Cross-organ metabolomic profiling identified acylcarnitine accumulation as a conserved systemic lipotoxic signature shared by diabetic retinopathy and diabetic nephropathy, with the SLC22A5-CPT2 axis representing a causal genetic mechanism and potential therapeutic target.
Key Findings
Results
Multi-tissue metabolomic profiling of diabetic mice identified a conserved systemic lipotoxic signature involving acylcarnitine accumulation across the retina, plasma, and kidney.
Streptozotocin-induced diabetic mice were used as the animal model for multi-tissue metabolomic profiling.
Metabolomic profiling was performed across three tissue compartments: retina, plasma, and kidney.
The lipotoxic signature was described as 'conserved' and 'systemic,' appearing consistently across all three tissues examined.
The finding linked diabetic retinopathy (DR) and diabetic nephropathy (DN) through a shared metabolic disturbance rather than organ-specific mechanisms.
Results
A predictive plasma panel comprised of free carnitine and two long-chain acylcarnitines was identified as a potential non-invasive indicator of microvascular risk.
The panel consisted of three circulating metabolites: free carnitine and two long-chain acylcarnitines.
The panel was derived from cross-organ metabolomic profiling and validated for clinical relevance using public human DR and DN transcriptomic datasets.
The authors propose this circulating carnitine/acylcarnitine signature 'may serve as a non-invasive indicator of microvascular risk.'
Clinical transcriptomics data from human DR and DN datasets supported the translational relevance of this plasma panel.
Results
The synchronous downregulation of the SLC22A5 and CPT2 axis was identified as a causal genetic signature underlying the observed lipid imbalance in diabetic microangiopathy.
Causal relationships were assessed using two-sample Mendelian randomization (MR) with eQTLGen and genome-wide association study (GWAS) summary statistics.
Both SLC22A5 (a carnitine transporter) and CPT2 (carnitine palmitoyltransferase 2, involved in mitochondrial fatty acid oxidation) were found to be synchronously downregulated.
The MR analysis was used to move beyond association to assess potential causal direction of the genetic-metabolic relationships.
The SLC22A5-CPT2 axis was identified as 'a potential therapeutic target' based on its causal role in acylcarnitine accumulation.
Results
In silico single-cell perturbation analysis revealed that the shared metabolic disturbance induced distinct transcriptional responses across retinal and renal tissues, suggesting tissue-specific molecular responses contributing to organ-specific microvascular dysfunction.
Single-cell in silico perturbation analysis was performed to predict organ-specific functional consequences of the shared metabolic signature.
Despite the shared systemic metabolic disturbance, the transcriptional responses were described as 'distinct' across tissues.
The tissue-specific responses were proposed to 'contribute to organ-specific microvascular dysfunction' in DR versus DN.
This finding suggests that a common upstream metabolic perturbation can produce divergent downstream molecular effects depending on the tissue context.
Results
Both diabetic retinopathy and diabetic nephropathy are associated with systemic disruption of acylcarnitine metabolism, supporting the concept that DR is a marker of systemic microvascular disease.
The study was motivated by the recognition that 'DR is often recognized as a marker of systemic microvascular disease, but the metabolic links to other complications, such as diabetic nephropathy, remain unclear.'
The shared acylcarnitine metabolic signature provides a biochemical basis for the clinical co-occurrence of DR and DN.
Clinical relevance was supported by analysis of public human transcriptomic datasets for both DR and DN.
The findings suggest that acylcarnitine dysregulation is not organ-specific but reflects a systemic metabolic dysfunction in diabetes.
What This Means
This research suggests that two common diabetes complications — diabetic retinopathy (damage to the blood vessels of the eye) and diabetic nephropathy (damage to the blood vessels of the kidney) — share a common underlying metabolic problem involving the buildup of fat-like molecules called acylcarnitines. Normally, carnitine helps transport fatty acids into the mitochondria (the cell's energy factories) to be burned for fuel. In diabetic mice, the researchers found that this process was disrupted in the retina, blood, and kidney simultaneously, causing acylcarnitines to accumulate across all three tissues. A key genetic driver appears to be the reduced activity of two proteins — SLC22A5 (which imports carnitine into cells) and CPT2 (which helps use it to process fats) — and Mendelian randomization analyses suggest this gene pair may causally contribute to the metabolic imbalance rather than simply being associated with it.
A particularly practical finding is that three molecules measurable in the blood — free carnitine and two long-chain acylcarnitines — may together serve as a non-invasive signal of systemic microvascular risk in diabetic patients. This research also suggests that while the metabolic problem is shared between the eye and kidney, the way each tissue responds at the molecular level is different, which may help explain why diabetes damages these organs in different ways. The SLC22A5-CPT2 pathway is proposed as a potential target for future therapies that might address microvascular complications in multiple organs at once.
Liu Q, Liu Y, Yang X, Liu T, Zhao Y, Xia J, et al.. (2026). Integrated Multi-Tissue Omics Identifies Acylcarnitine Accumulation as Shared Metabolic Marker of Diabetic Microangiopathy With Cross-Organ Validation.. Investigative ophthalmology & visual science. https://doi.org/10.1167/iovs.67.11.31