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Redox Biology May 2024Diabetes mellitus is a non-communicable metabolic disease hallmarked by chronic hyperglycemia caused by beta-cell failure. Diabetic complications affect the vasculature... (Review)
Review
Diabetes mellitus is a non-communicable metabolic disease hallmarked by chronic hyperglycemia caused by beta-cell failure. Diabetic complications affect the vasculature and result in macro- and microangiopathies, which account for a significantly increased morbidity and mortality. The rising incidence and prevalence of diabetes is a major global health burden. There are no feasible strategies for beta-cell preservation available in daily clinical practice. Therefore, patients rely on antidiabetic drugs or the application of exogenous insulin. Glutaredoxins (Grxs) are ubiquitously expressed and highly conserved members of the thioredoxin family of proteins. They have specific functions in redox-mediated signal transduction, iron homeostasis and biosynthesis of iron-sulfur (FeS) proteins, and the regulation of cell proliferation, survival, and function. The involvement of Grxs in chronic diseases has been a topic of research for several decades, suggesting them as therapeutic targets. Little is known about their role in diabetes and its complications. Therefore, this review summarizes the available literature on the significance of Grxs in diabetes and its complications. In conclusion, Grxs are differentially expressed in the endocrine pancreas and in tissues affected by diabetic complications, such as the heart, the kidneys, the eye, and the vasculature. They are involved in several pathways essential for insulin signaling, metabolic inflammation, glucose and fatty acid uptake and processing, cell survival, and iron and mitochondrial metabolism. Most studies describe significant changes in glutaredoxin expression and/or activity in response to the diabetic metabolism. In general, mitigated levels of Grxs are associated with oxidative distress, cell damage, and even cell death. The induced overexpression is considered a potential part of the cellular stress-response, counteracting oxidative distress and exerting beneficial impact on cell function such as insulin secretion, cytokine expression, and enzyme activity.
Topics: Humans; Glutaredoxins; Diabetes Mellitus; Diabetes Complications; Iron; Insulins
PubMed: 38377787
DOI: 10.1016/j.redox.2024.103043 -
International Journal of Molecular... Jan 2024Clinical and basic studies have documented that both hyperglycemia and insulin-resistance/hyperinsulinemia not only constitute metabolic disorders contributing to... (Review)
Review
Clinical and basic studies have documented that both hyperglycemia and insulin-resistance/hyperinsulinemia not only constitute metabolic disorders contributing to cardiometabolic syndrome, but also predispose to diabetic vasculopathy, which refers to diabetes-mellitus-induced microvascular and macrovascular complications, including retinopathy, neuropathy, atherosclerosis, coronary artery disease, hypertension, and peripheral artery disease. The underlying molecular and cellular mechanisms include inappropriate activation of the renin angiotensin-aldosterone system, mitochondrial dysfunction, excessive oxidative stress, inflammation, dyslipidemia, and thrombosis. These abnormalities collectively promote metabolic disorders and further promote diabetic vasculopathy. Recent evidence has revealed that endothelial progenitor cell dysfunction, gut dysbiosis, and the abnormal release of extracellular vesicles and their carried microRNAs also contribute to the development and progression of diabetic vasculopathy. Therefore, clinical control and treatment of diabetes mellitus, as well as the development of novel therapeutic strategies are crucial in preventing cardiometabolic syndrome and related diabetic vasculopathy. The present review focuses on the relationship between insulin resistance and diabetes mellitus in diabetic vasculopathy and related cardiovascular disease, highlighting epidemiology and clinical characteristics, pathophysiology, and molecular mechanisms, as well as management strategies.
Topics: Humans; Diabetic Angiopathies; Metabolic Syndrome; Peripheral Vascular Diseases; Insulin Resistance; Atherosclerosis; Diabetes Mellitus
PubMed: 38255878
DOI: 10.3390/ijms25020804 -
The American Journal of Geriatric... Aug 2023To evaluate the correlation between cognitive signatures and the risk of diabetic vascular complications and mortality, based on a multicountry prospective study.
OBJECTIVE
To evaluate the correlation between cognitive signatures and the risk of diabetic vascular complications and mortality, based on a multicountry prospective study.
METHODS
The participants comprised 27,773 diabetics from the UK Biobank (UKB) and 1307 diabetics from the Guangzhou Diabetic Eye Study (GDES) cohort. The exposures were brain volume and cognitive screening tests for UKB participants, whilst the global cognitive score (GCS) measuring orientation to time and attention, episodic memory, and visuospatial abilities were determined for GDES participants. The outcomes for the UKB group were mortality, as well as macrovascular (myocardial infarction [MI] and stroke), microvascular (end-stage renal disease [ESRD], and diabetic retinopathy [DR]) events. The outcomes for the GDES group were retinal and renal microvascular damage.
RESULTS
In the UKB group, a 1-SD reduction in brain gray matter volume was associated with 34%-77% higher risks of incident MI, ESRD, and DR. The presence of impaired memory was associated with 18%-73% higher risk of mortality and ESRD; impaired reaction was associated with 1.2-1.7-fold higher risks of mortality, stroke, ESRD, and DR. In the GDES group, the lowest GCS tertile exhibited 1.4-2.2-fold higher risk of developing referable DR and a twofold faster decline in renal function and retinal capillary density compared with the highest tertile. Restricting data analysis to individuals aged less than 65 years produced consistent results.
CONCLUSION
Cognitive decline significantly elevates the risk of diabetic vascular complications and is correlated with retinal and renal microcirculation damage. Cognitive screening tests are strongly recommended as routine tools for management of diabetes.
Topics: Humans; Cohort Studies; Prospective Studies; Diabetic Retinopathy; Diabetic Angiopathies; Cognition; Kidney Failure, Chronic; Stroke; Brain; Risk Factors; Diabetes Mellitus, Type 2
PubMed: 37230837
DOI: 10.1016/j.jagp.2023.04.010 -
International Journal of Molecular... Oct 2023This study investigated modifications to the ubiquitin proteasome system (UPS) in a mouse model of type 2 diabetes mellitus (T2DM) and their relationship to heart...
This study investigated modifications to the ubiquitin proteasome system (UPS) in a mouse model of type 2 diabetes mellitus (T2DM) and their relationship to heart complications. mice heart tissues were compared with mice tissues using RNA sequencing, qRT-PCR, and protein analysis to identify cardiac UPS modifications associated with diabetes. The findings unveiled a distinctive gene profile in the hearts of mice with decreased levels of mRNA and increased levels of , indicating potential cardiac dysfunction. The mRNA levels of (deubiquitinating enzyme), , and (proteasome β-subunits) were down-regulated in mice, while the mRNA levels of RNF167 (E3 ligase) were increased. Corresponding LMP2 and LMP7 proteins were down-regulated in mice, and RNF167 was elevated in diabetic mice. The reduced expression of LMP2 and LMP7, along with increased RNF167 expression, may contribute to the future cardiac deterioration commonly observed in diabetes. This study enhances our understanding of UPS imbalances in the hearts of diabetic mice and raises questions about the interplay between the UPS and other cellular processes, such as autophagy. Further exploration in this area could provide valuable insights into the mechanisms underlying diabetic heart complications and potential therapeutic targets.
Topics: Mice; Animals; Proteasome Endopeptidase Complex; Ubiquitin; Diabetes Mellitus, Type 2; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diabetes Complications; RNA, Messenger
PubMed: 37895057
DOI: 10.3390/ijms242015376 -
Cellular and Molecular Life Sciences :... Jan 2024Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if... (Review)
Review
Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration.
Topics: Animals; Humans; Diabetes Mellitus, Type 2; Neuroinflammatory Diseases; Neuroglia; Diabetic Retinopathy; Inflammation; Peripheral Nervous System Diseases
PubMed: 38236305
DOI: 10.1007/s00018-023-05024-y -
BMJ Open Diabetes Research & Care Nov 2023Diabetic foot ulcer (DFU) stands as a severe diabetic lower extremity complication, characterized by high amputation rates, mortality, and economic burden. We propose...
INTRODUCTION
Diabetic foot ulcer (DFU) stands as a severe diabetic lower extremity complication, characterized by high amputation rates, mortality, and economic burden. We propose using Mendelian randomization studies to explore shared and distinct risk factors for diabetic lower extremity complications.
RESEARCH DESIGN AND METHODS
We selected uncorrelated genetic variants associated with 85 phenotypes in five categories at the genome-wide significance level as instrumental variables. Genetic associations with DFU, diabetic polyneuropathy (DPN), and diabetic peripheral artery disease (DPAD) were obtained from the FinnGen and UK Biobank studies.
RESULTS
Body mass index (BMI) emerged as the only significant risk factor for DPAD, DPN, and DFU, independent of type 2 diabetes, fasting glucose, fasting insulin, and HbA1c. Educational attainment stood out as the sole significant protective factor against DPAD, DPN, and DFU. Glycemic traits below the type 2 diabetes diagnosis threshold showed associations with DPAD and DPN. While smoking history exhibited suggestive associations with DFU, indicators of poor nutrition, particularly total protein, mean corpuscular hemoglobin, and mean corpuscular volume, may also signal potential DFU occurrence.
CONCLUSIONS
Enhanced glycemic control and foot care are essential for the diabetic population with high BMI, limited education, smoking history, and indicators of poor nutrition. By focusing on these specific risk factors, healthcare interventions can be better tailored to prevent and manage DFU effectively.
Topics: Humans; Diabetic Foot; Diabetes Mellitus, Type 2; Mendelian Randomization Analysis; Risk Factors
PubMed: 37989345
DOI: 10.1136/bmjdrc-2023-003523 -
Kidney International Jan 2024Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA)...
Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation.
Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease. Mice with deletion of the GLP-1 receptor displayed an abnormal kidney phenotype that was accelerated by diabetes and improved with co-deletion of RAGE in vivo. Activation of the GLP-1 receptor pathway with liraglutide, an anti-diabetic treatment, downregulated kidney RAGE, reduced the expansion of bone marrow myeloid progenitors, promoted M2-like macrophage polarization and lessened markers of kidney damage in diabetic mice. Single cell transcriptomics revealed that liraglutide induced distinct transcriptional changes in kidney endothelial, proximal tubular, podocyte and macrophage cells, which were dominated by pathways involved in nutrient transport and utilization, redox sensing and the resolution of inflammation. The kidney-protective action of liraglutide was corroborated in a non-diabetic model of chronic kidney disease, the subtotal nephrectomised rat. Thus, our findings identify a novel glucose-independent kidney-protective action of GLP-1-based therapies in diabetic kidney disease and provide a valuable resource for exploring the cell-specific kidney transcriptional response ensuing from pharmacological GLP-1R agonism.
Topics: Rats; Mice; Animals; Receptor for Advanced Glycation End Products; Diabetic Nephropathies; Liraglutide; Glucagon-Like Peptide-1 Receptor; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Inflammation
PubMed: 38069998
DOI: 10.1016/j.kint.2023.09.029 -
BMC Ophthalmology Sep 2023Diabetic retinopathy is one of the most common and serious microvascular complications of diabetes mellitus. There are many factors leading to diabetic retinopathy, and... (Review)
Review
Diabetic retinopathy is one of the most common and serious microvascular complications of diabetes mellitus. There are many factors leading to diabetic retinopathy, and its pathogenesis is still unclear. At present, there are still no effective measures for the early treatment of diabetic retinopathy, and the treatment options available when diabetes progresses to advanced stages are very limited, and the treatment results are often unsatisfactory. Detailed studies on the molecular mechanisms of diabetic retinopathy pathogenesis and the development of new therapeutic agents are of great importance. This review describes the potential pathogenesis of diabetic retinopathy for experimental studies and clinical practice.
Topics: Humans; Diabetic Retinopathy; Diabetes Mellitus
PubMed: 37697295
DOI: 10.1186/s12886-023-03118-6 -
Frontiers in Endocrinology 2024
Topics: Humans; Comorbidity; Diabetes Mellitus; Diabetes Complications; Diabetes Mellitus, Type 2
PubMed: 38660511
DOI: 10.3389/fendo.2024.1406131 -
Communications Biology Sep 2023The occurrence of diabetic nephropathy (DN) and diabetic retinopathy (DR) are closely associated in patients with diabetes. However, the cellular and molecular linkage...
The occurrence of diabetic nephropathy (DN) and diabetic retinopathy (DR) are closely associated in patients with diabetes. However, the cellular and molecular linkage of DN and DR has not been elucidated, and further revelations are needed to improve mutual prognostic decisions and management. Here, we generate and integrate single-cell RNA sequencing profiles of kidney and retina to explore the cellular and molecular association of kidney and retina in both physiological and pathological conditions. We find renal mesangial cells and retinal pericytes share molecular features and undergo similar molecular transitions under diabetes. Furthermore, we uncover that chemokine regulation shared by the two cell types is critical for the co-occurrence of DN and DR, and the chemokine score can be used for the prognosis of DN complicated with DR. These findings shed light on the mechanism of the co-occurrence of DN and DR and could improve the prevention and treatments of diabetic microvascular complications.
Topics: Humans; Diabetic Nephropathies; Transcriptome; Kidney; Diabetic Retinopathy; Mesangial Cells; Diabetes Mellitus
PubMed: 37670124
DOI: 10.1038/s42003-023-05300-4