Carin Gustavsson

TNF-alpha is an independent serum marker for proliferative retinopathy in type 1 diabetic patients.

PURPOSE This study aimed to determine if there are any associations between serum levels of inflammatory markers and proliferative retinopathy (PDR) in type 1 diabetic patients. DESIGN A cross-sectional design was utilized for this study. METHODS One hundred twenty-eight type 1 diabetic patients underwent stereo fundus photography according to the Early Treatment Diabetic Retinopathy Study and were divided into two retinopathy groups: no or nonproliferative retinopathy (NDR/NPDR; n=62) and PDR (n=66). Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, IL-6, soluble vascular cellular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), P-selectin, and high-sensitivity C-reactive protein (hsCRP) were analyzed. Statistical analysis was performed using nonparametric Mann-Whitney U test and multivariate logistic regression analysis. RESULTS Patients with PDR had higher levels of TNF-alpha [7.0 pg/ml (<4-17) vs. 6.0 pg/ml (<4-25); P=.009], sVCAM-1 [860 ng/ml (360-2120) vs. 700 ng/ml (310-1820); P<.001], and P-selectin [180 ng/ml (39-400) vs. 150 ng/ml (42-440); P=.017; figures are expressed as median (range)]. There were no differences in serum levels of sICAM-1 or hsCRP. IL-1 beta was not detectable in any patient, and IL-6 was detectable in only 22.7% of the patients. In multivariate logistic regression analysis, TNF-alpha was the single, persistent, independent determinant inflammatory marker for PDR. CONCLUSION The association between TNF-alpha and PDR in type 1 diabetic patients suggests that inflammation might play a role in the pathogenesis of proliferative diabetic retinopathy.

Inflammatory markers in nondiabetic and diabetic rat retinas exposed to ischemia followed by reperfusion.

Purpose: To examine the retinal inflammatory response to ischemia–reperfusion in nondiabetic and diabetic rats injected with either an &ohgr;-3-polyunsaturated fatty acid (docosahexaenoic acid [DHA]) or a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (pravastatin). Methods: Diabetes was induced by an intraperitoneal injection of streptozocin, and retinal ischemia was induced by ligation of the optic nerve and vessels, followed by reperfusion for 1 hour or 24 hours. Five minutes before surgery, an intravenous injection of DHA, pravastatin, or vehicle (ethanol) was administered. The mRNA expressions of tumor necrosis factor (TNF)-&agr;, interleukin (IL)-6, caspase-1, IL-1&bgr;, P-selectin, vascular cellular adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1 were compared between ischemic and nonischemic retinas as well as diabetic and nondiabetic nonischemic retinas. Results: Ischemia induced increased expressions of TNF-&agr; (P ≤ 0.012), IL-1&bgr; (P ≤ 0.017), ICAM-1 (P ≤ 0.025), and IL-6 (P = 0.012), and diabetes induced increased expression of caspase-1 (P ≤ 0.046), VCAM-1 (P ≤ 0.027), ICAM-1 (P ≤ 0.016), IL-1&bgr; (P = 0.016), and IL-6 (P = 0.041). Ischemia plus diabetes did not increase these findings significantly. DHA and pravastatin had some inhibitory effects in diabetic rats (P ≤ 0.037). Conclusions: Inflammation triggered by ischemia–reperfusion may play a role in diabetic retinopathy. Intervention on lipid-based structures by &ohgr;-3-polyunsaturated fatty acids or statins seemed to have beneficial effects on inflammation in diabetes.

Tumor necrosis factor-alpha does not mediate diabetes-induced vascular inflammation in mice

Objective—Vascular inflammation is a key feature of both micro- and macrovascular complications in diabetes. Several lines of evidence have implicated the cytokine tumor necrosis factor (TNF)&agr; as an important mediator of inflammation in diabetes. In the present study we evaluated the role of TNF&agr; in streptozotocin (STZ)-induced diabetes on vascular inflammation in C57BL/6 wild-type and apoE−/− mice. Methods and Results—Diabetes increased the expression of vascular cell adhesion molecule (VCAM)-1 in cerebral arteries >150 &mgr;m in diameter as well as the macrophage accumulation in aortic root atherosclerotic plaques in apoE−/− mice. A more pronounced vascular inflammatory response was observed in diabetic TNF&agr;-deficient apoE−/− mice. These mice were also characterized by increased accumulation of IgG and IgM autoantibodies in atherosclerotic lesions. Diabetes also increased VCAM-1 expression and plaque formation in apoE-competent TNF&agr;−/− mice, whereas no such effects were observed in C57BL/6 wild-type mice. Conclusions—The present findings suggest that TNF&agr; does not mediate diabetic-induced vascular inflammation in mice and reveal an unexpected protective role for TNF&agr;. These effects are partly attributable to a direct antiinflammatory role of TNF&agr;, but may also reflect a defective development of the immune system in these mice.

Circulating antipericyte autoantibodies: a novel modifier of risk of progression of diabetic retinopathy?

Background: Antipericyte autoantibodies (APAAs) are present in high frequency among diabetic subjects with and without nonproliferative retinopathy. This study aimed to determine whether progression of retinopathy in type 2 diabetes was associated with the same medical risk factors in APAA-positive subjects as in APAA-negative subjects. Methods: Type 2 diabetic patients with nonproliferative diabetic retinopathy at baseline were followed prospectively for 2 years monitoring progression of retinopathy. Thirty-eight (21.7%) of 175 patients had progression in Early Treatment Diabetic Retinopathy Study grade by ≥2 steps in at least 1 eye. Serum APAAs were detected by immunofluorescence on tissue-cultured bovine retinal pericytes. Results: Progression of retinopathy was associated with HbA1c level (P = 0.002), diabetes duration (P = 0.03), and albumin/creatinine ratio (P = 0.02) in APAA-negative subjects but not in APAA-positive subjects. The association between progression and APAAs was strongest in the upper quartile for HbA1c level (>8.0%), where 71.4% of patients negative for APAAs had progression of retinopathy while only 24.1% of patients positive for APAAs had progression (P = 0.007). Conclusion: The results suggest that APAA presence is a modifier of risk of progression of retinopathy due to hyperglycemia and that it could be useful as a biochemical marker of risk of progression of diabetic retinopathy in type 2 diabetic patients with poor metabolic control.