßI and ßII) 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase C
/
Ilhotas Pancreáticas
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Compostos Bicíclicos Heterocíclicos com Pontes
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Glucose
/
Insulina
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cell Res
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
China