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Research Paper

c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo

Linda Cheung, Sevasti Zervou, Göran Mattsson, Sylvie Abouna, Luxian Zhou, Vasiliki Ifandi, Stella Pelengaris and Michael Khan

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c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise β-cell survival and function. We have shown that after Myc activation in adult β-cells in vivo, apoptosis is preceded by hyperglycemia, suggesting glucotoxicity might contribute to Myc-induced apoptosis. To address this question conditional Myc was activated in β-cells of adult pIns-c-MycERTAM mice in vivo in the presence or absence of various glucose-lowering treatments, including exogenous insulin and prior to transplantation with wild-type islets. Changes in blood glucose levels were subsequently correlated with changes in β-cell mass and markers of function/differentiation. Activation of c-Myc resulted in reduced insulin secretion, hyperglycemia and loss of β-cell differentiation, followed by reduction in mass. Glucose-lowering interventions did not prevent loss of β-cells. Therefore, Myc can cause diabetes by direct effects on β-cell apoptosis even in the absence of potentially confounding secondary hyperglycemia. Moreover, as loss of β-cell differentiation/function and hyperglycemia are not prevented by preventing β-cell apoptosis, we conclude that Myc might contribute to the pathogenesis of diabetes by directly coupling cell cycle entry and β-cell failure through 2 distinct pathways.

Authors

Linda Cheung

Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, Coventry UK

Sevasti Zervou

Department of Biological Sciences, University of Warwick, Coventry UK

Göran Mattsson

Department of Biological Sciences, University of Warwick, Coventry UK

Sylvie Abouna

Department of Biological Sciences, University of Warwick, Coventry UK

Luxian Zhou

Department of Biological Sciences, University of Warwick, Coventry UK

Vasiliki Ifandi

Department of Biological Sciences, University of Warwick, Coventry UK

Stella Pelengaris

Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, Coventry UK

Michael Khan Corresponding author: Michael.Khan@warwick.ac.uk

Department of Biological Sciences, University of Warwick, Coventry UK

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.