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

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.

► Hyperglycaemic mouse strain from the Munich ENU mouse mutagenesis project.
► We identified and characterised a novel mutation in exon 6 of the glucokinase gene.
► Genotype-dependent severity of hyperglycaemia due to reduced glucokinase activity.
► Oxidative stress, islet and β-cell mass reduction in homozygous mutants.
► Viable model for both, neonatal diabetes and maturity-onset diabetes of the young.