Scientific article

Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse

Published inDiabetes, vol. 52, no. 2, p. 409-416
Publication date2003

Autosomal dominant diabetes in the Akita mouse is caused by mutation of the insulin 2 gene, whose product replaces a cysteine residue that is engaged in the formation of an intramolecular disulfide bond. These heterozygous mice exhibit severe insulin deficiency despite coexpression of normal insulin molecules derived from three other wild-type alleles of the insulin 1 and 2 genes. Although the results of our previous study suggested that the mutant proinsulin 2 is misfolded and blocked in the transport from the endoplasmic reticulum to the Golgi apparatus, its dominant negative nature has not been fully characterized. In the present study, we investigated the possible pathogenic mechanisms induced by the mutant proinsulin 2. There is no evidence that the mutant proinsulin 2 attenuates the overall protein synthesis rate or promotes the formation of aberrant disulfide bonds. The trafficking of constitutively secreted alkaline phosphatase, however, is significantly decreased in the islets of Akita mice, indicating that the function of early secretory pathways is nonspecifically impaired. Morphological analysis has revealed that secretory pathway organelle architecture is progressively devastated in the beta-cells of Akita mice. These findings suggest that the organelle dysfunction resulting from the intracellular accumulation of misfolded proinsulin 2 is primarily responsible for the defect of coexisting wild-type insulin secretion in Akita beta-cells.

  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • CHO Cells
  • Cricetinae
  • Cysteine
  • Cysteine Endopeptidases/metabolism
  • DNA Primers
  • Diabetes Mellitus, Type 1/ genetics/pathology
  • Endoplasmic Reticulum/metabolism
  • Genes, Dominant
  • Golgi Apparatus/metabolism
  • Heterozygote
  • Islets of Langerhans/pathology/ physiology/ultrastructure
  • Mice
  • Mice, Mutant Strains
  • Multienzyme Complexes/metabolism
  • Mutagenesis, Site-Directed
  • Proinsulin/ genetics/metabolism/secretion
  • Protease Inhibitors/pharmacology
  • Proteasome Endopeptidase Complex
  • Protein Denaturation
  • Protein Folding
  • Protein Transport
  • Recombinant Proteins/metabolism
  • Transfection
Citation (ISO format)
IZUMI, Tetsuro et al. Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. In: Diabetes, 2003, vol. 52, n° 2, p. 409–416. doi: 10.2337/diabetes.52.2.409
Updates (1)
ISSN of the journal0012-1797

Technical informations

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