Role of advanced glycation end products and sorbitol dehydrogenase in the pathogenesis of diabetic retinopathy
Authors: Moemen Leqaa A. , Abdel Hamid Mona A. , Wahab Soher Abdel , Kenawy Mahmoud Kenawy M. , Abuelela Manal H. , Hassanin Olfat A. , Fouly Marwa A. , Abdelazeem Amira A. , Noweir Shahira Riad , Ismail Somaia M. , Abdel Gawad Yara Hossam Eldin R. , Refaat Safa , Amer Azza K. , Khalaf Nervana A. , Aboelmakarem Safya H. , Elsobky Mehry S. , Abdelrasool Mona R. , Karawya Sherif S. , Osman Zeinab M. 
Published: April 2020

Abstract
Background
Diabetic retinopathy is one of the common microvascular complications of diabetes. The formation of advanced glycation end products (AGE) exerts deleterious effects by acting directly to induce cross-linking of proteins promoting vascular damage. Hyperglycemia causes disturbance in glycogenesis pathway resulting in reduction of glucose to sorbitol which is converted to fructose by sorbitol dehydrogenase.

Methods
The levels of advanced glycation end products (AGE), lipid profile, and glycosylated Hb were estimated in 266 type I diabetic patients without retinopathy, patients with nonproliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy patients (PDR).The association between genotypes of two polymorphisms of sorbitol dehydrogenase gene (SDH) was estimated in the promoter region: a C/G transversion located at _1214 position and a G/C transversion at _888 position. This study showed allele–specific PCR for C-1214G polymorphism and restriction fragment length polymorphism (RFLP) technique for a G/C transversion at _ 888 position.

Results
Significant increase was detected in glycosylated Hb levels in diabetic group, both with retinopathy and without retinopathy. Also, a significant increase in Hb1c in PDR group compared to NPDR. Significant increase in total cholesterol, HDL, TG, and AGE in PDR group compared to the group without retinopathy. No significant change was observed in the same parameter between PDR and NPDR group. Significant increase in AGE in both PDR and NPDR group compared to the group without retinopathy. No significant change in PDR group compared to NPDR.
The results of this study showed no significant difference in genotype distribution (C/C, C/G, G/G) of the C˗1214G polymorphism between the two groups of patients with and without DR A2-. There was no statistically significant difference between the three genotypes (CC, CG, and GG) of the C˗1214G polymorphism in relation to DR severity in male genders. However, there was a statistically significant difference in female gender with increased frequency of CC genotype (2.7%, 21.9%, and 23.7%).
There was no significant difference in genotype distribution (C/C, G/C, and G/G) of the G˗888C polymorphism between the two groups of patients with DR and without DR. However, the CC genotype occurred more frequently in patients with DR than patients without DR (6.7% vs. 3.9%), and G/G genotype occurred more frequently in patients without DR than patients with DR (0.70.6 vs. 0.59.7).
There was no statistically significant influence of the three genotype (GG, GC, and CC) polymorphism on DR progression in both genders. However, there was an increased frequency of CC genotypes polymorphism with severity in both genders (0.0%, 4.2%, 6.9%) in males and (5.6%, 6.3%, 8.8%) in females.

Conclusion
The onset of diabetic retinopathy is multifactorial, and a cascade of hyperglycemia-oxidative pathways has been involved in the initiation and progression of this disease. However, further research is required to understand the cellular and molecular mechanism of diabetic retinopathy pathogenesis. So that novel anti–diabetic retinopathy strategies can be developed, aiming to reduce the major economical and medical burden caused by diabetic retinopathy.