Development of diabetic retinopathy and worsened outcomes after ischemic stroke in a transgenic mouse model of Type 1diabetes

Abstract

AIMS: Patients with Type 1 diabetes are more prone to develop retinopathy and display a more severe post-ischaemic outcome. We aim (i) to study the progressive effect of hyperglycaemia on retinal function and (ii) to investigate the potential mechanisms in the exacerbation in these patients after stroke. METHODS: Retinal functions of Ins2Akita/+ mice, a transgenic mouse model of Type 1 diabetes, were assessed using electroretinography (n=10–13). Two hour middle cerebral artery occlusion was induced in Ins2Akita/+ mice followed by 2h of reperfusion (n=10–12). Protein expressions in ipsilateral brains were detected by western blot analysis (n=4–7). RESULTS: (i) In electroretinography assessment, Ins2Akita/+ mice displayed diminished amplitude in b-wave at 20 weeks old (448 +/- 13uV vs 350 +/- 21uV, p < 0.001) and in a-wave (-181 +/- 7uV vs -126 +/- 11uV, p < 0.001) and ΣOPs (218 +/- 14uV vs 146 +/- 9uV, p < 0.001) at 36 weeks old. (ii) After reperfusion, Ins2Akita/+ mice exhibited increased mortality (0% vs 20%, p < 0.05), neurological deficits (1.7 +/- 0.5 vs 2.3 +/- 1.0, p < 0.05), infarct size (18.9% +/- 4.2% vs 34.9% +/- 4.1%, p < 0.05) and haemorrhage (0.07% +/- 0.07% vs 0.42% +/- 0.15%, p < 0.05). Decreased ZO-1 (0.6 +/- 0.1 vs 0.2 +/- 0.1, p < 0.01) but elevated VEGF (3.7 +/- 2.2 vs 11.5 +/- 3.8, p < 0.001) and pErk (12.5 +/- 7.9 vs 48.2 +/- 15.1, p < 0.001) protein expressions were observed in the post-ischaemic Ins2Akita/+ brain. CONCLUSIONS: Ins2Akita/+ mice showed hyperglycaemia-associated visual dysfunction and worsened outcomes after ischaemia, which were comparable to clinical studies. Ins2Akita/+ mice could therefore be used for studying the pathogenesis of early diabetic retinopathy. Vulnerable blood vessel integrity and pronounced inflammatory response may account for the post-ischaemia exacerbation, suggesting that VEGF and pErk are the potential therapeutic targets for diabetic subjects upon stroke.