Abstract
Purpose: :
We have previously demonstrated in type 1 and type 2 diabetes animal models that upregulation of the central enzyme of sphingolipid metabolism, Acid Sphingomyelinase (ASM) plays an important role in the pathogenesis of diabetic retinopathy. ASM was upregulated in the retinas of donors with diabetic retinopathy compared to control. Moreover, we have shown a dramatic downregulation of long chain fatty acid elongases Elovl2 and Elovl4 in diabetic retina. Elovl4 has recently been shown to play a major role in production of very long chain fatty acids and in very long chain (≥C28) ceramide production in the skin. This study was designed to determine changes in the sphingolipid profile in the vitreous of diabetic patients.
Methods: :
Vitrectomy samples were obtained from diabetic patients with active proliferative retinopathy (either vitreous hemorrhage or traction retinal detachment) or non-diabetic patients treated for macular hole. Vitreous sphingolipids were extracted with alkaline hydrolysis of gycerolipids, and sphingolipid profiles were determined by tandem mass spectrometry using precursor ion scanning of m/z 264 on a Thermo TSQ Vantage triple quadrupole mass spectrometer. Sphingolipid abundances were quantitated against appropriate internal standards.
Results: :
Vitreous samples from the patients with diabetic retinopathy had increased ceramide, hexosylceramide and lactsylceramide levels. Interestingly, sphingomyelin levels were also increased in diabetic retinopathy vitreous samples. Detailed species analysis revealed that the increase in ceramide and sphingomyelin is mainly due to a dramatic upregulation of 24:0 species with concomitant down regulation of 26:0 and 28:0 species.
Conclusions: :
Diabetes induced changes in retinal sphingomyelinases and fatty acid elongases leads to dramatic upregulation of sphingolipids in the vitreous mainly due to accumulation of 24:0 species. Overall, our study indicates that changes in sphingolipid metabolism play a role in the development of diabetic retinopathy.
Keywords: diabetic retinopathy • lipids • pathology: human