Diminished retinal complex lipid synthesis and impaired fatty acid β-oxidation associated with human diabetic retinopathy.

Patrice E Fort,Jerome E Roger,Subramaniam Pennathur,Matthias Kretzler,Farsad Afshinnia,Tanu Soni,Yang Shan,Robert G Nelson,George Michailidis,Thekkelnaycke M Rajendiran,Jaeman Byun,Helen C Looker,Thomas W Gardner,Steven F Abcouwer

doi:10.1172/jci.insight.152109

Abstract

BACKGROUNDThis study systematically investigated circulating and retinal tissue lipid determinants of human diabetic retinopathy (DR) to identify underlying lipid alterations associated with severity of DR.METHODSRetinal tissues were retrieved from postmortem human eyes, including 19 individuals without diabetes, 20 with diabetes but without DR, and 20 with diabetes and DR, for lipidomic study. In a parallel study, serum samples from 28 American Indians with type 2 diabetes from the Gila River Indian Community, including 12 without DR, 7 with mild nonproliferative DR (NPDR), and 9 with moderate NPDR, were selected. A mass-spectrometry–based lipidomic platform was used to measure serum and tissue lipids.RESULTSIn the postmortem retinas, we found a graded decrease of long-chain acylcarnitines and longer-chain fatty acid ester of hydroxyl fatty acids, diacylglycerols, triacylglycerols, phosphatidylcholines, and ceramide(NS) in central retina from individuals with no diabetes to those with diabetes with DR. The American Indians’ sera also exhibited a graded decrease in circulating long-chain acylcarnitines and a graded increase in the intermediate-length saturated and monounsaturated triacylglycerols from no DR to moderate NPDR.CONCLUSIONThese findings suggest diminished synthesis of complex lipids and impaired mitochondrial β-oxidation of fatty acids in retinal DR, with parallel changes in circulating lipids.TRIAL REGISTRATIONClinicalTrials.gov NCT00340678.FUNDINGThis work was supported by NIH grants R24 DK082841, K08DK106523, R03DK121941, P30DK089503, P30DK081943, P30DK020572, P30 EY007003; The Thomas Beatson Foundation; and JDRF Center for Excellence (5-COE-2019-861-S-B).

Highlights

Diabetic retinopathy (DR) is one the most common and most devastating diabetes complications, with an estimated global prevalence of over 380 million individuals affected [1, 2]
As for other diabetes complications, hyperglycemia is widely accepted as an important driver of DR in diabetes [8], but recent studies suggest a prominent role of altered lipid metabolism in DR pathology [9,10,11,12,13,14,15]
We take advantage of availability of serum biosamples from a very well phenotyped human cohort of patients with type 2 diabetes to identify the lipidomic signature associated with various stages of DR, in a similar fashion as we previously reported for diabetic kidney disease [6]

Summary

Introduction

Diabetic retinopathy (DR) is one the most common and most devastating diabetes complications, with an estimated global prevalence of over 380 million individuals affected [1, 2]. More recent studies have unveiled the important role of a variety of factors — including hypertension, inflammation, insulin resistance, and disordered lipid metabolism — in the generation and progression of multiple diabetes complications [5,6,7]. While these studies have shed some light on the pathogenesis of diabetic kidney disease and diabetic neuropathy, the metabolic basis of DR remains poorly understood. Human studies report alterations of erythrocyte phosphatidylcholines (PCs) [11] and circulating fatty acids and triglycerides [9] in association with DR; specific human retinal tissue analyses are still lacking. This study systematically investigated circulating and retinal tissue lipid determinants of human diabetic retinopathy (DR) to identify underlying lipid alterations associated with severity of DR

Methods

Results

Conclusion