Abstract
Clinical observations found vision-threatening diabetic retinopathy (DR) occurs in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients, but T1DM may perform more progressive retinal abnormalities at the same diabetic duration with or without clinical retinopathy. In the present study, T1DM and T2DM patients without manifestations of DR were included in our preliminary clinical retrospective observation study to investigate the differentiated retinal function at the preclinical stage. Then, T1DM and T2DM rat models with 12-week diabetic duration were constructed to explore the potential mechanism of the discrepancy in retinal disorders. Our data demonstrated T1DM patients presented a poor retinal function, a higher allele frequency for ALDH2GA/AA, and a depressed aldehyde dehydrogenase 2 (ALDH2) activity and silent information regulator 1 (SIRT1) level, compared to T2DM individuals. In line with this, higher amplitudes of neurovascular function-related waves of electroretinograms were found in T2DM rats. Furthermore, the retinal outer nuclear layers were reduced in T1DM rats. The levels of retinal oxidative stress biomarkers including total reactive oxygen species, NADPH oxidase 4 and mitochondrial DNA damage, and inflammatory indicators covering inducible/endothelial nitric acid synthase ratio, interleukin-1, and interleukin-6 were obviously elevated. Notably, the level of retinal ALDH2 and SIRT1 in T1DM rats was significantly diminished, while the expression of neovascularization factors was dramatically enhanced compared to T2DM. Together, our data indicated that the ALDH2/SIRT1 deficiency resulted in prominent oxidative stress and was in association with DR progression. Moreover, a differentiating ALDH2/SIRT1 expression may be responsible for the dissimilar severity of DR pathological processes in chronic inflammatory-related T1DM and T2DM.
Highlights
Diabetes mellitus (DM) has been a severe health-killer, and how to manage itself and its comorbidities is becoming a global concern [1]
All of the subjects had no clinical manifestations of Diabetic retinopathy (DR) such as microaneurysms, macular edema, or neovascularization, which was confirmed by fundus fluorescein angiography, slit lamp microscope, and optical coherence tomography (OCT) according to certified ophthalmologists, and the best-corrected visual acuity (BCVA) was beyond 20/20
The diabetic patients were classified into two cohorts by type of diabetes, and there were 15 patients with type 1 diabetes mellitus (T1DM) and 55 patients with type 2 diabetes mellitus (T2DM)
Summary
Diabetes mellitus (DM) has been a severe health-killer, and how to manage itself and its comorbidities is becoming a global concern [1]. Intricate interconnecting biochemical pathways are implicated in modulating the pathophysiology of diabetic retinopathy [10] Among those related mechanisms, oxidative stress (OS), as a consequence of hyperglycemiaprovoked overproduction of reactive oxygen species (ROS), is believed as the promising pathway to be responsible for DR progression. The disturbance of oxidative stress, including carbonyl stress (induced by lipid aldehydes), can interfere SIRT1 via downregulating nicotinamide adenine dinucleotide (NAD) levels, decreasing posttranslational modification’s ability, and inducing protein-protein interaction disorders [21, 22]. To this regard, ALDH2/SIRT1 may serve as one of the potent molecules to restore the redox homeostasis and mitochondrial health. Rat models, involving single high-dose streptozotocin- (STZ-) induced T1DM and high-calorie diet combined with low-dose STZinduced T2DM, were applied to investigate the retinal dysfunction characteristics and further explore the potential mechanism in the pathological processes of T1DM and T2DM
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