Systemic Levels Contribute Significantly to Increased Intraocular IGF-I, IGF-II and IFG-BP3 in Proliferative Diabetic Retinopathy

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Abstract
Increased intraocular levels of angiogenic growth factors such as insulin-like growth factor I (IGF-I) have been demonstrated in proliferative diabetic retinopathy (PDR). It is unclear whether increased leakage of the blood retina barrier or local synthesis primarily determine intraocular levels of IGFs in man, which is of special interest regarding possible therapeutic options with somatostatin analogues in PDR. This is the first study investigating parallely serum and vitreous levels of IGF-I/II, IGF-BP3 and the liver-derived permeability marker albumin to determine in vivo the amount of circulation-derived intraocular IGFs. A control group without retinal proliferation and patients with PDR were compared. Levels of IGF-I/II, IGF-BP3 and albumin were determined by immunological methods. Vitreous levels of albumin were 2.2-fold elevated in patients with PDR (254.1 ± 37.2 mg/dl; n = 27; p = 0.0027) compared to controls (115.7 ± 36.2 mg/dl; n = 10), whereas serum levels were slightly decreased in diabetes patients (5049 ± 196 mg/dl vs. 4330 ± 186 mg/dl; p = 0.0283). This was comparable to an increase of IGF-I/II and IGF-BP3 in vitreous from PDR patients (IGF-I: 2.3 ± 1.1 ng/ml; p = 0.005. IGF-II: 37.9 ± 4.9 ng/ml; p = 0.0003. IGF-BP3: 97.9 ± 26.9 ng/ml; p = 0.0001; n = 34) compared to controls (IGF-I: 0.7 ± 0.1 ng/ml. IGF-II: 21.3 ± 4.2 ng/ml. IGF-BP3: 31.3 ± 4.9 ng/ml; n = 19). Serum levels did not differ significantly among the groups regarding IGF-I, II and IGF-BP3. Intraocular albumin and IGF-I levels calculated as percentage of the respective serum levels correlated significantly (r = 0.42; p = 0.012). This study demonstrates that influx of IGF-I, II and IGF-BP3 in PDR quantitatively parallels influx of the liver derived serum protein albumin suggesting that leakage of the blood retina barrier and serum levels of IGF primarily determine intravitreal IGF levels rather than local synthesis. Suppression of systemic IGF levels by new, highly effective somatostatin-analogues therefore provides a promising approach to prevent PDR.