Aldose reductase and glutathione in senile cataract nucleus of diabetics and non-diabetics

**Background:** Cataract is the leading cause of preventable visual impairment worldwide, with diabetes mellitus increasing the risk of early cataract development up to five-fold. The polyol pathway, initiated by aldose reductase (AR), converts glucose to sorbitol, causing osmotic and oxidative stress in the lens. Glutathione (GSH) is a key antioxidant that protects lens proteins from oxidative damage. Previous studies have measured AR and GSH in blood, but few have directly assessed these parameters in the lens nucleus. This study aimed to evaluate AR and GSH activity in the nucleus of senile cataract in type 2 diabetic versus non-diabetic patients and correlate these with glycaemic control.

**Methods:** This prospective cross-sectional comparative study was conducted at Kasturba Medical College and Government Wenlock Hospital, Mangalore, from October 2019 to September 2021. A total of 62 patients (31 diabetics, 31 non-diabetics) undergoing small incision cataract surgery were enrolled. Inclusion criteria were senile cataract patients aged ≥50 years; diabetics were known type 2 cases on medication. Exclusion criteria included age <50 years, type 1 diabetes, and complicated/traumatic/congenital cataracts. Lens nucleus extracted during surgery was divided for AR and GSH assays: AR was measured by the method of Hayman et al. (homogenization, centrifugation at 27,000×g for 20 min at 4°C), and GSH was determined using Ellman's reagent after perchloric acid precipitation. Blood samples were collected for HbA1c and random blood sugar (RBS). Statistical analysis used IBM SPSS 25, with unpaired t-tests for continuous variables, chi-square for categorical variables, and Pearson's correlation for associations. A p-value <0.05 was considered significant.

**Key Results:** The diabetic group had a significantly lower mean age (60.29 vs 64.87 years, p=0.031), indicating earlier cataract progression. Gender distribution was similar (diabetic: 16F/15M; non-diabetic: 17F/14M; p=0.79). Cataract morphology in diabetics was predominantly mixed (posterior subcapsular + nuclear sclerosis, 45.2%), while non-diabetics had comparable distribution across types (p=0.43). Mean HbA1c was significantly higher in diabetics (7.34% vs 5.7%, p<0.001), as was RBS (151 vs 101 mg/dL, p<0.001). Mean AR activity was markedly elevated in diabetics (2.07 mU/mg protein) compared to non-diabetics (0.22 mU/mg protein, p<0.001). Conversely, mean GSH activity was significantly lower in diabetics (3.38 μMol/g lens) versus non-diabetics (7.47 μMol/g lens, p<0.001). Within the diabetic group, HbA1c showed a significant positive correlation with AR (correlation coefficient 0.394, p=0.028), but not with GSH (p=0.831). Duration of diabetes also correlated positively with AR (correlation coefficient 0.441, p=0.013), but not with GSH (p=0.408).

**Clinical Implications:** This study provides direct evidence from human lens nucleus that diabetic patients exhibit significantly higher AR activity and lower GSH levels compared to non-diabetics, supporting the role of the polyol pathway and oxidative stress in accelerated cataract formation. The positive correlation between HbA1c and AR suggests that poor glycaemic control exacerbates AR activation, while the inverse relationship with GSH indicates depletion of antioxidant defences. These findings underscore the importance of strict glycaemic management to mitigate cataract risk in diabetic patients. Additionally, the results highlight the potential of aldose reductase inhibitors (ARIs) as therapeutic agents to delay cataract progression, as previously demonstrated in animal models. The study's limitations include a relatively small sample size, non-random convenience sampling, and lack of assessment of other oxidative stress markers. Future research should explore longitudinal changes and the efficacy of ARIs in human diabetic cataract prevention.