Enhanced oxidative stress and endocrine pancreas alterations are linked to a novel glucokinase missense mutation in ENU-derived Munich Gck(D217V) mutants

Mol Cell Endocrinol. 2012 Oct 15;362(1-2):139-48. doi: 10.1016/j.mce.2012.06.001. Epub 2012 Jun 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blood Glucose
  • Body Weight
  • DNA Mutational Analysis
  • Eukaryotic Initiation Factor-2 / metabolism
  • Female
  • Genetic Association Studies
  • Genetic Linkage
  • Genotype
  • Glucokinase / genetics*
  • Heat-Shock Proteins / metabolism
  • Hyperglycemia / enzymology
  • Hyperglycemia / genetics*
  • Hyperglycemia / metabolism
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / pathology*
  • Lipid Peroxidation
  • Male
  • Malondialdehyde / blood
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mutagenesis
  • Mutation, Missense*
  • Oxidative Stress*
  • Transcription Factor CHOP / metabolism

Substances

  • Blood Glucose
  • Ddit3 protein, mouse
  • Eukaryotic Initiation Factor-2
  • Heat-Shock Proteins
  • Transcription Factor CHOP
  • Malondialdehyde
  • Glucokinase
  • molecular chaperone GRP78