In rabbit models of dyslipidemia and metabolic syndrome, a high cholesterol diet increases amyloid-beta (Aβ) levels in retinal photoreceptors, inner and outer neural layers, and ganglion cell layers (9). The proposed mechanism for this damage is a compromised blood–retina–barrier (BRB). Damage to the BRB results in the leakage of plasma contents and Aβ accumulation (10). Hypoxia secondary to excess Aβ induces structural changes in retinal ganglion cells (11). These structural changes precipitate loss of functionality and apoptosis of ganglion cells.

Numerous studies have described the neurotoxic effects of Aβ peptide accumulation (12). In vitro models using RPE cell lines demonstrated cholesterol dysmetabolism-induced Aβ peptide accumulation (13). Decreased activity of neprilysin (NEP) and α-secretase represents an additional mechanism contributing to Aβ accumulation (13). Elevated levels of Aβ peptide in the retina ultimately results in increased production of ROS and a decrease in peroxidase activity (9). Elevated levels of ROS produce deleterious effects for retinal ganglion cells (9, 10). Additional studies have confirmed this model by pharmacologically blocking the effects of Aβ peptide (14). These pharmacological interventions demonstrated a protective role for RGCs (14).

Hypercholesterolemia produces a number of oxidized byproducts that result in retinal damage. Notably, 7-ketocholesterol (7-KCh), a product formed from the oxidation of cholesterol. 7-KCh blood levels are elevated in diabetic patients (15). However, unlike Aβ peptide accumulation, elevated levels of 7-KCh have not been linked to a high cholesterol diet (15). 7-KCh activates multiple inflammatory pathways—including p38, MAP/ERK, and AKT-PKCζ-NFκB (16). Activation of the MAP/ERK pathway leads to increased oxidative stress and inflammation in retinal cells (17). 7-KCh accumulation is predominantly located in the retinal pigmented epithelium, where it can induce apoptosis secondary to the MAP/ERK signaling pathway (16). Additionally, 7-KCh induction of the NFκB pathway facilitates the expression of a number of cytokines that result in an inflammatory response (18). Notably, a primary mechanism of simvastatin’s protective role retinal ganglion cells has been attributed to the attenuation of the NFκB pathway (18).

In rabbit models, hypercholesteremia impairs retinal function by diminishing retinal ganglion cell density and decreasing thickness of the photoreceptor layer and inner nuclear layer (19). Destruction of these layers is correlated with an increase of inducible nitric oxide synthase (iNOS) activity (19). Increased iNOS activity results in increased oxidative damage to retinal ganglion cells. The increase iNOS activity is mediated through calcium-mediated pathways (19). Dyslipidemia plays a crucial role in stimulating this iNOS-mediated damage by increasing the intracellular calcium concentration (20). Calretinin levels, a marker for intracellular calcium levels, are elevated in the retinal neurons of animal models of dyslipidemia (20).

To further expound on the participation of lipids, we will discuss nitric oxide (NO), and the three distinct isoforms of NO synthase responsible for its synthesis: iNOS, neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS). These enzymes play a critical role in endothelial dysfunction in the context of DR development and progression. It is well-established that elevated lipid levels cause endothelial dysfunction due to a marked reduction in the bioavailability of NO. Microvascular complications in DR can be detected histologically as microvascular basement membrane thickening, closures and rarefaction of capillaries, and diagnosed clinically by impaired endothelial function and eNOS uncoupling (21). Endothelial dysfunction, eNOS uncoupling, and apoptosis occur in the metabolic syndrome and type 2 DM result in microvascular damage (21). Microvascular beds located in the eyes become leaky and develop inflammation, vasoconstriction, and an overall pro-thrombotic milieu (21). In regard to hypercholesterolemia and endothelial dysfunction, markedly elevated lipids inactivate dimethylarginine dimethylaminohydrolase (DDAH). This enzyme is responsible for the metabolism of asymmetric dimethylarginine (ADMA). Continued accumulation of ADMA inhibits eNOS, which significantly limits the availability of NO to vascular endothelial cells in the eye (22, 23). This subsequently initiates endothelial dysfunction (22, 23). This cascade of events is one of many mechanisms underlying the development of endothelial dysfunction in DR. This endothelial-damage results in the breakdown of the BRB and, consequently, the exudation of serum lipids and lipoproteins (24). Interestingly, it has been estimated that 20% of retinal vascular occlusion is connected to hyperlipidemia, primarily as a result of the process described above (25).

To date, the results from epidemiological studies focused on lipid profiles and DR are inconsistent. While some studies have determined a relationship between elevated levels of total cholesterol and LDL-cholesterol and the development and progression of DR, other studies were unable confirm these findings (26). Thus, the pathophysiologic model for the role of lipids in DR is commonly assumed to mirror the pathophysiology of atherosclerosis (26). This current model places greater emphasis on disruption of the BRB and extravasation of lipid particles in the retina, rather than attempting to simply correlate total plasma lipid and lipoprotein levels to the development of DR (26). Modified lipid particles are toxic to all retinal cell types, including endothelial cells of capillaries in the BRB. The transient disruption of the BRB ultimately leads to irreversible chronic damage. Therefore, the current consensus is that weakening of the BRB and subsequent local lipoprotein-mediated damage is more important than derangements in the overall serum lipid profile in predicting the development of DR (26).

A study from Montgomery et al. examined the retinal function of mice following the chemical induction of sustained dyslipidemia (27). Isolated dyslipidemia and its associated increase in lipid oxidation and oxidative stress led to a decline of retinal function and severely reduced b/a-wave ratios (27). The potential mechanisms for this damage include microvascular damage, disruption of neurovascular coupling, decreased apoA1 HDL and Muller cell dysfunction (27). While this retinal dysfunction did not alter the visual acuity, this study suggests that the oxidative stress from hyperlipidemia may create conditions in the retina that amplify damage from diabetes. This finding is commonly linked to retinal vascular obstruction.

TRPV4, a nonselective cation channel that responds to cell swelling has been implicated as a potential source for retinal damage in dyslipidemia states. In vivo studies using mice retinal tissue suggest TRPV4 is a sensor of both physical and chemical stimuli and helps regulate the permeability of the inner retinal endothelial barrier (28, 29). An in vivo study of mice models by Lakk in 2017 demonstrates that dyslipidemia causes dysregulation of these TRPV4 channels and subsequent glial cell damage (29). A study using pig retinal models found that RN-1734, a specific TPRV4 inhibitor, significantly increased the ganglion cell survival, preserved retinal laminar architecture and attenuated the gliotic response (30). This study also showed that use of TRPV4 agonist resulted in extensive degenerative damage and retinal remodeling. Furthermore, in vitro models have demonstrated that TRPV1 and TRPV4 channel inhibition led to suppression of retinal angiogenesis (31). These results suggest an opportunity for therapeutic intervention in vaso-proliferative retinal disorders such as DR.

One way oxidative stress causes damage to cells is by the free radical mediated degradation of macromolecules, some examples of which include cellular components like membrane lipids and apolipoproteins such as LDL, VLDL, among others (64). When free radicals and ROS trigger these peroxidation cascades, the end result is the generation of advanced lipoxidation end products (ALEs). ALEs are the adducts that accumulate as a result of the non-enzymatic chemical reactions that occur in cellular constituents subjected to oxidative stress (64). This process results in the disruption of intracellular signaling, the lipoxidative damage of DNA, and the compromise of structural integrity at the level of the plasma membrane and intracellular proteins (64). This deleterious phenomenon affects cells all throughout the body, and the retina is no different (65).

In fact, studies in rat models suggest that the state of diabetes decreases the synthesis of aldehyde dehydrogenase, an enzyme that detoxifies ALEs in order to protect the retina from above mechanisms that aggravate DR, such as the disruption of cellular responses and damage to intracellular proteins (65). This is corroborated by a study conducted by Zou et al. that reports a correlation between exposure to oxidized and glycated LDL and retinal cell apoptosis (66). This phenomenon is seen both in human and diabetes-induced rat models. More specifically, diabetes seemed to increase levels of oxidized and glycated LDLs in the retina of the animals even in the absence of comorbid dyslipidemia (66). This further suggests that ALEs such as oxidized LDL may accumulate in the retina in a state of isolated hyperglycemia without necessitating a high blood lipid burden in order for deleterious apolipoproteins to cause damage to retinal neurons.

Furthermore, retinal ischemia is critically involved in the pathophysiology of DR due to the oxidative stress that reperfusion injury inflicts on cells. Ischemia and reperfusion results in the creation of free radicals and ROS, including superoxide as a noteworthy example. The superoxide anion is particularly notable because it is a precursor to many other ROS and is produced by the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). For this reason, one might hypothesize that decreased levels of NOX should decrease the burden of oxidative stress in any cell in the body. A study tested this hypothesis on retinal neurons in mice with deletion of the NOX2 gene, which encodes a catalytic subunit of the active enzyme (67). The knockout mice with hypo-functioning NOX demonstrated reduced oxidative burden from free radical species, along with protection from neuronal death in the ganglion cell layer, when inflicted with ischemia and reperfusion in order to mimic the state of DR (67). As opposed to the NOX2 knockout mice, retinas from the wild type mice in the above study experienced markedly increased cell death apoptosis due to elevated levels of ROS and increased apoptosis signaling through phosphorylation of ERK and NFκB and subsequently allowing programmed cell death to transpire (67).

The polyol pathway is pathway that results in excess glucose getting converted to sorbitol in retinal capillaries (39). This pathway mediated by aldose reductase leads to increased osmotic stress and damage to the retina and plays a crucial role in the development of retinopathy (36). This pathway has been studied both in vivo and in vitro (40, 68). An in vitro study found that AR inhibition led to decreased inflammatory markers, decreased AGE formation and decreased VEGF production (40). An in vivo study involving AR-transgenic mice found that AR blockade prevented retinal microglia (RMG) migration into nuclear layers of the retina. This decreased influx of inflammatory cells suggests a potential pharmaceutical target for preventing ocular inflammation in DR (68).

The basic science literature regarding the oxidative stress that diabetes produces in the retina is corroborated with clinical research of patients. Diabetic patients have an increased level of oxidative stress placed on the retina. This level of oxidative stress is documented in patients with normal lipid levels and has also been correlated to the severity of disease (38). These conclusions are drawn by findings of elevated levels of markers for oxidative stress such as malondialdehyde (MDA) and conjugated dienes (CD) upon sampling of vitreous humor from diabetic patients (38). A study using similar markers of oxidative stress found increased levels of patients with PDR compared to NPDR (32). Their findings suggest a direct association of level of oxidative stress and severity. This higher level of oxidative stress seen in the retina of diabetic patients even in the absence of diabetes is likely related to hyperglycemic models of oxidative stress detailed in the basic science literature. A cross-sectional study evaluating the risks that individual components of metabolic syndrome play in retinopathy found hyperglycemia to have the highest odds ratio of 2.41 (2.05, 2.84) of any single component (32).The cross-sectional study from Mondal et al. evaluated patients with diabetic retinopathy to identify the biochemical pathways responsible for retinal damage (42). Their findings shed further light on the mechanisms of hyperglycemic-mediated damage. They found hyperglycemia increased apoptosis of retinal capillary endothelial cells secondary to oxidative stress, advanced glycation, glutamate toxicity and lipid peroxidation (Mondal). The demise of retinal capillary cells resulted in elevated levels of VEGF and VEGFR2, laying the framework of diabetic retinopathy (42).

As mentioned above, the polyol pathway, also known as the sorbitol-aldose reductase pathway is considered one the major pathways specifically linking hyperglycemia with retinopathy (39). The surplus of glucose leads to activation of aldose reductase and formation of sorbitol. The accumulation of sorbitol damage the retinal capillaries through osmotic stress (40). A case control study examining 3000 patients looked at patients with and without DR and evaluated them for polymorphisms in polyol pathway genes to assess the involvement of this pathway with the development of DR (41). It was found that individuals with polymorphisms that lead to a higher level of aldose reductase had enhanced conversion of glucose to sorbitol which lead to increased risk of DR (41).

Studies employing mouse models of type 1 and type 2 diabetes suggested that dyslipidemic states potentiated the deleterious effects of diabetes on retinal neurons. Specifically, one study noted that an increase in mitochondrial damage in secondary to a dyslipidemic state resulted in quicker apoptosis of retinal capillary cells, accelerating microvascular destruction and retinal damage from diabetes (16). This evidence suggests that controlled lipid levels in pre-diabetic patients can decrease the occurrence and progression of DR.

A study that developed new insight into the pathophysiology of diabetic retinopathy by administering oxidized LDL (ox-LDL) and ox-LDL immune complexes into human diabetic retinas post-mortem, using immunohistochemical staining for IgG in order to correlate its presence to proportional cytotoxic effects on retinal pericytes (69). Retinal pericyte cytotoxicity was determined by measuring the pericytes’ viability, receptor expression, apoptosis, endoplasmic reticulum (ER) stress and oxidative stress, and cytokine secretion; through analysis of all of these metrics, it was concluded that increased ox-LDL immune complexes predict the development of DR via induction of apoptosis, presence of oxidative stress and ER stress, and enhanced secretion of inflammatory cytokines (69). The study showed how retinas that displayed IHC staining for both IgG and ox-LDL had proportional severity of retinopathy, further elucidating a unique pathogenic mechanism of diabetic retinopathy which could potentially offer new targets for pharmaceutical intervention in diabetic retinas (69).

Several preclinical studies have identified specific molecular targets shared by the disease processes of both diabetes and dyslipidemia as relevant to both pathogenesis and disease progression; one such target is 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK). This molecule is activated within hepatocytes by metformin, a drug used to treat diabetes, resulting in both increased glucose utilization and favorable lipid profiles by lowering triglycerides and VLDL (75). In vitro models or rat retinal cells, AMPK-activating compounds decrease apoptosis in rat retinal Müller cells (76).

In mouse models, AMPK has been associated with improving insulin sensitivity (77, 78) and ameliorating dyslipidemia (77–80) through its regulation of lipid and glucose metabolism (81). AMPK-activating compounds reduce diabetes-induced retinal inflammation (82), demonstrating the interconnectedness of diabetes, dyslipidemia, and DR.

PPARβ/δ signaling positively affects the lipid profile by increasing HDL cholesterol and lowering LDL cholesterol (83). Hydroxymethylglutaryl (HMG)-CoA reductase inhibitors, or statins, represent another pharmacotherapy whose pleiotropic effects offer insights into shared mechanisms of pathophysiology between dyslipidemia and diabetes. This highly efficacious lipid-lowering drug class inhibits the rate-limiting step of cholesterol synthesis (84). The pleiotropic anti-diabetes and antioxidant effects of statins (85), however, allow insights into the interconnectedness of mechanisms of both dyslipidemia and DM. Retinal microvascular endothelial cells (RMECs) treated with simvastatin demonstrated an upregulated peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), an endogenous molecule which activates PPARγ (86). Upregulation of the PGC-1α pathway decreased generation of ROS, which contribute to DR pathogenesis by exposing both pericytes and endothelial cells of the retinal vasculature to oxidative stress thereby contributing to vascular degeneration (86). Decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and poly (ADP-ribose) polymerase (PARP) activity also contributed to this reduced generation of ROS (86). Furthermore, in vivo administration of simvastatin reduced ROS-mediated apoptosis of both pericytes and vascular endothelial cells in rats and attenuated apoptosis of bovine retinal endothelial cells in vitro by decreasing p38 mitogen-activated protein kinase (MAPK) activity, modulating PARP signaling, along with decreasing vascular endothelial growth factor (VEGF) expression and vascular permeability (86). Pharmacological control of the PPARγ pathway and its regulators by both TZDs and statins, respectively used for treating diabetes and dyslipidemia, illustrates the molecular interplay among pathways involved in the pathogenesis and therapy of these two disease states. Furthermore, it illustrates their mutual connections to key mediators in DR pathogenesis such as elevated ROS production and apoptosis of retinal neurons and cellular components of the retinal vasculature.

Simvastatin administration in RMEC models generated increased nitric oxide (NO) release resulting in vascular repair through induction of Akt signaling and activation of eNOS (86). In addition, in vivo, rosuvastatin increases Akt phosphorylation, thereby activating systemic insulin sensitivity (38); this further illustrates that diabetes and dyslipidemias share a range of common molecular targets.

Within the peroxisome-proliferator-activated receptor (PPAR) protein family of transcription factors that regulate lipid metabolism, PPARα is activated by fibrates, a class of lipid-lowering drugs (87). PPARβ/δ contributes to AMPK signaling in both dyslipidemia and DM (88), as PPARβ/δ increases AMPK levels in mouse liver (89), and synergistically activates gene expression alongside AMPK in mouse skeletal muscle, resulting in a cooperative activity that augments glucose utilization (88). Furthermore, PPARβ/δ specifically activates the AMPK pathway itself in mouse skeletal muscle, preventing ER stress-associated inflammation and insulin resistance (90). ER stress results in apoptotic cell death (91), and ER stress can be attenuated by the protective effect of AMPK activity resulting in reduced apoptosis during DR pathogenesis (92). Potential mechanistic connections among obesity, insulin resistance, and dyslipidemia resulting in ER stress (93), provide a strong rationale that such epigenetic phenomena common to dyslipidemia and diabetes can be targeted mechanistically and pharmacologically by activating AMPK.

In addition, PPARβ/δ plays a unique role in each disease state independent of AMPK activation. In mouse models of diabetes, PPARβ/δ increases insulin sensitivity through increased glucose catabolism, shunting glucose into lipogenesis pathways and increasing fatty acid oxidation in skeletal muscle (94).

Protective properties of PPARs were tested in an ex vivo model of ototoxicity using gentamicin to induce ROS production, lipid peroxidation, and apoptosis in cultured explants of the mouse organ of Corti (95). Administration of fibrates and TZDs in order to activate both PPARα and PPARγ, respectively conferred protection and attenuated apoptosis of hair cells resulting from ROS and lipid peroxide insults (95). It has been established in literature that apoptosis, free radical insult, and lipid peroxidation all contribute to disease progression in DR (92); the above study is encouraging in cementing PPAR’s cytoprotective effects throughout various disease states.

Lipid peroxidation has been identified as a hallmark of disease development and progression in both dyslipidemia and hyperglycemia, resulting in oxidative stress in retinas of diabetic rats, which contain double the amount of lipid peroxides than retinas of control rats (96). Further evidence of the inextricable linkage between chronically elevated glucose levels and dyslipidemia stems from the findings that when blood cholesterol, such as LDL, is heavily glycosylated secondary to high blood sugars, it is more likely to be oxidized when it extravasates from blood vessels (97). Moreover, distinct, disease-relevant lipid species, such as highly oxidized LDL, induce oxidative stress in the retina resulting in mitochondrial dysfunction, apoptosis and autophagy (97). When human retinal capillary pericytes (HRCP), which are critical for a functioning blood-retina barrier, are exposed to highly oxidized-glycated low-density lipoprotein (HOG-LDL), apoptosis of these pericytes resulting from HOG-LDL exposure appears to be independent of MAPK activity (98). This is therapeutically significant as increased MAPK activity results in increased apoptosis of retinal endothelial cells, a molecular pathway that is responsive to simvastatin treatment (86), as discussed above. This suggests that multiple mechanisms and signaling pathways related to oxidative stress affect retinal cell types and their function. However, both glucotoxicity and lipotoxicity aggravate diabetic retinopathy through activation of NADPH oxidase and ROS-mediated mitochondrial damage in the affected retina (99).

A critical signaling molecule at the intersection of the two pathologies is fibroblast growth factor (FGF) 21. When administered to mice, it reduces plasma glucose and triglycerides, while also lowering LDL, raising HDL, and increasing insulin sensitivity (100, 101). In addition to normalizing lipid profiles and insulin resistance, FGF21 also proved beneficial in diabetic nephropathy by improving lipid metabolism in the kidney as well as ameliorating oxidative stress (102). Systemic knockout of the FGF21 gene in mice with diabetic nephropathy resulted in more severe kidney damage, while administration of FGF21 to mice with the same pathology attenuated the nephropathy phenotype due to decreased renal lipid accumulation and oxidative stress (103). Dosing with FGF21 promoted also a small, but significant weight loss in rodents (100). Conversely, obese mice displayed resistance to FGF21 signaling (104), providing additional support for its role in controlling both diabetes and obesity (100).

After induction of dyslipidemia and subsequently of diabetes in rats to assess the degree of oxidative stress conferred by each disease mechanism, markers of inflammation and oxidative stress were assessed (52). While in dyslipidemic rats, increased serum levels of oxidative stress (lipid peroxidation, nitric oxide, and protein carbonyl), pro-inflammatory cytokines (C-reactive protein, interleukin-1β, Monocyte chemoattractant protein-1, and tumor necrosis factor-α), and eicosanoids (prostaglandin E₂, leukotriene B₄, and leukotriene C₄) were found independent of age (52), young rats that were also diabetes-induced had significantly higher concentrations of oxidative stress and inflammatory markers (52). This finding supports the notion that these disease states contribute to the same disease burden systemically, especially with regard to factors such as oxidative stress and inflammation that worsen DR (52, 92).

An observational clinical study investigating lipid peroxidation and inflammation in patients with both diabetes and dyslipidemia yielded similar findings to Acharya’s experiment in rats; both lipid peroxidation and inflammation are higher with the presence of these two disease states (51). A marker of lipid peroxidation, serum malondialdehyde (MDA), was measured in dyslipidemic and diabetic patients—while elevated in dyslipidemic patients with or without diabetes, the highest levels were found in patients with poorly controlled diabetes complicated by dyslipidemia (51). Furthermore, pro-inflammatory cytokines (interleukin -1β, interleukin -6, interleukin -8, tumor necrosis factor-α) were progressively elevated as diabetes and dyslipidemia worsened (51). Importantly, TNF-α specifically is associated with diabetic retinopathy (92), providing a basis by which diabetes and dyslipidemia could synergistically worsen DR.

Another study obtaining similar findings as that of Acharya et al (52). concluded that omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, decreased oxidative stress in human test subjects with either dyslipidemia or diabetes (55). In this trial, patients were not affected by concomitant diabetes and dyslipidemia; in each leg of the study, patients had either one disease or the other. However, the fact that oxidative stress, measured by evaluating F(2) isoprostane levels in both serum and urine, was reduced by omega-3 fatty acids in each disease state is encouraging in suggesting intertwined pathophysiology between diabetes and dyslipidemia, resulting in oxidative insult throughout the body (53).

Further clinical evidence of the systemic burden of oxidative stress and lipid peroxidation placed on the body by dyslipidemia and diabetes can be elucidated through examining statins’ effects on these parameters. Different statins have shown different levels of therapeutic benefits in various trials, as evidenced by atorvastatin for example. One study found that atorvastatin decreased markers of inflammation such as CRP as well as cellular adhesion molecules, such as intercellular adhesion molecule 1 (55). Notably, adhesion molecules cause leukostasis and increased inflammation which both contribute to DR pathophysiology (92), demonstrating a potential protective mechanism on behalf of atorvastatin. However, a more recent study assessed atorvastatin’s impact on different inflammatory mediators and saw no benefit (56). One such mediator tested was total body NO production (56); the generation of NO, specifically within mitochondria, aggravates DR (92), indicating one area of DR pathogenesis in which atorvastatin may not have therapeutic impact.

In another study assessing the impact of statins on lipid peroxidation, simvastatin treatment is associated with lower levels of malondialdehyde, C-reactive protein, and paraoxonase activity in human leukocytes taken from dyslipidemic patients with T2DM, indicating that simvastatin plays a protective role in decreasing oxidative stress and reducing lipid peroxides (57).

Statin therapy results in improvement in retinal vasculature and reduction of progression of diabetic retinopathy in both laboratory models as well as clinical studies (58, 85). This beneficial effect is the cumulative effect of altering several molecular pathways. VEGF is a driving force of proliferation in retinopathy. Simvastatin decreases mitochondrial production of ROS species through attenuation of PGC-1a pathway (85). This results in a subsequent reduction in VEGF production as well as a decrease in retinal apoptosis due to blocking -38- MAPK activation (85).

A novel PPARα agonist, AVE8134, improves both lipid profiles and glucose metabolism in diabetic mice without adverse effects of increased body weight or heart weight seen with existing anti-diabetic thiazolidinedione (TZD) medication (105). Furthermore, PPARα has therapeutic benefit in rat models of diabetic retinopathy (106). A study with novel PPARα agonist Y-0452, exhibiting reduced vascular leakage, neovascularization, and retinal cell death while improving retinal function (106).

Fibrates and other PPARα agonists that alleviate complications of diabetes elicit a range of pleiotropic effects (87). Notably, PPARα activation results in reduced inflammation as fibrates and novel PPARα agonists lower interleukin (IL)-1 induced expression of C-reactive protein (CRP), a molecule associated with coronary and vascular disease, as well as with an increased systemic inflammatory state (107). Similarly, PPARγ, a transcription factor in the PPAR protein family and a target of TZDs, diabetes drugs also known as glitazones, has beneficial effects on glycemic control while simultaneously promoting cholesterol efflux from macrophages, similar to the activity of HDL cholesterol (108, 109). Furthermore, apart from being implicated in the pathophysiology of both dyslipidemia (110) and diabetes (111), PPARγ activation through its endogenous ligand 15d-PGJ2 regulates inflammation, angiogenesis, and apoptosis in the retinal pigmented endothelium (112).

Interestingly, omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), attenuated oxidative stress and inflammation in these diabetic and dyslipidemic rats (52), positioning them as a potential preventative therapy for DR (112). Furthermore, when omega-3 polyunsaturated fatty acids are given to male leptin-receptor-deficient (db/db) mice, creating a diabetic and dyslipidemic state in this mouse model, omega-3 PUFA preserved retinal function to a degree similar to the control mice (113). This is likely a result of the fact that the levels of large n-3 PUFAs are typically decreased in DR, especially in the later stages of DR (114), together with a reduction in the expression of the enzymes involved with PUFA synthesis (115).

The therapeutic strategies mentioned above that primarily focus on fatty acids for treating DR are based on the unique physiological properties of the human retina. For example, polyunsaturated fatty acids, which are extremely susceptible to oxidation, are present in the membranes of photoreceptor outer segments in high concentrations (25). As the retina’s oxygen consumption is the highest of any tissue and is characterized by high oxygen tension, this potentially results in a higher susceptibility of the retina to cellular damage, such as caused by hydrogen peroxide generated from lipid peroxidation (25). The therapeutic intervention with DHA and EPA described above is founded on the fact that the retina has relatively low levels of glutathione peroxidase and catalase to counteract hydrogen peroxide generation, although it should be mentioned that the retina does possess alternative antioxidant systems such as vitamin E and superoxide dismutase (116).

As previously discussed, both diabetes and dyslipidemia cause retinal damage as a result of exposure to oxidative stress, including free radical damage that ultimately leads to deleterious accumulation of ALEs. Interestingly, administering the antioxidant tempol, which acts by neutralizing the superoxide anion, into mouse retinas with DR results in a reduction in retinal cell death as well as a reduction in intraretinal oxidized LDL and glycated LDL levels (66). This provides a possible paradigm for DR therapy directed at scavenging and inactivating hyperglycemia-induced free radicals and ALEs.