Selective decrease in alpha(1)-antitrypsin levels in diabetic retinopathy: Could the levels of it be playing a role in the pathophysiology of diabetic retinopathy?

BACKGROUND & OBJECTIVES: Type 2 diabetes mellitus (T2DM) is known to induce inflammation and activation of neutrophils causing the release of neutrophil elastase (NE), a pro-inflammatory proteinase. The activity of NE is regulated by endogenous inhibitors alpha(1)-antitrypsin (α(1)-AT) and alpha(2)-macroglobulin (α(2)-MG). Disrupted proteolytic homeostasis in T2DM patients is one of the causes for vascular complications. This study was carried out for evaluating the levels of plasma NE, α(1)-AT, α(2)-MG and NE-α(1)-AT complex to understand their roles in the pathophysiology of diabetic nephropathy (DN) and diabetic retinopathy (DR). METHODS: A total of 240 participants (Control, n=60; T2DM, n=60; DN, n=60; and DR, n=60) were recruited after recording history, clinical examination and laboratory investigations. Retinopathy was confirmed by fundoscopy and nephropathy by urinary albumin excretion and serum creatinine levels. NE was measured using STANA. α(1)-AT, α(2)-MG and NE-α(1)-AT complex were estimated by ELISA. RESULTS: Baseline clinical and laboratory findings were confirmatory to the study groups. The mean elastase activity was higher (P<0.0005) in diabetes groups (T2DM=0.73±0.31, DN=0.87±0.35, DR=0.76±0.41) than controls (0.35±0.20). The levels of α(1)-AT were lower in DR (8.77±2.85) than DN (26.26±6.16) and T2DM (41.13±14.06) when juxtaposed with controls (122.95±25.71). The approximate fold decrease of α(1)-AT levels was 15 for DR and four for DN compared to controls. The levels of α(2)-MG were lowered in T2DM (167.29±30.45), DN (144.66±13.72), and DR (104.67±11.47) than controls (208.87±31.16). The NE-α(1)-AT complex levels were: controls (215.83±13.61), T2DM (98.85±23.85), DN (129.26±20.40) and DR (153.25±17.11). INTERPRETATION & CONCLUSIONS: Homeostasis of NE, α(1)-AT and α(2)-MG is disrupted in T2DM, DN and DR. Strikingly reduced levels of α(1)-AT observed in DR are indicative of its possible role in the pathophysiology of retinopathy and emphasizes α(1)-AT as a plausible therapeutic target.