New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism
Diabetes adversely affects multiple organs, including the kidney, eye and nerve, leading to diabetic kidney disease, diabetic retinopathy and diabetic neuropathy, respectively. In both type 1 and type 2 diabetes, tissue damage is organ specific and is secondary to a combination of multiple metabolic insults. Hyperglycaemia, dyslipidaemia and hypertension combine with the duration and type of diabetes to define the distinct pathophysiology underlying diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. Only recently have the commonalities and differences in the metabolic basis of these tissue-specific complications, particularly those involving local and systemic lipids, been systematically examined. This review focuses on recent progress made using preclinical models and human-based approaches towards understanding how bioenergetics and metabolomic profiles contribute to diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. This new understanding of the biology of complication-prone tissues highlights the need for organ-specific interventions in the treatment of diabetic complications.
KeywordsDiabetes Diabetic complications Lipid metabolism Omics Review Specific mechanisms
Action to Control Cardiovascular Risk in Diabetes
Fenofibrate Intervention and Event Lowering in Diabetes
Liver X receptor
Peroxisome proliferator-activated receptor
Polyunsaturated fatty acid
Diabetes continues to be a major public health problem, currently affecting over 425 million people worldwide . This number is expected to increase due to the growing rates of obesity, which contributes to a rising incidence of type 2 diabetes and a projected increase in the prevalence of type 1 diabetes globally [2, 3]. Despite the different aetiologies of type 1 and type 2 diabetes, both are associated with a number of complications affecting the cardiovascular system, kidneys, eyes and nerves . Cardiovascular disorders, heart failure, atherosclerosis and cerebrovascular events primarily result from damage to the macrovasculature. The other major complications have been long considered as ‘microvascular’ injuries and manifest as a ‘diabetic triopathy’ of diabetic kidney disease, diabetic retinopathy and diabetic neuropathy . These complications account for the majority of morbidity and mortality risks associated with diabetes. While glucose and glucose metabolism have been the focus of research to understand the pathophysiology of these complications for decades, altered lipid metabolism has recently received increasing attention as a key player in disease pathology. In this review, we address the recent progress made using preclinical models and human-based approaches to shed new light on the relative roles of glucose and lipid metabolism in the onset and progression of diabetic microvascular complications.
Clinical overview of diabetic complications
Diabetic kidney disease
Diabetic kidney disease affects 30–40% of all individuals with diabetes and is the leading cause of end-stage renal disease in the USA, accounting for significant morbidity and mortality risks in individuals with type 1 and type 2 diabetes . Clinically, diabetic kidney disease is characterised by increased urinary albumin output and a decline in the glomerular filtration rate, both reflecting a progressive deterioration of renal function . This loss of function coincides with histopathological changes, including glomerular and tubular hypertrophy with gradual thickening of the glomerular and tubular basement membranes, podocyte effacement and eventually glomerulosclerosis and tubulointerstitial fibrosis .
Diabetic retinopathy is the primary cause of blindness among the working-age population worldwide. After 20 years of diabetes, virtually all individuals with type 1 diabetes and more than 60% of those with type 2 diabetes eventually develop signs of diabetic retinopathy . After years of clinically silent intraretinal changes, vascular tortuosity, retinal haemorrhage, microaneurysm, cotton-wool spots and lipid exudates become evident as features of non-proliferative diabetic retinopathy . Some affected individuals develop pathological retinal neovascularisation, recognised as proliferative diabetic retinopathy. Fluid accumulation within the central neural retina, referred to as diabetic macula oedema (DME), manifests as abnormal retinal thickening and cystoid formation and is the most common cause of visual loss in individuals with diabetic retinopathy [10, 11].
Diabetic neuropathy is a highly prevalent complication of both type 1 and type 2 diabetes, affecting at least 50% of individuals with diabetes . Various types of peripheral nerve disorders can develop, the most common being distal symmetric polyneuropathy, affecting nerves of the extremities in a bilateral, symmetric pattern and progressing in a distal-to-proximal manner. Distal symmetric polyneuropathy, referred to as diabetic neuropathy from this point onwards, is a highly debilitating complication associated with an increased susceptibility to ulcerations and infections and may eventually lead to lower-limb amputations. In addition to the well-characterised axonal injury , diabetes also targets Schwann cells and the vascular endothelium as demonstrated by segmental demyelination and endoneurial microangiopathy .
Mechanisms of onset and progression of diabetic complications
The importance of intensive glycaemic control in reducing the progression of complications in type 1 diabetes was confirmed in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trials . Based on these studies, patient care has been focused on intensifying glucose control, which improved but did not prevent the development and progression of all three diabetic complications in type 1 diabetes. In type 2 diabetes, intensive glycaemic control has a modest effect on these complications . The UK Prospective Diabetes Study  and the Steno-2 trial  demonstrated amelioration of diabetic kidney disease and diabetic retinopathy following 10 years of intensive glucose-lowering therapy in individuals newly diagnosed with type 2 diabetes but no effect on diabetic neuropathy was found. Other large intervention trials failed to report clear beneficial effects of near normalisation of blood glucose levels on all three complications associated with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE) and Veteran Affairs Diabetes Trial (VADT)  trials showed modest improvements in the early manifestations of diabetic kidney disease, while no improvements in diabetic retinopathy or diabetic neuropathy were observed between the intensive and the conventional therapy groups [20, 21]. Collectively, these studies suggest that glucose alone is not responsible for diabetic complications, especially in individuals with type 2 diabetes. Rather, responsibility lies with a cluster of factors, including obesity, hypertension, dyslipidaemia, inflammation and insulin resistance, which have an impact on the adipose tissue fatty acid metabolism that underlies the onset and progression of diabetic kidney disease, retinopathy and neuropathy . Thus, this review will focus on our increased understanding of the basic physiology underlying the global and tissue-specific changes in cellular metabolism that contribute to the pathogenesis of diabetic complications.
Role of hyperglycaemia in tissue-specific injury
Pathway summary of in vivo metabolic flux analysis in kidney cortex, sciatic nerve and retina from 24-week-old diabetic mice compared with control mice
Pentose phosphate pathway
In the following sections, we will discuss these alternative mechanisms and highlight the utility of systems biology approaches for improving our understanding of the differential roles of glucose and lipid metabolism in tissue-specific complications pathophysiology.
Rise of the role of lipid metabolism in diabetic complications
Lipogenesis and dyslipidaemia
Dyslipidaemia is defined as elevated levels of plasma triacylglycerols and cholesteryl esters, which are components of low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol. Increased hepatic lipogenesis and adipose tissue fatty acid metabolism in response to elevated blood glucose and insulin resistance contribute to dyslipidaemia in both type 1 and type 2 diabetes [35, 36]. Multiple preclinical and clinical studies have proposed dyslipidaemia as a major contributor to the pathophysiology of diabetic kidney disease (reviewed in ). In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, treatment with fenofibrate, a lipid-lowering drug, was found to reduce albuminuria and delay the decline of renal function in individuals with type 2 diabetes . However, the effect of statins (antihyperlipidemic drugs) on diabetic kidney disease progression remains controversial. While several preclinical and clinical studies have shown a beneficial effect of statin treatment on kidney function [39, 40], other clinical trials failed to show any improvement in estimated glomerular filtration rate in individuals with type 2 diabetes [41, 42]. Additionally, it remains unclear whether the beneficial effects of statin therapy are the result of a pleiotropic action of the drug on renal function, independent of its lipid-lowering effect .
Controversy also exists regarding the exact role of dyslipidaemia in diabetic retinopathy [44, 45, 46]. Several small uncontrolled studies examining the effects of statin use on diabetic retinopathy risk found a beneficial effect [47, 48] but were contradicted by larger studies [49, 50]. On the other hand, a recent well-conducted large study in Taiwan, of more than 18,000 individuals with type 2 diabetes with age and sex-matched controls, found that statin use significantly reduced retinopathy risk, diminished the incidence of macular oedema and reduced the need for further interventions . Moreover, the FIELD and ACCORD Eye studies found that fenofibrate use significantly lowered the risk of diabetic retinopathy progression and/or the need for laser intervention in diabetic individuals [52, 53]. However, meta-analysis of studies examining the contribution of serum lipids to the risk of diabetic retinopathy confirmed that while fenofibrate treatment is beneficial, only a slight increase in systemic LDL-cholesterol was associated with diabetic retinopathy risk . Recent studies in diabetic rodents suggest that fenofibrate improves retinal pathology by exerting direct effects on the tissue itself as it improves neuronal survival and function, promotes neuroprotective mechanisms and reduces local inflammation [55, 56, 57, 58].
Emerging evidence indicates that dyslipidaemia is a major player in the pathogenesis of diabetic neuropathy [59, 60]. In these studies, increased plasma triacylglycerols correlated with neuropathy progression in type 2 diabetes while obesity and systemic dyslipidaemia were independently associated with an increased risk of developing neuropathy. In the FIELD study, lipid-lowering therapy was associated with a reduced risk of lower-limb amputations, suggesting that lipid lowering may have beneficial effects on diabetic neuropathy . In the aforementioned study of more than 18,000 individuals with type 2 diabetes from Taiwan, statin therapy significantly reduced the risk of new-onset diabetic neuropathy and foot ulcers . While the mechanisms involved are not fully understood, oxidised LDL-cholesterol induced oxidative stress has been shown to mediate nerve damage in a mouse model of dyslipidaemia-induced neuropathy  and likely plays a similar role in neural injury in diabetic neuropathy .
Collectively, these results suggest that circulating lipids may have distinct effects on ‘microvascular’ complications. While increasing evidence suggests an important role for lipid metabolism in diabetic complications, future mechanistic studies are needed to provide more insight into the contribution of dyslipidaemia to diabetes-induced kidney, eye and nerve damage.
Distinct patterns of lipid metabolism in diabetes complications
Fatty acid regulation
Insulin directly regulates circulating fatty acids by controlling the conversion of non-esterified fatty acids to triacylglycerol and its subsequent secretion from the liver. As such, diabetes, low insulin levels and insulin resistance disrupt plasma fatty acid and complex lipid composition . Insulin resistance is linked to changes in levels of several lipid classes, including triacylglycerols, while diabetes risk correlates with lower fatty acid carbon number and lower degree of fatty acid saturation . Recently, lipidomic analysis was used to associate plasma fatty acid and triacylglycerol composition with progression of kidney disease in diabetes [27, 29]. Of note, as diabetic kidney disease progresses and the glomerular filtration barrier deteriorates, the kidney is likely to encounter higher levels of albumin-bound fatty acids in the filtrate, potentially increasing the impact of dyslipidaemia on tubular cells.
In the retina, highly enriched polyunsaturated fatty acids (PUFAs) have been intensely studied in the context of their role in regulating vascular function and angiogenesis . In models associated with late stages of diabetic retinopathy, lipidomic analyses identified a reduction in some of the largest n-3 PUFAs , while transcriptomics revealed reduced expression of the enzymes involved in PUFA synthesis . Interestingly, dietary manipulations focusing on PUFAs caused a positive impact on pathological retinal neovascularisation in an animal model of oxygen-induced retinopathy. This effect may be related to the role of PUFAs in inflammation  or in the synthesis of very-long-chain ceramides, which seem to maintain vascular integrity in experimental diabetes .
Diabetic neuropathy, of the three complications, most closely associates with dyslipidaemia . Obesity induced by a diet rich in saturated fatty acids is associated with the development of diabetic neuropathy in individuals with type 2 diabetes  and, as with diabetic retinopathy, PUFA supplementation ameliorates symptoms of diabetic neuropathy . This clinical finding is strongly supported by the preclinical work of Yorek and colleagues (reviewed in ), that shows clinical benefit of PUFA treatment in multiple rodent models of diabetic neuropathy. Moreover, transcriptomic analysis reveals an upregulation in fatty acid metabolism in the nerves of BKS db/db mice with diabetic neuropathy . In cellular studies, high concentrations of the saturated fatty acid palmitate impair sensory neuron mitochondrial trafficking and alter mitochondrial energy production . However, supplementation of cultured neurons with monounsaturated fatty acids such as oleate prevents palmitate-induced mitochondrial abnormalities through lipid droplet formation . We also found that cultured Schwann cells increase the expression of medium-to-long-chain acylcarnitines in response to long-chain fatty acid treatment. Accumulation of these acylcarnitines has been associated with neurotoxicity and insulin resistance [78, 79].
Collectively, these preclinical and clinical studies suggest an important role for fatty acid dysregulation in all three diabetic complications. Overall, saturated fatty acids are damaging to complication-prone tissues, while supplementation with PUFAs may restore normal function and provide a treatment modality. While more research is needed, the concept of ‘bad’ (saturated) and ‘good’ (unsaturated) fatty acids holds true at the present time.
Peroxisome proliferator-activated receptors (PPARs) and PPAR, gamma, coactivator 1, alpha (PGC1-α) play a key role in the regulation of fatty acid oxidation as they regulate the expression of proteins responsible for fatty acid uptake, such as the multifunctional fatty acid translocase CD36. In animal models and humans, PPAR signalling is highly dysregulated in diabetes [34, 75, 80, 81]. CD36 is upregulated in kidneys of diabetic animals and individuals with diabetes [63, 82], and is involved in mediating the apoptotic and oxidative effects of oxidised LDL immune complexes in metabolically challenged human retinal pericytes . Similarly, CD36 expression is increased in peripheral nerves of BKS db/db mice and individuals with progressive diabetic neuropathy [34, 75].
Fatty acid profiles in tissues not only depend on plasma levels and uptake capacity, as discussed above, but also on the local lipid metabolism in these tissues. We hypothesised that, like glucose, there would be tissue-specific alterations in lipid β-oxidation with diabetes. Indeed, using a combination of transcriptomic and metabolomic approaches to assess the impact of type 2 diabetes on β-oxidation, we demonstrated a tissue-specific response of this pathway in BKS db/db mice . Whereas transcriptomic analyses revealed increased expression of genes for fatty acid oxidation enzymes in the diabetic kidney and nerve, diabetes increased levels of the metabolites associated with fatty acid metabolism and β-oxidation in the kidney and retina and decreased these metabolites in peripheral nerves. The use of palmitic acid labelled with the stable isotope 13C to analyse the effects of type 2 diabetes on the metabolic flux through fatty acid catabolism showed increased palmitate uptake in all three tissues. Moreover, the analysis confirmed a progressive increase in β-oxidation in the kidney only, while suggesting incomplete fatty acid catabolism in retina and peripheral nerves. Consistent with these findings, Schwann cells exposed to high levels of long-chain fatty acids undergo incomplete fatty acid catabolism. This leads to altered acylcarnitine accumulation, which is known to have neurotoxic properties , as discussed earlier in this review.
We observed increased kidney β-oxidation in a preclinical murine model of diabetic kidney disease, while transcriptomic analysis using kidney tissue from individuals with chronic kidney disease revealed decreased expression of fatty acid oxidation enzymes in the presence of fibrosis . This dichotomy suggests that lipid metabolism may be differentially regulated throughout disease progression, something that has not been thoroughly examined in each of the complication-prone tissues. On a tissue-specific level, lipid β-oxidation may regulate tissue function by inducing epigenetic changes  and metabolic intermediates of lipid β-oxidation, such as succinate and fumarate, have been shown to stimulate pathogenic pathways [87, 88]. Additionally, lipid β-oxidation (especially of very-long-chain fatty acids) may mediate diabetes-induced increases in oxidative stress, potentially to a greater degree than increased glucose catabolism, thus driving diabetic complications [89, 90].
Lipids and mitochondrial dysfunction
Given their role in energy metabolism, mitochondria are presumably a key interaction point between glucose metabolism, lipid metabolism and diabetic complications. In addition to undergoing β-oxidation in mitochondria (as discussed above), lipids also directly affect mitochondrial function (reviewed in ). Cardiolipins (inner mitochondrial membrane lipids) are important for mitochondrial structure and mitochondrial metabolism. We recently identified an increase in immature cardiolipins in the diabetic kidney , which is associated with reduced bioenergetics , a hallmark of diabetic kidney disease . Interestingly, preserving mitochondrial structure with a cardiolipin-binding peptide maintains mitochondrial function in the kidney [94, 95], reverses visual decline in diabetic mice  and improves bioenergetics and mitochondrial trafficking in neurons . Additionally, exposure of Schwann cells to a mixture of long-chain fatty acids similar to that observed under diabetic conditions impairs mitochondrial function and induces oxidative stress . As discussed above, saturated fatty acids damage sensory axons by depolarising neuronal mitochondria and impairing mitochondrial trafficking . Supplementation with monounsaturated fatty acids prevents mitochondrial dysfunction through lipid droplet formation, highlighting again a complex role for lipid products and metabolism in diabetes complications .
Lipids in inflammation
Integration of omics studies have revealed correlations, if not causal relationships, between altered lipid metabolism and inflammation. PUFAs, especially n-3 PUFAs, can regulate inflammation by inhibition of NF-κB activation and nuclear translocation [98, 99]. In contrast, n-6 PUFAs are precursors of bioactive lipids such as arachidonic acid, which would itself promote a proinflammatory environment and development of diabetic complications. Elevated arachidonic acid-derived eicosanoids in serum independently predict diabetic kidney disease progression , while altered plasma fatty acid composition is associated with retinal and systemic inflammation . Multiple studies suggest that dietary manipulations that increase the ratio of n-3 to n-6 PUFAs, decrease the risk of diabetic complications in adult participants with type 2 diabetes [100, 101, 102]. Lipid levels are dependent on multiple mechanisms of regulation including dietary intake and de-novo synthesis, and also on the exchange and recycling systems. Among those regulatory mechanisms, reverse cholesterol transport and its regulation by specific receptors, namely the farnesoid X receptor (FXR) and the liver X receptor (LXR), has been receiving increasing attention in relation to inflammation, especially in the pathogenesis of diabetic kidney disease [103, 104] and diabetic retinopathy . LXR activation was also shown to improve peripheral nerve function in rodents with obesity and diabetes-induced neuropathy, specifically by reducing endoplasmic reticulum stress or restoring myelin lipid composition; however, little is known about the anti-inflammatory effects of LXR in the setting of neuropathy [106, 107]. These studies are intriguing and certainly warrant further exploration of the implication of these mechanisms in the onset and progression of diabetic complications.
Other aspects of lipid metabolism have been suggested to impact systemic as well as local inflammation. Multiple studies using unbiased approaches analysing the transcriptome, proteome or metabolome of various tissues affected by diabetes have reported lipid metabolism and inflammation as being among the top pathways affected [26, 85, 108, 109, 110, 111]. These studies in animal models of diabetes are now complemented and supported by studies in individuals with diabetes. For example, we recently used transcriptomic analysis to demonstrate that abnormal lipid metabolism and inflammation in peripheral nerves are conserved across multiple mouse models of type 2 diabetes and in individuals with progressive diabetic neuropathy . Moreover, several studies found positive associations between serum markers of inflammation, lipid metabolism and onset and progression of complications in individuals with type 1 and type 2 diabetes [29, 112, 113].
Treatment of diabetic complications: one size does not fit all
Tissues with distinct structures and functions are affected by diabetes, suggesting the involvement of tissue-specific mechanisms in the pathogenesis of the disease. In the kidney, metabolism is associated with haemodynamic factors and diminishing filtration, which allow waste products to accumulate in blood . In the retina, metabolic alterations have been proposed to be responsible for dysregulation of the glutamine–glutamate cycle in retinal Müller glial cells, an effect believed to be associated with glutamate excitotoxicity and cell death . In the peripheral nerves, metabolic irregularities in Schwann cells are thought to induce mitochondrial deficits, accumulation of neurotoxic species and transfer of lipotoxic species to axons, a series of injurious events that may lead to axonal degeneration [24, 79]. Altogether, these studies, while not being exhaustive, highlight once more some of the ‘tissue/cell’ specificity of the impact of diabetes and emphasise the need for global analysis to assess the tissue-specific mechanisms at play in order to develop targeted interventions.
While it is tempting to combine ‘microvascular’ complications under one mechanism, it is clear that diabetes dysregulates metabolism in a tissue-specific manner. A role for generalised mechanisms cannot be fully excluded but the current body of knowledge strongly suggests that tissue-specific metabolic alterations, rather than a single unifying metabolic mechanism, are driving the onset and progression of diabetic complications. Metabolic dysregulation includes not only hyperglycaemia but also alterations in systemic and local lipid metabolism. Therapeutic development for diabetic complications will require a better understanding of the crosstalk between glucose and lipid metabolism in individual tissues, if not individual cell types, which most likely differs in each tissue despite the common underlying condition. Additionally, while the large amount of information gathered from numerous animal models of diabetes relative to the pathophysiology of these complications has been critical, difficulties associated with translation still highlight the need for human-based studies. Discovery approaches, especially those performed in human tissues across the gene–transcript–protein–metabolite continuum, have already demonstrated a potential for identifying tissue-specific adaptations and will continue to be the starting point in unveiling the mechanisms of diabetic complications and identifying novel therapeutic targets. Ultimately, a better integration and communication between researchers working on the respective complications, combined with a broader use of human samples and clinical data, is necessary to perform integrated analysis of complications pathophysiology, characterise their respective mechanisms and define new treatment options.
All authors were responsible for drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.
Work in the authors laboratories is supported by the National Institutes of Health (1R24082841 to SFA, ELF, TWG, SP and PEF; P30DK081943 to SP; R01EY020582 to SFA, TWG and PEF; R01EY029349 and R01EY020823 to SFA; R01EY020895 to PEF; P30EY007003 Kellogg Eye Center Core Center for Vision Research to SFA, TWG and PEF; R24DK08284, P30DK081943 and P30DK89503 to KMS and SP), the Novo Nordisk Foundation (NNF14OC0011633 to ELF and SE), Milstein, Nathan and Rose Research Fund (to SE) and the Program for Neurology Research & Discovery (to ELF and SE).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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