PuSH - Publication Server of Helmholtz Zentrum München: Enhanced oxidative stress and endocrine pancreas alterations are linked to a novel glucokinase missense mutation in ENU-derived Munich <em>Gck</em><sup>D217V </sup>mutants.

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van Buerck, L.* ; Schuster, M.* ; Rathkolb, B. ; Sabrautzki, S. ; Hrabě de Angelis, M. ; Wolf, E.* ; Aigner, B.* ; Wanke, R.* ; Herbach, N.*

Enhanced oxidative stress and endocrine pancreas alterations are linked to a novel glucokinase missense mutation in ENU-derived Munich Gck^D217Vmutants.

Mol. Cell. Endocrinol. 362, 139-148 (2012)

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Open Access Green as soon as Postprint is submitted to ZB.

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In the large-scale Munich N-ethyl-N-nitrosourea (ENU) mouse mutagenesis project murine models recapitulating human diseases were generated. In one strain, a novel missense mutation (D217V) in the glucokinase (Gck) gene was identified, resulting in decreased glucokinase activity. Heterozygous mutants display mild hyperglycaemia, disturbed glucose tolerance, and decreased glucose-induced insulin secretion. In contrast, homozygous mutants exhibit severe but not survival affecting hyperglycaemia, mild growth retardation, diminished oxidative capacity, and increased abundance of CHOP protein in the islets. Furthermore, the total islet and β-cell volumes and the total volume of isolated β-cells are significantly decreased in adult homozygous mutants, whereas in neonatal mice, β-cell mass is not yet significantly decreased and islet neogenesis is unaltered. Therefore, reduced total islet and β-cell volumes of adult homozygous mutants might predominantly emerge from disturbed postnatal islet neogenesis. Thus, we identified a novel Gck mutation in mice, with relevance in humans, leading to glycaemic disease.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Maturity-onset diabetes of the young, Neonatal diabetes; Glucokinase; β-cell dysfunction; ENU; Experimental genetics; Beta-Cell Glucokinase; Dependent Diabetes-Mellitus; Glucose-Homeostasis; Nitrosourea Mutagenesis; Insulin-Secretion; Protein Stability; Genome-Wide; Mouse Model; Gene; Young

ISSN (print) / ISBN 0303-7207

e-ISSN 1872-8057

Journal Molecular and Cellular Endocrinology

Quellenangaben Volume: 362, Issue: 1-2, Pages: 139-148

Publisher Elsevier

Publishing Place Shannon

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)

PuSH - Publication Server of Helmholtz Zentrum München

Enhanced oxidative stress and endocrine pancreas alterations are linked to a novel glucokinase missense mutation in ENU-derived Munich GckD217V mutants.

Enhanced oxidative stress and endocrine pancreas alterations are linked to a novel glucokinase missense mutation in ENU-derived Munich Gck^D217Vmutants.