It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These ...complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.
A recent study has highlighted the relationship between mitochondrial ATP generation and protection against organ injury following ischaemia–reperfusion injury in the kidney. Kidneys are fuel-hungry ...organs and only second to the heart in mitochondrial number and oxygen consumption. This article speculates on why this might be so.
Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population and is now a major cause of liver disease-related premature illness and deaths in the world. Treatment is largely ...based on lifestyle modification, which is difficult to achieve in most patients. Progression of simple fatty liver or steatosis to its severe form non-alcoholic steatohepatitis (NASH) and liver fibrosis has been explained by a 'two-hit hypothesis'. Whilst simple steatosis is considered the first hit, its transformation to NASH may be driven by a second hit. Of several factors that constitute the second hit, advanced glycation end products (AGEs), which are formed when reducing-sugars react with proteins or lipids, have been implicated as major candidates that drive steatosis to NASH via the receptor for AGEs (RAGE). Both endogenous and processed food-derived (exogenous) AGEs can activate RAGE, mainly present on Kupffer cells and hepatic stellate cells, thus propagating NAFLD progression. This review focuses on the pathophysiology of NAFLD with special emphasis on the role of food-derived AGEs in NAFLD progression to NASH and liver fibrosis. Moreover, the effect of dietary manipulation to reduce AGE content in food or the therapies targeting AGE/RAGE pathway on disease progression is also discussed.
In parallel with the growing diabetes pandemic, there is an increasing burden of micro- and macrovascular complications, occurring in the majority of patients. The identification of a number of ...synergistic accelerators of disease, providing therapeutic pathways, has stabilised the incidence of complications in most western nations. However, the primary instigators of diabetic complications and, thus, prevention strategies, remain elusive. This has necessitated a refocus on natural history studies, where tissue and plasma samples are sequentially taken to determine when and how disease initiates. In addition, recent Phase III trials, wherein the pleiotropic effects of compounds were arguably as beneficial as their glucose-lowering capacity in slowing the progression of complications, have identified knowledge gaps. Recently the influence of other widely recognised pathological pathways, such as mitochondrial production of reactive oxygen species, has been challenged, highlighting the need for a diverse and robust global research effort to ascertain viable therapeutic targets. Technological advances, such as -omics, high-resolution imaging and computational modelling, are providing opportunities for strengthening and re-evaluating research findings. Newer areas such as epigenetics, energetics and the increasing scrutiny of our synergistic inhabitants, the microbiota, also offer novel targets as biomarkers. Ultimately, however, this field requires concerted lobbying to support all facets of diabetes research.
It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between ...hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes.
Oxidative phosphorylation (OXPHOS) drives ATP production by mitochondria, which are dynamic organelles, constantly fusing and dividing to maintain kidney homoeostasis. In diabetic kidney disease ...(DKD), mitochondria appear dysfunctional, but the temporal development of diabetes-induced adaptations in mitochondrial structure and bioenergetics have not been previously documented. In the present study, we map the changes in mitochondrial dynamics and function in rat kidney mitochondria at 4, 8, 16 and 32 weeks of diabetes. Our data reveal that changes in mitochondrial bioenergetics and dynamics precede the development of albuminuria and renal histological changes. Specifically, in early diabetes (4 weeks), a decrease in ATP content and mitochondrial fragmentation within proximal tubule epithelial cells (PTECs) of diabetic kidneys were clearly apparent, but no changes in urinary albumin excretion or glomerular morphology were evident at this time. By 8 weeks of diabetes, there was increased capacity for mitochondrial permeability transition (mPT) by pore opening, which persisted over time and correlated with mitochondrial hydrogen peroxide (H2O2) generation and glomerular damage. Late in diabetes, by week 16, tubular damage was evident with increased urinary kidney injury molecule-1 (KIM-1) excretion, where an increase in the Complex I-linked oxygen consumption rate (OCR), in the context of a decrease in kidney ATP, indicated mitochondrial uncoupling. Taken together, these data show that changes in mitochondrial bioenergetics and dynamics may precede the development of the renal lesion in diabetes, and this supports the hypothesis that mitochondrial dysfunction is a primary cause of DKD.
The endoplasmic reticulum (ER) is an organelle that primarily functions to synthesise new proteins and degrade old proteins. Owing to the continual and variable nature of protein turnover, protein ...synthesis is inherently an error-prone process and is therefore tightly regulated. Fortunately, if this balance between synthesis and degradation is perturbed, an intrinsic response, the unfolded protein response (UPR) is activated to restore ER homoeostasis through the action of inositol-requiring protein 1, activating transcription factor 6 and PKR-like ER kinase transmembrane sensors. However, if the UPR is oversaturated and misfolded proteins accumulate, the ER can shift into a cytotoxic response, a physiological phenomenon known as ER stress. The mechanistic pathways of the UPR have been extensively explored; however, the role of this process in such a synthetic organ as the kidney requires further clarification. This review will focus on these aspects and will discuss the role of ER stress in specific resident kidney cells and how this may be integral in the pathogenesis and progression of diabetic nephropathy (DN). Given that diabetes is a perturbed state of protein turnover in most tissues, it is important to understand if ER stress is a secondary or tertiary response to other changes within the diabetic milieu or if it is an independent accelerator of kidney disease. Modulators of ER stress could provide a valuable tool for the treatment of DN and are under active investigation in other contexts.
Diabetes affects oxygen availability in the kidney, forcing the renal environment to rapidly and sustainably adapt. Physiological adaptations including activation of hypoxia inducible factor-1α and ...metabolic reprogramming toward pathways requiring less oxygen to maintain adenosine triphosphate production such as anaerobic glycolysis are impaired in the diabetic kidney. However, this study by Hasegawa et al. demonstrates renoprotection in diabetic kidney disease via the use of the hypoxia inducible factor-1α stabilizer enarodustat, opening a new therapeutic avenue to tackle these metabolic abnormalities.
Glucose metabolism in the kidney is currently foremost in the minds of nephrologists, diabetologists and researchers globally, as a result of the outstanding success of SGLT2 inhibitors in reducing ...renal and cardiovascular disease in individuals with diabetes. However, these exciting data have come with the puzzling but fascinating paradigm that many of the beneficial effects on the kidney and cardiovascular system seem to be independent of the systemic glucose lowering actions of these agents. This manuscript places into context an area of research highly relevant to renal glucose metabolism, that of glycogen accumulation and metabolism in the diabetic kidney. Whether the glycogen that abnormally accumulates is pathological (the villain), is somehow protective (the hero) or is inconsequential (the bystander) is a research question that may provide insight into the link between diabetes and diabetic kidney disease.
•The kidneys play an increasingly appreciated role in the body's glucose control systems.•Glycogen is a highly branched glucose storage polymer found in many tissues, with its role being tissue dependent.•Diabetes involves a breakdown in blood glucose control and is associated with changes in glycogen content and structure.•Glycogen accumulates in kidneys with diabetes, however its effects on blood glucose and kidney function remain unknown.
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