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BTBR ob/ob mouse model of type 2 diabetes exhibits early loss of retinal function and retinal inflammation followed by late vascular changes.
Diabetologia. 2018 11; 61(11):2422-2432.D

Abstract

AIMS/HYPOTHESIS

Diabetic retinopathy is increasing in prevalence worldwide and is fast becoming a global epidemic and a leading cause of visual loss. Current therapies are limited, and the development of effective treatments for diabetic retinopathy requires a greater in-depth knowledge of disease progression and suitable modelling of diabetic retinopathy in animals. The aim of this study was to assess the early pathological changes in retinal morphology and neuronal, inflammatory and vascular features consistent with diabetic retinopathy in the ob/ob mouse model of type 2 diabetes, to investigate whether features similar to those in human diabetic retinopathy were present.

METHODS

Male and female wild-type (+/+), heterozygous (+/-) and homozygous (-/-) BTBR ob/ob mice were examined at 6, 10, 15 and 20 weeks of age. Animals were weighed and blood glucose was measured. TUNEL and brain-specific homeobox/POU domain protein 3A (BRN3A) markers were used to examine retinal ganglion cells. We used immunostaining (collagen IV and platelet endothelial cell adhesion molecule [PECAM]/CD31) to reveal retinal vessel degeneration. Spectral domain optical coherence tomography was used to reveal changes in the thickness and structure of the retinal layer. Vitreous fluorophotometry was used to investigate vascular permeability. A-waves, b-waves and oscillatory potentials were measured under photopic and scotopic conditions. Concanavalin A leucostasis and immunostaining with glial fibrillary acidic protein (GFAP) and ionised calcium-binding adapter molecule 1 (IBA-1) identified differences in inflammatory status. Paraffin sections and transmission electron microscopy were used to reveal changes in the thickness and structure of the retinal layer.

RESULTS

Following the development of obesity and hyperglycaemia in 2-week-old and 3-week-old ob-/ob- mice, respectively (p < 0.001), early functional deficits (p < 0.001) and thinning of the inner retina (p < 0.001) were identified. Glial activation, leucostasis (p < 0.05) and a shift in microglia/macrophage phenotype were observed before microvascular degeneration (p < 0.05) and elevated vascular permeability occurred (p < 0.05).

CONCLUSIONS/INTERPRETATION

The present characterisation of the development of diabetic retinopathy in the ob/ob mouse represents a platform that will enable the development of new therapies, particularly for the early stages of disease.

Authors+Show Affiliations

Translational Vision Research, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.Translational Vision Research, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.Translational Vision Research, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.Translational Vision Research, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.Translational Vision Research, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.Translational Vision Research, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.Translational Vision Research, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.Translational Vision Research, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK. d.shima@ucl.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30094465

Citation

Lee, Vivian K., et al. "BTBR Ob/ob Mouse Model of Type 2 Diabetes Exhibits Early Loss of Retinal Function and Retinal Inflammation Followed By Late Vascular Changes." Diabetologia, vol. 61, no. 11, 2018, pp. 2422-2432.
Lee VK, Hosking BM, Holeniewska J, et al. BTBR ob/ob mouse model of type 2 diabetes exhibits early loss of retinal function and retinal inflammation followed by late vascular changes. Diabetologia. 2018;61(11):2422-2432.
Lee, V. K., Hosking, B. M., Holeniewska, J., Kubala, E. C., Lundh von Leithner, P., Gardner, P. J., Foxton, R. H., & Shima, D. T. (2018). BTBR ob/ob mouse model of type 2 diabetes exhibits early loss of retinal function and retinal inflammation followed by late vascular changes. Diabetologia, 61(11), 2422-2432. https://doi.org/10.1007/s00125-018-4696-x
Lee VK, et al. BTBR Ob/ob Mouse Model of Type 2 Diabetes Exhibits Early Loss of Retinal Function and Retinal Inflammation Followed By Late Vascular Changes. Diabetologia. 2018;61(11):2422-2432. PubMed PMID: 30094465.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BTBR ob/ob mouse model of type 2 diabetes exhibits early loss of retinal function and retinal inflammation followed by late vascular changes. AU - Lee,Vivian K, AU - Hosking,Brett M, AU - Holeniewska,Joanna, AU - Kubala,Ewa C, AU - Lundh von Leithner,Peter, AU - Gardner,Peter J, AU - Foxton,Richard H, AU - Shima,David T, Y1 - 2018/08/09/ PY - 2018/04/20/received PY - 2018/06/21/accepted PY - 2018/8/11/pubmed PY - 2019/1/8/medline PY - 2018/8/11/entrez KW - Diabetes KW - Diabetic retinopathy KW - Eye KW - Obesity KW - Retina KW - Type 2 diabetes mellitus SP - 2422 EP - 2432 JF - Diabetologia JO - Diabetologia VL - 61 IS - 11 N2 - AIMS/HYPOTHESIS: Diabetic retinopathy is increasing in prevalence worldwide and is fast becoming a global epidemic and a leading cause of visual loss. Current therapies are limited, and the development of effective treatments for diabetic retinopathy requires a greater in-depth knowledge of disease progression and suitable modelling of diabetic retinopathy in animals. The aim of this study was to assess the early pathological changes in retinal morphology and neuronal, inflammatory and vascular features consistent with diabetic retinopathy in the ob/ob mouse model of type 2 diabetes, to investigate whether features similar to those in human diabetic retinopathy were present. METHODS: Male and female wild-type (+/+), heterozygous (+/-) and homozygous (-/-) BTBR ob/ob mice were examined at 6, 10, 15 and 20 weeks of age. Animals were weighed and blood glucose was measured. TUNEL and brain-specific homeobox/POU domain protein 3A (BRN3A) markers were used to examine retinal ganglion cells. We used immunostaining (collagen IV and platelet endothelial cell adhesion molecule [PECAM]/CD31) to reveal retinal vessel degeneration. Spectral domain optical coherence tomography was used to reveal changes in the thickness and structure of the retinal layer. Vitreous fluorophotometry was used to investigate vascular permeability. A-waves, b-waves and oscillatory potentials were measured under photopic and scotopic conditions. Concanavalin A leucostasis and immunostaining with glial fibrillary acidic protein (GFAP) and ionised calcium-binding adapter molecule 1 (IBA-1) identified differences in inflammatory status. Paraffin sections and transmission electron microscopy were used to reveal changes in the thickness and structure of the retinal layer. RESULTS: Following the development of obesity and hyperglycaemia in 2-week-old and 3-week-old ob-/ob- mice, respectively (p < 0.001), early functional deficits (p < 0.001) and thinning of the inner retina (p < 0.001) were identified. Glial activation, leucostasis (p < 0.05) and a shift in microglia/macrophage phenotype were observed before microvascular degeneration (p < 0.05) and elevated vascular permeability occurred (p < 0.05). CONCLUSIONS/INTERPRETATION: The present characterisation of the development of diabetic retinopathy in the ob/ob mouse represents a platform that will enable the development of new therapies, particularly for the early stages of disease. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/30094465/BTBR_ob/ob_mouse_model_of_type_2_diabetes_exhibits_early_loss_of_retinal_function_and_retinal_inflammation_followed_by_late_vascular_changes_ L2 - https://doi.org/10.1007/s00125-018-4696-x DB - PRIME DP - Unbound Medicine ER -