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Involvement of Notch signaling in Human Beta-Cell Dedifferentiation

Lookup NU author(s): Dr Michael White, Professor James Shaw


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Background: Inadequate insulin secretion by beta cells is thehallmark of Type 2 diabetes. The prevailing view over the last decadehas been that this is due to irreversible loss of beta cell mass throughapoptosis; however, pathological tissue analysis provides littlesupport for this. Rodent studies have provided convincing evidencefor beta cell de-differentiation as a novel mechanism underlying betacell failure. Here, loss of mature beta cell phenotypic markers isaccompanied by the expression of progenitor (oct4), EMT (vimen-tin) and alpha cell (glucagon) related markers, a phenotype we havedescribed in human diabetes. Recently, reversal of rodent beta cellde-differentiation following inhibition of the TGF-b pathway hasbeen demonstrated.Aims: To develop an in vitro model of human beta cell de-differentiation and to determine the impact of TGF-b signalling onhuman beta cell de-differentiation.Methods: Following ethical consent, human islets were placed inadherent culture for 7 days. Gene expression and beta cell functionwere analysed by qPCR and glucose stimulated insulin secretion.Immunofluorescent studies were employed to determine changes inphenotypic/de-differentiation markers.Results: Following 7 days in adherent culture, human beta cellsundergo de-differentiation, which is characterised by insulin lossand increased expression of glucagon, oct4 and vimentin. Follow-ing treatment with small molecule inhibitors of the TGF-b pathway(Y27632 and SB431542), significant increases in insulin expressionwere associated with significantly reduced levels of glucagon, oct4and vimentin. Furthermore, beta cell function was significantlyimproved compared to DMSO treated controls.Conclusions: The data presented here provide evidence for aninvolvement of TGF-b signalling in human beta cell de-differen-tiation/reprogramming, thereby providing a potential therapeutictarget for restoring/maintaining beta cell function

Publication metadata

Author(s): White MG, Shaw JAM

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: American Diabetes Association 74th Scientific Sessions

Year of Conference: 2014

Pages: A545-A545

Print publication date: 20/07/2014

Online publication date: 14/07/2014

Acceptance date: 10/07/2014

Publisher: Diabetes