title: c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo.
abstract: 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-MycER(TAM) 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 two distinct pathways.
authors.affiliation: Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, Coventry UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Cheung
authors.forename: Sevasti
authors.initials: S
authors.lastname: Zervou
authors.forename: Göran
authors.initials: G
authors.lastname: Mattsson
authors.forename: Sylvie
authors.initials: S
authors.lastname: Abouna
authors.forename: Luxian
authors.initials: L
authors.lastname: Zhou
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Ifandi
authors.forename: Stella
authors.initials: S
authors.lastname: Pelengaris
authors.forename: Michael
authors.initials: M
authors.lastname: Khan
mesh_terms: D000818:Animals; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D016259:Genes, myc / Q000502:physiology*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009929:Organ Size / Q000235:genetics; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D019076:Transgenes / Q000502:physiology; D015854:Up-Regulation
chemical_list: D007328:Insulin