Cheung, Linda, Zervou, Sevasti I., Mattsson, Göran, Abouna, Sylvie, Zhou, Luxian, Ifandi, Vasiliki, Pelengaris, Stella and Khan, Michael. (2010) c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo. Islets, Volume 2 (Number 1). pp. 37-45. ISSN 1938-2014

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Abstract

c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise beta-cell survival and function. We have shown that after Myc activation in adult beta-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 beta-cells of adult plns-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 beta-cell mass and markers of function/differentiation. Activation of c-Myc resulted in reduced insulin secretion, hyperglycemia and loss of beta-cell differentiation, followed by reduction in mass. Glucose-lowering interventions did not prevent loss of beta-cells. Therefore, Myc can cause diabetes by direct effects on beta-cell apoptosis even in the absence of potentially confounding secondary hyperglycemia. Moreover, as loss of beta-cell differentiation/function and hyperglycemia are not prevented by preventing beta-cell apoptosis, we conclude that Myc might contribute to the pathogenesis of diabetes by directly coupling cell cycle entry and beta-cell failure through two distinct pathways.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Hyperglycemia, Myc oncogenes -- Research, Insulin -- Secretion, Pancreatic beta cells, Apoptosis, Diabetes -- Pathogenesis
Journal or Publication Title:	Islets
Publisher:	Landes Bioscience
ISSN:	1938-2014
Date:	2010
Volume:	Volume 2
Number:	Number 1
Page Range:	pp. 37-45
Identification Number:	10.4161/isl.2.1.10196
Status:	Peer Reviewed
Publication Status:	Published
Funder:	Wellcome Trust (London, England), Leverhulme Trust (LT), General Charities of the City of Coventry, Yews Trust, Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Association for International Cancer Research (AICR)
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URI:	http://wrap.warwick.ac.uk/id/eprint/41462

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