Search Results (77)

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease characterized by chronic hyperglycemia and progressive microvascular complications, including retinopathy, nephropathy, and neuropathy. While traditional markers like HbA1c capture average glycemic control, they often fail to predict microvascular damage risk. Glycated CD59 (GCD59), a complement regulatory protein modified under hyperglycemic conditions, has emerged as a promising biomarker reflecting complement dysregulation and endothelial injury. This study aimed to examine the relationship between plasma GCD59 levels and the presence of microvascular complications in patients with type 2 diabetes mellitus and to evaluate whether GCD59 shows potential for future use as a predictive biomarker, pending prospective validation. Methods: In this single-center, prospective case–control study, 246 participants were enrolled: 82 healthy controls, 82 T2DM patients without microvascular complications (DM − MC), and 82 T2DM patients with microvascular complications (DM + MC). Microvascular complications were defined based on standardized criteria for retinopathy, nephropathy, and neuropathy. Plasma GCD59 levels were measured using validated ELISA methods. Receiver operating characteristic (ROC) analyses, forest plots, and odds ratio calculations were employed to assess the discriminatory performance of GCD59. Statistical significance was set at p < 0.05. Results: Plasma GCD59 levels were significantly elevated across all diabetic groups compared to healthy controls (p < 0.001), with the highest levels in the DM + MC group (median 4.5 ng/mL) versus DM − MC (median 1.9 ng/mL) and controls (median 1.2 ng/mL). ROC analysis demonstrated excellent diagnostic performance for distinguishing DM + MC from healthy controls (AUC = 0.946, sensitivity 89%, specificity 97.6%) and good performance for distinguishing DM + MC from DM − MC (AUC = 0.849, sensitivity 72%, specificity 87.8%). Forest plot analyses confirmed significantly elevated odds ratios for GCD59 across all microvascular subgroups. Importantly, GCD59 levels correlated positively with inflammatory markers (CRP, ESR, leukocyte count), suggesting a combined role of complement dysregulation and chronic inflammation in diabetic microangiopathy. Conclusions: Plasma GCD59 may be a promising biomarker for identifying T2DM patients who may be at increased risk for microvascular complications, independent of conventional glycemic markers. Given the cross-sectional design of this study, causal inference is not possible; prospective validation is required. The observed strong discriminatory performance highlights potential future clinical utility, pending further validation of diagnostic thresholds, assay standardization, and feasibility in routine care settings. Full article

Diabetic cardiomyopathy (DCM) is a significant complication of diabetes, particularly affecting East Asian populations with a high prevalence of the ALDH2*2 (Glu504Lys) genetic variant. This variant impairs aldehyde detoxification, leading to increased oxidative stress, mitochondrial dysfunction, and chronic inflammation, exacerbating cardiac damage and fibrosis. This review aimed to systematically delineate the pathological role of ALDH2 enzyme deficiency in DCM by integrating clinical observations with mechanistic insights from experimental models and evaluating emerging therapies for genetically susceptible populations. In vitro and in vivo studies demonstrate that ALDH2*2 amplifies oxidative stress and disrupts mitochondrial homeostasis under hyperglycemic conditions, leading to enhanced cardiac fibrosis and functional decline. Additionally, ALDH2*2 carriers show heightened susceptibility to metabolic stress, further aggravating DCM. Given the high prevalence of ALDH2*2 in East Asian populations, targeted therapeutic strategies are urgently needed. Promising approaches include ALDH2 activators (e.g., Alda-1) that enhance detoxification of reactive aldehydes, and SGLT2 inhibitors (e.g., empagliflozin) that improve mitochondrial function and reduce oxidative damage. These therapies can mitigate oxidative stress and preserve cardiac function in ALDH2*2 carriers, thereby potentially reducing DCM burden, especially in high-risk East Asian populations. Further clinical investigations are warranted to validate these therapeutic approaches and optimize management for ALDH2-deficient individuals. Full article

Enteric neurons regulating motility display regional damage to diabetes. By inhibiting neuroinflammation, insulin can contribute to neuronal survival, therefore, we aimed to investigate the presence of insulin in myenteric neurons and their nitrergic population in acute and chronic rat models of type 1 diabetes. One or ten weeks after the onset of hyperglycemia, gut segments and the pancreas of control, diabetic, and insulin-treated diabetic rats were investigated. In the controls, insulin-immunoreactive neurons comprised 8–9% of the total myenteric neuronal population in the ileum and colon and 2–4% in the duodenum. Except for the duodenum, this proportion was significantly increased in acute hyperglycemic rats and was decreased in the colon of the chronic ones. However, the proportion of insulin-immunoreactive nitrergic neurons remained unchanged in all segments in chronic hyperglycemia. Immunogold electron microscopy revealed an increased density of insulin-labelling gold particles in diabetic duodenal ganglia of the chronic experiment. Insulin mRNA was not detected in intestinal samples either in controls or diabetics. These findings support time-dependent and regional alterations in the proportion of insulin-immunoreactive myenteric neurons and their nitrergic subpopulation. Regionally different insulin content of myenteric neurons may contribute to their protection from diabetic damage. Full article

The hyperglycemic microenvironment in diabetic wounds predisposes them to bacterial infections, sustains chronic inflammation, and hinders therapeutic efficacy. In this study, antibiotic-loaded fast-crosslinked hybrid nanogel wound dressings (florfenicol nanogels) based on Schiff’s base bond were obtained through N, O-carboxymethyl chitosan (N, O-CMCS) and oxidized hyaluronic acid (OHA). The successfully prepared florfenicol N, O-CMCS/OHA nanogels exhibited obvious pH- and HAase-responsiveness release, which allowed it to quickly release florfenicol at infected wounds to exert on-demand antibacterial activity, as well as accelerate diabetic bacterial-infected wound healing. The nanogel dressings showed excellent antibacterial activity by destroying the bacterial cell membrane and wall. More specifically, the glucose oxidase in the dressings can catalyze the breakdown of high-concentration glucose, generating abundant ROS that directly cause cellular damage. According to the results of wound healing, the dressings showed satisfactory anti-inflammatory and therapeutic effects for the full-thickness mouse skin defect wounds. The nanogel dressings are anticipated to be excellent wound dressings to synergistically overcome the theraputic difficulty of diabetic bacterial wounds. Full article

Myocardial oxidative stress increases under conditions of hyperglycemia and ischemia/reperfusion (I/R) injury, leading to cellular damage. Inhibition of oxidative stress is involved in the cardioprotective effects of hydrogen sulfide (H₂S) during I/R and diabetes, and H₂S has the potential to protect the heart. However, the mechanism by which H₂S regulates the level of cardiac reactive oxygen species (ROS) during I/R and hyperglycemic conditions remains unclear. Therefore, the objective of this study was to evaluate the cytoprotective effect of H₂S in primary cardiomyocyte cultures subjected to hyperglycemia, hypoxia–reoxygenation (HR), or both conditions, by assessing the PPAR-α/Keap1/Nrf2/p47phox/NOX4/p-eNOS/CAT/SOD and the PPAR-γ/PGC-1α/AMPK/GLUT4 signaling pathways. Treatment with NaHS (100 μM) as an H₂S donor in cardiomyocytes subjected to hyperglycemia, HR, or a combination of both increased cell viability, total antioxidant capacity, and tetrahydrobiopterin (BH₄) concentrations, while reducing ROS production, malondialdehyde concentrations, 8-hydroxy-2′-deoxyguanosine, and dihydrobiopterin (BH₂) concentrations. Additionally, the H₂S donor treatment increased the expression and activity of PPAR-α, reversed the reduction in the expression of PPAR-γ, PGC-1α, AMPK, GLUT4, Nrf2, p-eNOS, SOD, and CAT, and decreased the expression of Keap1, p47phox and NOX4. Therefore, the treatment with the H₂S donor protects cardiomyocytes from damage caused by hyperglycemia, HR, or both conditions by reducing oxidative stress markers and improving antioxidant mechanisms, thereby increasing cell viability and “cardiomyocyte ultrastructure”. Full article

Type 2 diabetes (T2D) is a chronic disease that damages blood vessels and increases the risk of cardiovascular disease (CVD). Heat-shock protein 70 (HSP70), a family of chaperone proteins, has been recently reported as a key player in vascular reactivity that affects large blood vessels like the aorta. Hyperglycemia, a hallmark of diabetes, correlates with the severity of vascular damage and circulating HSP70 levels. In diabetes, blood vessels often show impaired contractility, contributing to vascular dysfunction. However, HSP70’s specific role in T2D-related vascular contraction remains unclear. We hypothesized that blocking HSP70 would improve vascular function in a widely used diabetic mouse model (db/db). To test this, we measured both vascular intracellular and serum circulating HSP70 levels in control and diabetic male mice using immunofluorescence and Western blotting. We also examined the aorta’s contractile response using a wire myograph system, which measured the force produced in response to phenylephrine (PE), both with and without VER155008, a pharmacological inhibitor that targets the ATPase domain of HSP70, and after removing extracellular calcium. Our findings show that intracellular HSP70 (iHSP70) levels were similar in control and diabetic groups, while circulating HSP70 (eHSP70) levels were higher in the serum of diabetic mice, altering the iHSP70/eHSP70 ratio. Even though VER155008 attenuated both phases of the contractile curve in the diabetic and control groups, enhanced vasoconstriction to PE was only observed in the tonic phase of the curve in the db/db group, which was prevented by iHSP70 inhibition. This effect involved calcium mobilization, as both the maximal and total contraction forces to PE were restored in groups treated with VER155008. Additionally, internal calcium levels in aortic rings treated with VER155008 decreased, as observed in force generation upon calcium reintroduction, which was further corroborated using a biochemical calcium assay. In conclusion, our study demonstrates that blocking HSP70 improves vascular reactivity in the hyperglycemic state of T2D by restoring proper vascular contraction. Full article

Moringa oleifera (MO) has gained recognition as a potent natural intervention for preventing and managing chronic diseases (CDs) due to its diverse phytochemical composition and pharmacological properties. Rich in antioxidants, polyphenols, flavonoids, and glucosinolates, MO exerts anti-inflammatory, anti-hyperglycemic, cardioprotective, and anti-obesity effects. These properties make it a valuable therapeutic agent for CDs, including diabetes, cardiovascular diseases, obesity, neurodegenerative disorders, and cancer. MO’s ability to modulate oxidative stress and inflammation—key drivers of CDs—highlights its significant role in disease prevention and treatment. MO enhances insulin sensitivity, regulates lipid profiles and blood pressure, reduces inflammation, and protects against oxidative damage. MO also modulates key signaling pathways involved in cancer and liver disease prevention. Studies suggest that MO extracts possess anticancer activity by modulating apoptosis, inhibiting tumor cell proliferation, and interacting with key signaling pathways, including YAP/TAZ, Nrf2-Keap1, TLR4/NF-κB, and Wnt/β-catenin. However, challenges such as variability in bioactive compounds, taste acceptability, and inconsistent clinical outcomes limit their widespread application. While preclinical studies support its efficacy, large-scale clinical trials, standardized formulations, and advanced delivery methods are needed to optimize its therapeutic potential. MO’s multifunctional applications make it a promising and sustainable solution for combating chronic diseases, especially in resource-limited settings. Full article

High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic glycosylation, carbamylation, oxidative stress and systemic inflammation can cause changes in the quantity and quality of HDL, resulting in reduced HDL levels and abnormal function. Dysfunctional HDL can also have a negative impact on pancreatic β cells and kidney cells, leading to the progression of DKD. Based on these findings, new HDL-related DKD risk predictors have gradually been proposed. Interventions aiming to improve HDL levels and function, such as infusion of recombinant HDL (rHDL) or lipid-poor apolipoprotein A-I (apoA-I), can significantly improve glycemic control and also show renal protective effects. However, recent studies have revealed a U-shaped relationship between HDL-C levels and DKD, and the loss of protective properties of high levels of HDL may be related to changes in composition and the deposition of dysfunctional particles that exacerbate damage. Further research is needed to fully elucidate the complex role of HDL in DKD. Given the important role of HDL in metabolic health, developing HDL-based therapies that augment HDL function, rather than simply increasing its level, is a critical step in managing the development and progression of DKD. Full article

Diabetic retinopathy is characterized by hyperglycemic retinal pigment epithelial cells that secrete excessive pro-inflammatory cytokines and VEGF, leading to retinal damage and vision loss. Cobalt protoporphyrin (CoPP) is a compound that can reduce inflammatory responses by inducing high levels of HO-1. In the present study, the therapeutic effects of CoPP were examined in ARPE-19 cells under hyperglycemia. ARPE-19 cells were incubated in culture media containing either 5.5 mM (NG) or 25 mM (HG) glucose, with or without the addition of 0.1 µM CoPP. Protein expressions in samples were determined by either Western blotting or immunostaining. A Seahorse metabolic analyzer was used to assess the impact of CoPP treatment on mitochondrial respiration in ARPE-19 cells in NG or HG media. ARPE-19 cells cultured in NG media displayed different cell morphology than those cultured in HG media. CoPP treatment induced high HO-1 expressions and significantly enhanced the viability of ARPE-19 cells under hyperglycemia. Moreover, CoPP significantly downregulated expressions of inflammatory and apoptotic markers and significantly upregulated mitochondrial respiration in APRPE-19 cells under hyperglycemia. CoPP treatment significantly enhanced cell viability in ARPE-19 cells under hyperglycemia. The treatment also downregulated the expressions of pro-inflammatory and upregulated mitochondrial respiration in the hyperglycemic cells. Full article

Diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus, is primarily characterized by damage to Schwann cells caused by oxidative stress under hyperglycemic conditions. Recently, we demonstrated the ability of coumarin-rich Ficus formosana Maxim. to alleviate DPN in ovariectomized diabetic mice. However, the underlying mechanisms remain unclear. In this study, we established an in vitro DPN model using RSC96 Schwann cells exposed to high glucose levels. Daphnetin, a natural coumarin found abundantly in Ficus formosana Maxim., was co-incubated with Schwann cells in a high-glucose medium to investigate its protective effects against DPN. The free radical scavenging capacity of daphnetin was evaluated, along with assessments of cell viability, apoptosis, H₂O₂ levels, and the expression of proteins by the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutamate–cysteine ligase catalytic subunit (GCLC) pathway in RSC96 Schwann cells. The results showed that daphnetin was non-toxic within the tested concentration range of 6.25 μM to 50 μM in RSC96 Schwann cells. Moreover, daphnetin significantly improved cell viability, exhibited strong antioxidant activity, reduced H₂O₂ levels, and regulated the Nrf2/GCLC pathway protein expressions in RSC96 cells cultured in high-glucose medium. Additionally, daphnetin influenced apoptosis-related proteins by decreasing the expression levels of Bax and Caspase 3, while increasing the Bcl-2 expression level in high-glucose-treated RSC96 cells. These findings suggest that daphnetin may alleviate oxidative stress induced by high glucose levels through activation of the Nrf2/GCLC pathway and inhibition of Schwann cell apoptosis, underscoring its potential as a therapeutic agent for DPN. Full article

There is an increasing prevalence of diabetes mellitus (DM), particularly type 2 DM (T2DM), and its associated complications. T2DM is linked to insulin resistance, chronic inflammation, and oxidative stress, which can lead to both macrovascular and microvascular complications, including peripheral diabetic neuropathy (PDN). Inflammatory processes play a key role in the development and progression of T2DM and its complications, with specific markers like C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor (TNF)-α being associated with increased risk. Other key inflammatory markers such as nuclear factor kappa B (NF-κB) are activated under hyperglycemic and oxidative stress conditions and contribute to the aggravation of PDN by regulating inflammatory gene expression and enhancing endothelial dysfunction. Other important roles in the inflammatory processes are played by Toll-like receptors (TLRs), caveolin 1 (CAV1), and monocyte chemoattractant protein 1 (MCP1). There is a relationship between vitamin D deficiency and PDN, highlighting the critical role of vitamin D in regulating inflammation and immune responses. The involvement of macrophages in PDN is also suspected, emphasizing their role in chronic inflammation and nerve damage in diabetic patients. Vitamin D supplementation has been found to reduce neuropathy severity, decrease inflammatory markers, and improve glycemic control. These findings suggest that addressing vitamin D deficiency could offer therapeutic benefits for PDN. These molecular pathways are critical in understanding the pathogenesis of DM complications and may offer potential biomarkers or therapeutic targets including anti-inflammatory treatments, vitamin D supplementation, macrophage phenotype modulation, and lifestyle modifications, aimed at reducing inflammation and preventing PDN. Ongoing and more extensive clinical trials with the aim of investigating anti-inflammatory agents, TNF-α inhibitors, and antioxidants are needed to advance deeper into the understanding and treatment of painful diabetic neuropathy. Full article

Activation of the transcription factor NF-κB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-κB controls the expression of an array of pro-inflammatory cytokines and chemokines. We recently discovered that the stress response protein regulated in development and DNA damage response 1 (REDD1) was required for increased pro-inflammatory cytokine expression in the hearts of diabetic mice. The studies herein were designed to extend the prior report by investigating the role of REDD1 in NF-κB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-κB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNFα or hyperglycemic conditions. A similar suppressive effect on NF-κB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3β. NF-κB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3β variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3β at S9 and upregulation of IL-1β and CCL2. Diabetic REDD1^+/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1^−/− mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1^−/− mice, as compared to diabetic REDD1^+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3β-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice. Full article

Diabetic retinopathy is one of the major causes of visual impairment and blindness in adult population. The pathology is complex, the metabolic changes induced by the hyperglycemic environment leading to neurodegeneration, microvascular damage, with secondary ischemic and inflammatory changes in the retina. This review aims to update the literature data related to the role of inflammation in the onset and progression of diabetic retinopathy. Thus, the molecular and biochemical mechanisms triggered by excess glucose increase the expression of genes involved in inflammatory processes, which leads to the synthesis of inflammatory cytokines such as Il1, Il6, TNF alpha as well as complement activation. Furthermore, recent evidence has demonstrated that both systemic and ocular prolonged inflammation are correlated with the progression of diabetic retinopathy. In conclusion, preventing and/or reducing the progression of diabetic retinopathy requires both rigorous glycemic control in diabetic patients and targeted interference of the specific inflammatory pathways involved. Full article

Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition. Full article

The probability of acute kidney injury (AKI) is higher in septic diabetic patients, which is associated with, among other factors, proximal tubular cell (PTC) injury induced by the hypoxic/hyperglycemic/inflammatory microenvironment that surrounds PTCs in these patients. Here, we exposed human PTCs (HK-2 cells) to 1% O₂/25 mM glucose/inflammatory cytokines with the aim of studying the role of prostaglandin uptake transporter (PGT) and dipeptidyl peptidase-4 (DPP-4, a target of anti-hyperglycemic agents) as pharmacological targets to prevent AKI in septic diabetic patients. Our model reproduced two pathologically relevant mechanisms: (i) pro-inflammatory PTC activation, as demonstrated by the increased secretion of chemokines IL-8 and MCP-1 and the enhanced expression of DPP-4, intercellular leukocyte adhesion molecule-1 and cyclo-oxygenase-2 (COX-2), the latter resulting in a PGT-dependent increase in intracellular prostaglandin E₂ (iPGE₂); and (ii) epithelial monolayer injury and the consequent disturbance of paracellular permeability, which was related to cell detachment from collagen IV and the alteration of the cell cytoskeleton. Most of these changes were prevented by the antagonism of PGE₂ receptors or the inhibition of COX-2, PGT or DPP-4, and further studies suggested that a COX-2/iPGE2/DPP-4 pathway mediates the pathogenic effects of the hypoxic/hyperglycemic/inflammatory conditions on PTCs. Therefore, inhibitors of PGT or DPP-4 ought to undergo testing as a novel therapeutic avenue to prevent proximal tubular damage in diabetic patients at risk of AKI. Full article