Therapeutic effects of natural compounds against diabetic complications via targeted modulation of ferroptosis.

Diabetes mellitus, a chronic metabolic disorder, can result in serious tissue and organ damage due to long-term metabolic dysfunction, leading to various complications. Therefore, exploring the pathogenesis of diabetic complications and developing effective prevention and treatment drugs is crucial. The role of ferroptosis in diabetic complications has emerged as a significant area of research in recent years. Ferroptosis, a recently discovered form of regulated cell death closely linked to iron metabolism imbalance and lipid peroxidation, has garnered increasing attention in studies exploring the potential role of natural products in its regulation. This review provides an overview of the mechanisms underlying ferroptosis, outlines detection methods, and synthesizes information from natural product databases. It also summarizes current research on how natural products may regulate ferroptosis in diabetic complications. Studies have shown that these products can modulate the ferroptosis process by influencing iron ion balance and combating oxidative stress. This highlights the potential of natural products in treating diabetic complications by regulating ferroptosis, offering a new strategy for managing such complications.

Research Progress of Coenzyme Q in Diabetes Mellitus and Its Common Complications.

Coenzyme Q has garnered significant attention due to its potential role in enhancing cellular energy production and its antioxidant properties. We delve into the therapeutic potential of coenzyme Q in managing diabetes mellitus and its complications, highlighting its capacity to improve mitochondrial function, reduce inflammation and oxidative stress, and correct lipid profiles. Coenzyme Q has shown promise in ameliorating insulin resistance and alleviating complications such as diabetic peripheral neuropathy, kidney disease, retinopathy, and cardiomyopathy. However, its clinical application is limited by poor bio-availability. This review also provides a comprehensive overview of current therapeutic strategies for diabetes complications involving coenzyme Q, including stimulating endogenous synthesis and utilizing carrier transport systems, offering insights into mechanisms for enhancing coenzyme Q bio-availability. These findings suggest that, with improved delivery methods, coenzyme Q could become a valuable adjunct therapy in the management of diabetes mellitus.

TRPV1: A novel target for the therapy of diabetes and diabetic complications.

BACKGROUND: Diabetes mellitus is a chronic metabolic disease characterized by abnormally elevated blood glucose levels. Type II diabetes accounts for approximately 90% of all cases. Several drugs are available for hyperglycemia treatment. However, the current therapies for managing high blood glucose do not prevent or reverse the disease progression, which may result in complications and adverse effects, including diabetic neuropathy, retinopathy, and nephropathy. Hence, developing safer and more effective methods for lowering blood glucose levels is imperative. Transient receptor potential vanilloid-1 (TRPV1) is a significant member of the transient receptor potential family. It is present in numerous body tissues and organs and performs vital physiological functions. PURPOSE: This review aimed to develop new targeted TRPV1 hypoglycemic drugs by systematically summarizing the mechanism of action of the TRPV1-based signaling pathway in preventing and treating diabetes and its complications. METHODS: Literature searches were performed in the PubMed, Web of Science, Google Scholar, Medline, and Scopus databases for 10 years from 2013 to 2023. The search terms included "diabetes," "TRPV1," "diabetic complications," and "capsaicin." RESULTS: TRPV1 is an essential potential target for treating diabetes mellitus and its complications. It reduces hepatic glucose production and food intake and promotes thermogenesis, metabolism, and insulin secretion. Activation of TRPV1 ameliorates diabetic nephropathy, retinopathy, myocardial infarction, vascular endothelial dysfunction, gastroparesis, and bladder dysfunction. Suppression of TRPV1 improves diabetes-related osteoporosis. However, the therapeutic effects of activating or suppressing TRPV1 may vary when treating diabetic neuropathy and periodontitis. CONCLUSION: This review demonstrates that TRPV1 is a potential therapeutic target for diabetes and its complications. Additionally, it provides a theoretical basis for developing new hypoglycemic drugs that target TRPV1.

The challenging inhibition of Aldose Reductase for the treatment of diabetic complications: a 2019-2023 update of the patent literature.

INTRODUCTION: Aldose reductase (AKR1B1, EC: 1.1.1.21) is a recognized target for the treatment of long-term diabetic complications since its activation in hyperglycemia and role in the polyol pathway. In particular, the tissue-specificity of AKR1B1 expression makes the design of the traditional Aldose Reductase Inhibitors (ARIs) and the more recent Aldose Reductase Differential Inhibitors (ARDIs) exploitable strategies to treat pathologies resulting from diabetic conditions. AREAS COVERED: A brief overview of the roles and functions of AKR1B1 along with known ARIs and ARDIs was provided. Then, the design of the latest inhibitors in the scientific scenario was discussed, aiming at introducing the research achievement in the field of intellectual properties. Patents dealing with AKR1B1 and diabetes filed in the 2019-2023 period were collected and analyzed. Reaxys, Espacenet, SciFindern, and Google Patents were surveyed, using 'aldose reductase' and 'inhibitor' as the reference keywords. The search results were then filtered by PRISMA protocol, thus obtaining 16 records to review. EXPERT OPINION: Although fewer in number than in the early 2000s, patent applications are still being filed in the field of ARIs, with a large number of Chinese inventors reporting new synthetic ARIs in favor of the repositioning approach.

Exosomes and Macrophages: Bidirectional Mutual Regulation in the Treatment of Diabetic Complications.

Purpose: The bidirectional regulation of macrophages and exosomes provides a meaningful research direction for the treatment of complications arising from both type 1 and type 2 diabetes mellitus. However, there is currently no comprehensive evaluation of the bidirectional regulatory role of macrophages and exosomes in diabetic complications. In this review, we aim to provide the detailed process of the bidirectional regulation mechanism of macrophages and exosomes, and how macrophage-associated exosomes use this mechanism to make it better applied to clinical practice through biotechnology. Methods: Therefore, we summarized the bidirectional regulation mechanism of macrophages and exosomes and the application based on the bidirectional regulation mechanism from two aspects of inflammation and insulin resistance. Results: As key regulators of the immune system, macrophages are crucial in the progression of diabetic complications due to their significant impact on the regulation of cellular metabolism, inflammation, and insulin sensitivity. Furthermore, exosomes, as innovative mediators of intercellular communication, transport miRNAs, proteins, and various bioactive molecules, influencing the occurrence and progression of diabetic complications through the regulation of inflammation and insulin resistance. The bidirectional regulation between macrophages and exosomes provides a promising pathway for the treatment of diabetic complications aimed at regulating the immune response and improving insulin sensitivity. Conclusions: Understanding the complexity of the interaction between macrophages and exosomes can advance the treatment of diabetic complications and drug development, and bringing more innovative and effective treatment strategies for diabetic complications.

Advanced glycation end products and reactive oxygen species: uncovering the potential role of ferroptosis in diabetic complications.

Advanced glycation end products (AGEs) are a diverse range of compounds that are formed when free amino groups of proteins, lipids, and nucleic acids are carbonylated by reactive carbonyl species or glycosylated by reducing sugars. Hyperglycemia in patients with diabetes can cause an overabundance of AGEs. Excess AGEs are generally acknowledged as major contributing factors to the development of diabetic complications because of their ability to break down the extracellular matrix directly and initiate intracellular signaling pathways by binding to the receptor for advanced glycation end products (RAGE). Inflammation and oxidative stress are the two most well-defined pathophysiological states induced by the AGE-RAGE interaction. In addition to oxidative stress, AGEs can also inhibit antioxidative systems and disturb iron homeostasis, all of which may induce ferroptosis. Ferroptosis is a newly identified contributor to diabetic complications. This review outlines the formation of AGEs in individuals with diabetes, explores the oxidative damage resulting from downstream reactions of the AGE-RAGE axis, and proposes a novel connection between AGEs and the ferroptosis pathway. This study introduces the concept of a vicious cycle involving AGEs, oxidative stress, and ferroptosis in the development of diabetic complications.

Hallmarks of diabetes mellitus and insights into the therapeutic potential of synergy-based combinations of phytochemicals in reducing oxidative stress-induced diabetic complications.

Diabetes mellitus (DM) is a serious health issue and is still one of the major causes of mortality around the globe. Natural products have progressively integrated into modern, advanced medical practices. Phytoconstituents from some medicinal plants have demonstrated therapeutic activity in treating different metabolic disorders and have been used to treat DM and its severe complications. The present review provides details of the major anti-diabetic targets identified in the literature and also provides comprehensive information regarding the therapeutic role of a synergy-based combination of phytoconstituents that functions by controlling specific molecular pathways synchronously by inhibiting certain key regulators involved in the development and progression of DM. The review also implicated the role of oxidative stress in diabetic complications and presented scientific validations of phytochemicals and their synergy-based combination using in vitro and or in vivo approaches.

Mitochondrial dysfunction and onset of type 2 diabetes along with its complications: a multi-omics Mendelian randomization and colocalization study.

Background: Mitochondrial dysfunction plays a crucial role in Type 2 Diabetes Mellitus (T2DM) and its complications. However, the genetic pathophysiology remains under investigation. Through multi-omics Mendelian Randomization (MR) and colocalization analyses, we identified mitochondrial-related genes causally linked with T2DM and its complications. Methods: Summary-level quantitative trait loci data at methylation, RNA, and protein levels were retrieved from European cohort studies. GWAS summary statistics for T2DM and its complications were collected from the DIAGRAM and FinnGen consortiums, respectively. Summary-data-based MR was utilized to estimate the causal effects. The heterogeneity in dependent instrument test assessed horizontal pleiotropy, while colocalization analysis determined whether genes and diseases share the same causal variant. Enrichment analysis, drug target analysis, and phenome-wide MR were conducted to further explore the biological functions, potential drugs, and causal associations with other diseases. Results: Integrating evidence from multi-omics, we identified 18 causal mitochondrial-related genes. Enrichment analysis revealed they were not only related to nutrient metabolisms but also to the processes like mitophagy, autophagy, and apoptosis. Among these genes, Tu translation elongation factor mitochondrial (TUFM), 3-hydroxyisobutyryl-CoA hydrolase (HIBCH), and iron-sulfur cluster assembly 2 (ISCA2) were identified as Tier 1 genes, showing causal links with T2DM and strong colocalization evidence. TUFM and ISCA2 were causally associated with an increased risk of T2DM, while HIBCH showed an inverse causal relationship. The causal associations and colocalization effects for TUFM and HIBCH were validated in specific tissues. TUFM was also found to be a risk factor for microvascular complications in T2DM patients including retinopathy, nephropathy, and neuropathy. Furthermore, drug target analysis and phenome-wide MR underscored their significance as potential therapeutic targets. Conclusions: This study identified 18 mitochondrial-related genes causally associated with T2DM at multi-omics levels, enhancing the understanding of mitochondrial dysfunction in T2DM and its complications. TUFM, HIBCH, and ISCA2 emerge as potential therapeutic targets for T2DM and its complications.

Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes.

Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC50 = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC50 = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.

A small, focused library comprising 8 novel compounds was synthesised using a series of substituted quinoxaline sulfonohydrazide derivatives.All synthesised compounds were tested against phospholipase A2 (sPLA2) and α-glucosidase enzymes.The compounds exhibited activities against α-glucosidase and were potent at nanomolar concentrations against sPLA2 isozymes.Structure-based molecular modelling was employed to rationalise the SAR of the compounds.

Aldose reductase with quinolone antibiotics interaction: In vitro and in silico approach of its relationship with diabetic complications.

Aldose reductase (AR, EC1.1.1.21), a member of the aldo-keto reductase family, is critically implicated in the pathogenesis of chronic complications associated with diabetes mellitus, including neuropathy, nephropathy, and retinopathy. Hyperglycemia-induced AR overactivity results in intracellular sorbitol accumulation, NADPH depletion, and oxidative stress. Consequently, AR is recognized as a key mediator of oxidative and inflammatory signaling pathways involved in diverse human pathologies such as cardiovascular diseases, inflammatory disorders, and cancer. This has sparked renewed interest in developing novel AR inhibitors (ARIs) with enhanced therapeutic profiles. In this study, we evaluated the inhibitory potential of five quinolone antibiotics-gatifloxacin, lomefloxacin, nalidixic acid, norfloxacin, and sparfloxacin-as ARIs relevant to various physiological and pathological conditions. Through comprehensive in vitro and in silico analyses, we explored these antibiotics' binding interactions and affinities within the AR active site. Our findings reveal that these quinolones moderately inhibit AR at micromolar concentrations, with inhibition constants (KIs) ranging from 1.03 ± 0.13 µM to 4.12 ± 0.51 µM, compared to the reference drug epalrestat (KI of 0.85 ± 0.06 µM). The combined in vitro and in silico results underscore significant interactions between these drugs and AR, suggesting their potential as therapeutic agents against the aforementioned pathological conditions. Furthermore, these insights will aid in optimizing clinical dosing regimens and mitigating unexpected drug-drug interactions when these antibiotics are co-administered with other treatments.

Exploring aldose reductase inhibitors as promising therapeutic targets for diabetes-linked disabilities.

Diabetes mellitus significantly increases mortality and morbidity rates due to complications like neuropathy and nephropathy. It also leads to retinopathy and cataract formation, which is a leading cause of vision disability. The polyol pathway emerges as a promising therapeutic target among the various pathways associated with diabetic complications. This review focuses on the development of natural and synthetic aldose reductase inhibitors (ARIs), along with recent discoveries in diabetic complication treatment. AR, pivotal in the polyol pathway converting glucose to sorbitol, plays a key role in secondary diabetes complications' pathophysiology. Understanding AR's function and structure lays the groundwork for improving ARIs to mitigate diabetic complications. New developments in ARIs open up exciting possibilities for treating diabetes-related complications. However, it is still challenging to get preclinical successes to clinical effectiveness because of things like differences in how the disease starts, drug specificity, and the complexity of the AR's structure. Addressing these challenges is crucial for developing targeted and efficient ARIs. Continued research into AR's structural features and specific ARIs is essential. Overcoming these challenges could revolutionize diabetic complication treatment, enhance patient outcomes, and reduce the global burden of diabetes-related mortality and morbidity.

Exploring the role of miRNA in diabetic neuropathy: from diagnostics to therapeutics.

Diabetic neuropathy (DN) is one of the major microvascular complications of diabetes mellitus affecting 50% of the diabetic population marred by various unmet clinical needs. There is a need to explore newer pathological mechanisms for designing futuristic regimens for the management of DN. There is a need for post-transcriptional regulation of gene expression by non-coding RNAs (ncRNAs) to finetune different cellular mechanisms with significant biological relevance. MicroRNAs (miRNAs) are a class of small ncRNAs (~ 20 to 24 nucleotide length) that are known to regulate the activity of ~ 50% protein-coding genes through repression of their target mRNAs. Differential expression of these miRNAs is associated with the pathophysiology of diabetic neuropathy via regulating various pathways such as neuronal hyperexcitability, inflammation, axonal growth, regeneration, and oxidative stress. Of note, the circulating and extracellular vesicular miRNAs serve as potential biomarkers underscoring their diagnostic potential. Recent pieces of evidence highlight the potential of miRNAs in modulating the initiation and progression of DN and the possibility of developing miRNAs as treatment options for DN. In this review, we have elaborated on the role of different miRNAs as potential biomarkers and emphasized their druggable aspects for promising future therapies for the clinical management of DN.

Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes.

OBJECTIVE: Chronic inflammation and oxidative stress mediate the pathological progression of diabetic complications, like diabetic retinopathy (DR), peripheral neuropathy (DPN) and impaired wound healing. Studies have shown that treatment with a stable form of arginase 1 that reduces l-arginine levels and increases ornithine and urea limits retinal injury and improves visual function in DR. We tested the therapeutic efficacy of PEGylated arginine deiminase (ADI-PEG20) that depletes l-arginine and elevates l-citrulline on diabetic complications in the db/db mouse model of type 2 diabetes (T2D). METHODS: Mice received intraperitoneal (IP), intramuscular (IM), or intravitreal (IVT) injections of ADI-PEG20 or PEG20 as control. Effects on body weight, fasting blood glucose levels, blood-retinal-barrier (BRB) function, visual acuity, contrast sensitivity, thermal sensitivity, and wound healing were determined. Studies using bone marrow-derived macrophages (BMDM) examined the underlying signaling pathway. RESULTS: Systemic injections of ADI-PEG20 reduced body weight and blood glucose and decreased oxidative stress and inflammation in db/db retinas. These changes were associated with improved BRB and visual function along with thermal sensitivity and wound healing. IVT injections of either ADI-PEG20, anti-VEGF antibody or their combination also improved BRB and visual function. ADI-PEG20 treatment also prevented LPS/IFNℽ-induced activation of BMDM in vitro as did depletion of l-arginine and elevation of l-citrulline. CONCLUSIONS/INTERPRETATION: ADI-PEG20 treatment limited signs of DR and DPN and enhanced wound healing in db/db mice. Studies using BMDM suggest that the anti-inflammatory effects of ADI-PEG20 involve blockade of the JAK2-STAT1 signaling pathway via l-arginine depletion and l-citrulline production.

Deciphering interleukin-18 in diabetes and its complications: Biological features, mechanisms, and therapeutic perspectives.

Interleukin-18 (IL-18), a potent and multifunctional pro-inflammatory cytokine, plays a critical role in regulating ß-cell failure, ß-cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro-inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and ß-cells death. Abnormal alterations in IL-18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL-18 may present a novel and promising approach for DM therapy. An increasing number of IL-18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL-18. Next, we shed light on how IL-18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of ß-cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL-18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL-18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment.

Environmental endocrine disruptor-induced mitochondrial dysfunction: a potential mechanism underlying diabetes and its complications.

Diabetes and its complications significantly affect individuals' quality of life. The etiology of diabetes mellitus and its associated complications is complex and not yet fully understood. There is an increasing emphasis on investigating the effects of endocrine disruptors on diabetes, as these substances can impact cellular processes, energy production, and utilization, ultimately leading to disturbances in energy homeostasis. Mitochondria play a crucial role in cellular energy generation, and any impairment in these organelles can increase susceptibility to diabetes. This review examines the most recent epidemiological and pathogenic evidence concerning the link between endocrine disruptors and diabetes, including its complications. The analysis suggests that endocrine disruptor-induced mitochondrial dysfunction-characterized by disruptions in the mitochondrial electron transport chain, dysregulation of calcium ions (Ca2+), overproduction of reactive oxygen species (ROS), and initiation of signaling pathways related to mitochondrial apoptosis-may be key mechanisms connecting endocrine disruptors to the development of diabetes and its complications.

Diabetes and its Silent Partner: A Critical Review of Hyperinsulinemia and its Complications.

In this complex realm of diabetes, hyperinsulinemia is no longer regarded as just a compensatory response to insulin resistance but rather has evolved into an integral feature. This comprehensive review provides a synthesis of the current literature, including various aspects associated with hyperinsulinemia in diabetic complications. Hyperinsulinemia has been shown to be more than just a compensatory mechanism, and the key findings demonstrate how hyperinsulinism affects the development of cardiovascular events as well as microvascular complications. Additionally, recognizing hyperinsulinemia as a modifiable factor, the diabetes management paradigm shifts towards cognitive ones that consider the use of lifestyle modifications in combination with newer pharmacotherapies and precision medicine approaches. These findings have crucial implications for the clinical work, requiring a careful appreciation of hyperinsulinemia's changing aspects as well as incorporation in personalized treatment protocol. In addition, the review focuses on bigger issues related to public health, showing that prevention and early diagnosis will help reduce the burden of complications. Research implications favor longitudinal studies, biomarker discovery, and the study of emerging treatment modalities; clinical practice should adopt global evaluations, patient education, and precision medicine adaptation. Finally, this critical review provides an overview of the underlying processes of hyperinsulinemia in diabetes and its overall health effects.

Circulating glutamine/glutamate ratio is closely associated with type 2 diabetes and its associated complications.

Objective: This study aims to conduct a comprehensive investigation of the serum amino acid profiles of individuals with type 2 diabetes (T2D) and its related complications. Methods: Patients with T2D were enrolled in this study. Sixteen kinds of common amino acids in the fasting circulating were assessed through liquid chromatography-mass spectrometry (LC-MS). Subsequently, correlation, regression analyses, and receiver operating characteristic (ROC) curves were conducted to assess the associations between amino acids and clinical indicators. Results: Thirteen different kinds of amino acids were identified in diabetic patients, as compared with normal controls. The Glutamine/Glutamate (Gln/Glu) ratio was negatively correlated with BMI, HbA1c, serum uric acid, and the triglyceride-glucose (TyG) index, while it was positively correlated with HDL-C. Logistic regression analyses indicated that Gln/Glu was a consistent protective factor for both T2D (OR = 0.65, 95% CI 0.50-0.86) and obesity (OR = 0.79, 95% CI 0.66-0.96). The ROC curves demonstrated that Gln/Glu, proline, valine, and leucine provided effective predictions for diabetes risk, with Gln/Glu exhibiting the highest AUC [0.767 (0.678-0.856)]. In patients with T2D, Gln was the only amino acid that displayed a negative correlation with HbA1c (r = -0.228, p = 0.017). Furthermore, HOMA-ß exhibited a negative correlation with Glu (r = -0.301, p = 0.003) but a positive correlation with Gln/Glu (r = 0.245, p = 0.017). Notably, logistic regression analyses revealed an inverse correlation of Gln/Glu with the risk of diabetic kidney disease (OR = 0.74, 95% CI 0.55-0.98) and a positive association with the risk of diabetic retinopathy (OR = 1.53, 95% CI 1.08-2.15). Conclusion: The Gln/Glu ratio exhibited a significant association with diabetes, common metabolic parameters, and diabetic complications. These findings shed light on the pivotal role of Gln metabolism in T2D and its associated complications.

A translational model of chronic diabetic nephropathy in the Nile grass rat.

Diabetic nephropathy (DN) is a major healthcare challenge for individuals with diabetes and associated with increased cardiovascular morbidity and mortality. The existing rodent models do not fully represent the complex course of the human disease. Hence, developing a translational model of diabetes that reproduces both the early and the advanced characteristics of DN and faithfully recapitulates the overall human pathology is an unmet need. Here, we introduce the Nile grass rat (NGR) as a novel model of DN and characterize key pathologies underlying DN. NGRs spontaneously developed insulin resistance, reactive hyperinsulinemia, and hyperglycemia. Diabetic NGRs evolved DN and the key histopathological aspects of the human advanced DN, including glomerular hypertrophy, infiltration of mononuclear cells, tubular dilatation, and atrophy. Enlargement of the glomerular tufts and the Bowman's capsule areas accompanied the expansion of the Bowman's space. Glomerular sclerosis, renal arteriolar hyalinosis, Kimmelsteil-Wilson nodular lesions, and protein cast formations in the kidneys of diabetic NGR occurred with DN. Diabetic kidneys displayed interstitial and glomerular fibrosis, key characteristics of late human pathology as well as thickening of the glomerular basement membrane and podocyte effacement. Signs of injury included glomerular lipid accumulation, significantly more apoptotic cells, and expression of KIM-1. Diabetic NGRs became hypertensive, a known risk factor for kidney dysfunction, and showed decreased glomerular filtration rate. Diabetic NGRs recapitulate the breadth of human DN pathology and reproduce the consequences of chronic kidney disease, including injury and loss of function of the kidney. Hence, NGR represents a robust model for studying DN-related complications and provides a new foundation for more detailed mechanistic studies of the genesis of nephropathy, and the development of new therapeutic approaches.