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Shlomit Schaal, Rahele Rahimi Darabad, Qun Zeng, Daxin Tang, Tongalp Tezel; Serum Huntingtin Level is Associated with the Presence and the Severity of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5404.
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To determine whether serum huntingtin (HTT) levels correlate with the presence and the severity of diabetic retinopathy (DR).
Serum and vitreous samples were obtained from 31 patients with diabetes (6 IDDM /25 NIDDM) and 6 non-diabetic controls. HTT levels were determined using ELISA. Clinical exam, stereo fundus photography and fluorescein angiography were used to assess the clinical severity of DR. Correlation was sought between the clinical grades of DR and serum HTT levels. A similar relationship was also tested using female and male heterozygous C57BL/6-Ins2Akita/J mice that develop mild and severe hyperglycemia, respectively. Normoglycemic C57BL/6J animals were used as controls. Immunohistochemistry and western blotting for HTT were done to confirm the results.
Patient cohort included 4 patients without structural lesions of DR, 14 with non-proliferative DR (NPDR) and 13 with proliferative DR (PDR). HTT was not detected in the serum of the control group. There was a gradual elevation in serum HTT levels with increasing severity of DR (0.12±0.12 µg/ml in patients without structural DR, 0.14±0.14 µg/ml in NPDR patients and 0.66±0.45 µg/ml in PDR patients, r=0.88). The highest HTT level was detected in vitreous samples of patients with PDR (0.94±0.23 µg/ml). None of the C57BL/6-Ins2Akita/J mice serum samples were positive for HTT. However, immunohistochemistry, ELISA and western blotting revealed a linear correlation between the level of hyperglycemia and retinal HTT expression (r=0.99, p=0.03).
HTT is up-regulated with hyperglycemia in the outer retina prior to the development of structural lesions associated with DR. Its presence in the systemic circulation may indicate photoreceptor cell death. This may explain why serum HTT levels were undetectable in C57BL/6-Ins2Akita/J mouse which is not characterized with significant neuronal loss. Sequestration of HTT into the systemic circulation makes it an ideal candidate for monitoring the retinal damage and the severity of DR.
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