The Ins2Akita mouse as a model of diabetic retinopathy

Abstract

Abstract: : Purpose: The aim of this study was to identify a mouse model of type I diabetes that could be used for genetic approaches to study the impact of diabetes on the retina. Ins2^Akita mice are from the C57BL/6 background with a dominant mutation in the Ins2 gene, which results in a loss of beta cell function and failed insulin secretion 4–6 weeks postpartum. Methods: An Ins2^Akita mouse colony was established and blood glucose levels were measured weekly to identify diabetic (+/–) and non–diabetic (+/+) mice. The mice were housed for a further 1 to 3 months before sacrifice. The retinas were analyzed for alterations in: vascular permeability to fluorescein–labeled bovine serum albumin (FITC–BSA); immunoreactivity for occludin, active caspase–3 and glial fibrillary acidic protein; and insulin receptor kinase activity. Results: The mean blood glucose of Ins2^Akita diabetic and non–diabetic mice at sacrifice was 412±18.3 and 159±9.6 mg/dL, respectively, while the average body weights were 24.2±1.21 and 33.2±1.18 g, respectively. Retinal vascular permeability to FITC–BSA was significantly increased in Ins2^Akita diabetic compared to non–diabetic mice (p<0.005). Occludin immunoreactivity was more punctate in large arterioles, and there were significantly more caspase–3 positive cells in Ins2^Akita diabetic compared to non–diabetic mice (p<0.01). GFAP immunoreactivity was unchanged in the Ins2^Akita diabetic mice but the astrocytes appeared atrophied. Ins2^Akita diabetes also significantly reduced insulin receptor kinase activity by 27% of control (p<0.05). Conclusions: Consistent with the streptozotocin–diabetic rat, vascular permeability, tight junction disruption, apoptosis and glial abnormalities increase, while insulin receptor function is diminished in the diabetic Ins2^Akita mouse. These data show that the Ins2^Akita mouse is an excellent animal model for molecular genetic studies of diabetic retinopathy.

Keywords: diabetic retinopathy • apoptosis/cell death • cell adhesions/cell junctions