Diabetic retinopathy : from glycation to clinical aspects
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AbstractNon-enzymatic formation of Advanced Glycation End products is observed in the human body and accelerated in disease such as diabetes and its complications. The range of functionally and structurally different AGEs makes it difficult to point out the most pathogenic AGE. However, hydroimidazolone (MG-H1) is the quantitatively dominating AGE-modification in vivo and forms when arginine reacts with the α-oxoaldehyde methylglyoxal, in itself capable of provoking oxidative stress. We used immunoassay as method of detection of levels of MG-H1. Also other compounds were cross-sectionally measured in different body compartments of different patients with type 1 and type 2 diabetes and related to extent of diabetic eye disease; diabetic retinopathy (DR).
In addition, a clinical method for classification of retinal photographs was applied on an epidemiological follow-up study determining cumulative incidence of proliferative diabetic retinopathy (PDR) in 294 patients diagnosed with diabetes type 1 in Norway in the period between 1973 and 1982.
Compared to those without retinopathy, we found increased serum levels of MG-H1 in both type 1 and type 2 diabetic patients with retinopathy. Serum levels of MG-H1 were increased in PDR compared to NPDR (diabetes mellitus type 2).
Vitreous levels of MG-H1 were a) increased in type 2-diabetic patients compared to age-matched controls due to leakage from serum, and b) increased in PDR compared to NPDR in type 2-diabetic patients, originating from the vasculature due to breakdown of the inner blood-retinal barrier (iBRB).
The growth factor VEGF was increased in vitreous fluid of patients with diabetes type 2. Even higher levels were found in PDR. This increase in VEGF was not due to a spill-over effect from the circulation, even though the iBRB is disrupted, supporting that it is produced intraocularly.
Patients with type 1 diabetes of 24 years duration and retinopathy staged from fundus photographs had 89.1% cumulative incidence for DR. 10.5% of these have PDR. Intervention can be made on modifiable risk factors, combined with regular screening for diabetic retinopathy. The positive association between retinopathy and hydroimidazolone in both type 2 and type 1 diabetes remains to be causally investigated.
List of papers:
1. Increased serum levels of the specific advanced glycation end product methylglyoxalderived hydroimidazolone are associated with retinopathy in patients with type 2 diabetes mellitus. (Metabolism. 2006; 55 (2):232-6)
2. Increased vitreous levels of hydroimidazolone in type 2 diabetes patients are associated with retinopathy.(Acta Ophthalmol Scand. 2007; 85(6):618-22)
3. Serum levels of the Advanced Glycation End product hydroimidazolone is associated with retinopathy in type 1 diabetes patients. (Submitted)
4. Low cumulative incidence of proliferative retinopathy in childhood-onset type 1 diabetes in Norway.(Diabetologia. 2006; 49(10):2281-90.)