c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo
Volume 2, Issue 1
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Pages 37 - 45http://dx.doi.org/10.4161/isl.2.1.10196
Authors: Linda Cheung, Sevasti Zervou, Göran Mattsson, Sylvie Abouna, Luxian Zhou, Vasiliki Ifandi, Stella Pelengaris and Michael Khan View affiliations
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.
Received: July 27, 2009; Accepted: September 28, 2009