The validity of peripheral mtDNA damage as a possible biomarker of diabetic retinopathy is further supported by our results from type 2 diabetic animal models; although mtDNA damage and its transcription are not observed in peripheral blood of ZDF rats at 12 weeks of age, an age when these animals show no signs of retinopathy and retinal mtDNA damage,
8 at 40 weeks, an age when retinopathy and mtDNA damage are detectable in the retina and its vasculature, mtDNA damage is also observed in the blood. These results clearly suggest that despite severe hyperglycemia/hyperlipidemia, during the earlier stages of the disease, peripheral blood mtDNA is not altered, but with the extending duration of hyperglycemia/hyperlipidemia (40 weeks of age), blood also shows mtDNA damage. These results also document that type 1 and type 2 diabetes share similar phenomena. As with experimental models, mtDNA damage and decrease in its transcription and copy numbers have been observed in the retinal microvasculature from human donors with diabetic retinopathy.
12,13 The results presented here clearly demonstrate that the peripheral blood from patients with diabetic retinopathy also has increased mtDNA damage and decreased copy numbers compared with their age-matched nondiabetic counterparts; however, such damage is not detected in the blood from diabetic patients without retinopathy. These results support a close association between peripheral blood mtDNA damage and diabetic retinopathy, and confirm the validity of peripheral blood mtDNA damage as a possible biomarker of diabetic retinopathy. Consistent with our results, others have shown a decrease in mtDNA copy numbers and increase in mtDNA damage in the peripheral blood from diabetic patients with proliferative retinopathy and neuropathy.
29,30 We recognize that the number of patients used in the present study is limited, and we do not have details about the severity of hyperglycemia; additional blood samples will be required to confirm relationship between mtDNA damage in the blood and the severity of retinopathy, blood sugar control, and other systemic factors. In addition, we cannot rule out the role of other systemic conditions, including blood pressure and other diabetic complications, in mtDNA damage in the blood of these patients. However, data from diabetic patients with/without retinopathy is consistent with our results from animal models of type 1 diabetes with pharmacologic/genetic therapies to inhibit the development of diabetic retinopathy,
10,18,21 and ZDF rats with/without retinopathy, and support the possibility of blood mtDNA damage as a potential biomarker of diabetic retinopathy. Furthermore, a similar metabolic phenomenon is observed in the progression of diabetic retinopathy,
4 and, here our results showing the failure of mtDNA damage in blood to benefit from reversal of hyperglycemia imply a strong relationship between blood mtDNA damage and diabetic retinopathy.