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Diabetologia. 2006 Dec;49(12):2959-68. Epub 2006 Oct 11.

Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction.

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  • 1Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Science, Nanjing Medical University, Nanjing, PR China.

Abstract

AIMS/HYPOTHESIS:

Prostaglandin E(2) (PGE(2)) is a well-recognised inhibitor of glucose-stimulated insulin secretion (GSIS). The aim of this study was to investigate the signalling pathway of PGE(2) in beta cell function regulation in HIT-T15 cells and isolated rat islets.

MATERIALS AND METHODS:

mRNA levels of the prostaglandin E receptor 3 (Ptger3) were measured by real-time PCR. Western blot analysis was used to detect changes in the levels of PTGER3, phosphorylated and total Akt, phosphorylated and total forkhead box 'Other' (Foxo). Transient transfection and reporter assays were used to measure Foxo transcriptional activity. The biological significance of PGE(2) in beta cell function was analysed using MTT, flow cytometry and GSIS assays.

RESULTS:

We found that treating HIT-T15 cells with exogenous PGE(2) stimulated Ptger3 gene expression specifically, and diminished cAMP generation. These were accompanied by the downregulation of Akt and Foxo phosphorylation in HIT-T15 cells and isolated rat islets. Moreover, PGE(2) upregulated basal and partially reversed constitutively active Akt-inactivated Foxo transcriptional activity. Furthermore, GSIS was impaired in PGE(2)-treated HIT-T15 cells and isolated islets. However, the dosage used in the above experiments did not affect beta cell viability and apoptosis. In addition, insulin-like growth factor 1 (IGF-1) pretreatment reversed the effects of PGE(2), and wortmannin treatment abolished the preventive effects of IGF-1.

CONCLUSIONS/INTERPRETATION:

Our observations strongly suggest that PGE(2) can induce pancreatic beta cell dysfunction through the induction of Ptger3 gene expression and inhibition of Akt/Foxo phosphorylation without impacting beta cell viability. These results shed light on the mechanisms of PGE(2) actions in pancreatic beta cell dysfunction.

[PubMed - indexed for MEDLINE]
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