The Ins2Akita mouse as a model of early retinal complications in diabetes

Alistair J. Barber, David A. Antonetti, Timothy S. Kern, Chad E N Reiter, Rohit S. Soans, J. Kyle Krady, Steven W. Levison, Thomas W. Gardner, Sarah K. Bronson

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339 Scopus citations

Abstract

PURPOSE. This study tested the Ins2Akita mouse as an animal model of retinal complications in diabetes. The Ins2Akita mutation results in a single amino acid substitution in the insulin 2 gene that causes misfolding of the insulin protein. The mutation arose and is maintained on the C57BL/6J background. Male mice heterozygous for this mutation have progressive loss of β-cell function, decreased pancreatic β-cell density, and significant hyperglycemia, as early as 4 weeks of age. METHODS. Heterozygous Ins2Akita mice were bred to C57BL/6J mice, and male offspring were monitored for hyperglycemia, beginning at 4.5 weeks of age. After 4 to 36 weeks of hyperglycemia, the retinas were analyzed for vascular permeability, vascular lesions, leukostasis, morphologic changes of micro- and macroglia, apoptosis, retinal degeneration, and insulin receptor kinase activity. RESULTS. The mean blood glucose of Ins2Akita mice was significantly elevated, whereas the body weight at death was reduced compared with that of control animals. Compared with sibling control mice, the Ins2Akita mice had increased retinal vascular permeability after 12 weeks of hyperglycemia (P < 0.005), a modest increase in acellular capillaries after 36 weeks of hyperglycemia (P < 0.0008), and alterations in the morphology of astrocytes and microglia, but no changes in expression of Müller cell glial fibrillary acidic protein. Increased apoptosis was identified by immunoreactivity for active caspase-3 after 4 weeks of hyperglycemia (P < 0.01). After 22 weeks of hyperglycemia, there was a 16.7% central and 27% peripheral reduction in the thickness of the inner plexiform layer, a 15.6% peripheral reduction in the thickness of the inner nuclear layer (P < 0.001), and a 23.4% reduction in the number of cell bodies in the retinal ganglion cell layer (P < 0.005). In vitro insulin receptor kinase activity was reduced (P < 0.05) after 12 weeks of hyperglycemia. CONCLUSIONS. The retinas of heterozygous Ins2Akita mice exhibit vascular, neural, and glial abnormalities generally consistent with clinical observations and other animal models of diabetes. In light of the relatively early, spontaneous onset of the disease and the popularity of the C57BL/6J inbred strain as a background for the generation and study of other genetic alterations, combining the Ins2Akita mutation with other engineered mutations will be of great use for studying the molecular basis of retinal complications of diabetes.

Original languageEnglish (US)
Pages (from-to)2210-2218
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number6
DOIs
StatePublished - Jun 2005

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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