Uncontrolled diabetes mellitus (DM) accelerates atherosclerosis and vascular diseases, leading to micro- and macrovascular complications. Early cardiac and kidney involvement necessitates an early biomarker. Sclerostin is a Wnt-signaling inhibitor, having a pathophysiological role in vasculopathy, and could be used as a vasculopathy marker. Nevertheless, few data are available in pediatric patients with type 1 diabetes mellitus (T1DM). We aimed at assessing its serum level, and relation to diabetic microvascular and macrovascular complications.

This is a case control study on patients with T1DM, and healthy controls. Patients were divided into non-diabetic nephropathy (DN), and DN groups according to proteinuria. Patients' clinicodemographic and anthropometrics were obtained, with withdrawal of fasting serum lipid profile, kidney function test, and serum sclerostin. Carotid intimal media thickness (CIMT), a marker of subclinical atherosclerosis, was measured.

We had 75 comparable subjects, where median (IQR) serum sclerostin levels were significantly higher in DN, compared to non-DN and controls [90.83 (82.32 - 115.1), vs. 33.29 (28.37 - 38.53), vs. 13.5 (10.32 - 15.72) ng/mL,respectively, p, < 0.001]. Similarly, median (IQR) CIMT was significantly higher in DN, than in non-DN and controls [1.1 (0.8 - 1.3), vs. 0.11 (0.1 - 0.2), vs. 0.11 (0.1 - 0.2) mm, respectively, p < 0.001]. Serum sclerostin level correlated positively with disease duration, higher HgbA1c%, albuminuria level, and CIMT in all patients. The cut-off values of serum sclerostin > 60.0 ng/mL and CIMT > 0.3 mm were able to detect DN.

Serum sclerostin levels may serve as a potential biomarker for microvascular and macrovascular complications in pediatric patients with T1DM.

Diabetic nephropathy (DN) is a serious microvascular complication that can progress to end-stage renal disease, with its prevalence and associated mortality increasing globally. However extensive research, the precise mechanisms underlying DN pathogenesis remain unclear, and the current treatment options for DN are limited to dialysis or renal replacement therapy, although several experimental approaches have shown potential, they remain investigational and lack clinical translation. Exosomes play a pivotal role in disease diagnosis and prognosis. Urinary exosomes, originating from various kidney cells, reflect the kidney's pathological condition and are involved in cell-to-cell communication through autocrine or paracrine signaling; therefore, they could contribute to the pathogenesis of DN and potential therapeutic approaches. Additionally, due to their diverse cargo, which depend on cellular origin and pathological state, exosomes may act as biomarkers for the early prediction of DN. This review presents a comprehensive overview of the latest findings on the role of exosomes in the diagnosis, pathogenesis, and treatment of DN.

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and has the complex pathogenesis. The previous study reported that protein kinase Bγ (AKT3) was involved in DN progression. Our aim was to explore the detailed mechanisms of AKT3 in DN development.

RT-qPCR was performed to measure the levels of specificity protein 1 (SP1) and AKT3. Mesangial cells were treated with high glucose (30 mM) to form DN cell model in vitro. Western blot was conducted to detect the protein expression of AKT3, SP1, fibrosis-related proteins, and AKT/mTOR pathway-related proteins. Cell proliferation and inflammation were evaluated via MTT, EdU staining, and ELISA assays, respectively. Oxidative stress was determined via measuring ROS and MDA levels. ChIP and dual-luciferase reporter assays were carried out to verify the relationship between SP1 and AKT3. C57BL/6 mice-treated with streptozotocin for 5 days were used to establish DN mouse model in vivo, and HE and Masson staining were conducted to evaluate pathological changes of mouse kidney tissues.

AKT3 and SP1 were highly expressed in DN kidney tissues and HG-induced mesangial cells. AKT3 depletion could relieve HG treatment-caused cell damage of mesangial cells through repressing cell proliferation, fibrosis, inflammation and oxidative stress. SP1 can bind to the promoter of AKT3 and serve as a translation regulation factor of AKT3. SP1 overexpression worsened HG treatment-caused cell damage of mesangial cells. Moreover, AKT3 upregulation could block the suppressive effects of SP1 depletion on cell proliferation, fibrosis, inflammation and oxidative stress in HG-induced mesangial cells. SP1 depletion reduced AKT3 expression to inactivate the AKT/mTOR pathway in HG-induced mesangial cells. Besides, AKT3 knockdown inhibited the activation of the AKT/mTOR pathway to hamper the development of DN in mice through alleviating fibrosis and inflammation in vivo.

Our results indicated that SP1 activated AKT3 and AKT/mTOR pathway to promote mesangial cell proliferation, fibrosis, inflammation and oxidative stress, thereby facilitating DN development.

Ultrasound stimulation of internal organs and peripheral nerves has demonstrated promising potential in regulating blood glucose metabolism. This study aims to assess the effectiveness of low-intensity pulsed ultrasound stimulation (LIPUS) on intestine in improving insulin resistance with type 2 diabetes mellitus (T2DM).

C57BL/6J mice, both normal and T2DM, were randomly divided into three groups: Control, T2D-sham, and T2D-LIPUS. The T2D-LIPUS group received LIPUS stimulation in the intestine. The parameters were as follows: 1 MHz frequency, 1.0 kHz pulse repetition frequency (PRF), 20% duty cycle, 100 mW/cm² intensity spatial average temporal average (ISATA), for 20 minutes per session, five days per week, over four weeks.

Blood glucose analysis indicated that mice in the T2D-LIPUS group displayed significantly lower area under the curve (AUC) of glucose tolerance tests (GTT) and insulin tolerance tests (ITT) (p < 0.001), HOMA-IR (p < 0.001), and fasting serum insulin levels (p < 0.01) compared to the T2D-sham group. LIPUS treatment effectively lowered serum levels of IL-1β (p < 0.001) and TNF-α (p < 0.01) along with mRNA expression levels of IL-1β (p < 0.01) and IL-18 (p < 0.001) in the intestines of T2DM mice. Additionally, Western blot analysis revealed a reduction in the protein levels of NLRP3, caspase-1, and GSDMD-N in the intestinal tissues of mice treated with LIPUS.

These findings suggest that LIPUS can reduce inflammation and cellular apoptosis, while improving insulin resistance by inhibiting the NLRP3/Caspase-1/GSDMD signaling pathway. This research introduces a novel, non-pharmacological approach for managing T2DM.

Diabetic nephropathy, a severe problem of diabetes mellitus, is exacerbated by high-fat diets, prompting a need for interventions. Previous study from our laboratory has shown that β-sitosterol, a potent plant sterol has anti-inflammatory and glucose-lowering efficacy by involving insulin metabolic signalling pathway but its role on anti-oxidant signaling pathways, play a crucial role in mitigating oxidative stress and inflammation associated diabetic nephropathy, highlighting its importance as a potential therapeutic target for managing this debilitating complication of diabetes is unknown. This study was aimed to intricate the molecular mechanisms involved in the potential of β-sitosterol (BSIT) on TGF-β1/Nrf2/SIRT1/p53 signaling in high fat diet (HFD) and sucrose induced diabetic nephropathy (DN) in the rat kidney by employing various comprehensive bioinformatic analysis. We have used various comprehensive methods such as pathway predictions, Drug-Protein Interaction, Functional annotation analysis, and molecular docking techniques. Further, in vivo analysis of BSIT on biochemical profiles, gene and protein expression analysis of anti-oxidant and inflammatory signaling molecules was performed in the kidney of high fat diet (HFD) and sucrose-induced diabetic nephropathy. Computational studies provided insights into β-sitosterol's binding affinities and interaction modes with key proteins, suggesting its potential to regulate TGF-β1/Nrf2/SIRT1/p53 signaling pathways. Results of in vivo findings validated computational predictions, showcasing BSIT's multifaceted effects in mitigating diabetic nephropathy and associated complications including regulation of lipid metabolism, combating oxidative stress, and inflammation. The findings underscore BSIT's therapeutic potential by preserving cellular viability, regulating cell death, enhancing antioxidant defence, and stabilizing metabolic processes. Our study concludes that BSIT's ability to potentially regulate TGF-β1/Nrf2/SIRT1/p53 pathways, emphasizing its promising role in managing diabetic nephropathy and associated complications.

The effects of gut microbiome and its metabolites on diabetic nephropathy (DN) have been inadequately elucidated. The aim of this study is to assess the causal effect of gut microbiome on DN and the mediated effect of metabolites by a two-step Mendelian randomization (MR).

Datasets of gut microbiome, metabolites, and DN were acquired in genome-wide association studies and screened for single nucleotide polymorphisms according to the underlying assumptions of MR. Subsequently, inverse variance weighted was used as the primary method for MR analysis to assess the causal effect of gut microbiome on DN and the mediated effect of metabolites. Finally, MR-Egger intercept, Cochran's Q test, and leave-one-out sensitivity analysis were used to assess the horizontal pleiotropy, heterogeneity, and robustness of the results, respectively.

The MR analysis demonstrated that Parabacteroides merdae increased the genetic susceptibility to DN by reducing acetylcarnitine (C2) to propionylcarnitine (C3) ratio (mediated proportion 8.95%, mediated effect 0.024) and alpha-ketobutyrate to 3-methyl-2-oxovalerate ratio (mediated proportion 19.90%, mediated effect 0.053). MR Egger showed that these results lack horizontal pleiotropy (p ≥ 0.05). Cochran's Q and sensitivity analysis suggested these results had no heterogeneity (p ≥ 0.05) and were robust.

Our findings revealed the pathway by which Parabacteroides merdae increased the genetic susceptibility to DN by regulating acetylcarnitine (C2) to propionylcarnitine (C3) ratio and alpha-ketobutyrate to 3-methyl-2-oxovalerate ratio. It provides new genetic insights for understanding the pathogenesis of DN and related drug research.

The complex etiology and spectrum of kidney diseases necessitate vigilant attention; the focus on early diagnosis and intervention in kidney diseases remains a critical issue in medical research. Recently, with the expanding studies on extracellular vesicles, exosomes have garnered increasing interest as a promising tool for the diagnosis and treatment of kidney diseases. Exosomes are nano-sized extracellular vesicles that transport a diverse array of bioactive substances, which can influence various pathological processes associated with kidney diseases and exhibit detrimental or beneficial effects. Within the kidney, exosomes derived from the glomeruli and renal tubules possess the ability to enter systemic circulation or urine. The biomarkers they carry can reflect alterations in the pathological state of the kidneys, thereby offering novel avenues for early diagnosis. Furthermore, research studies have confirmed that exosomes originating from multiple cell types exhibit therapeutic potential in treating kidney disease; notably, those derived from mesenchymal stem cells (MSCs) have shown significant treatment efficacy. This comprehensive review summarizes the contributions of exosomes from different cell types within the kidneys while exploring their physiological and pathological roles therein. Additionally, we emphasize recent advancements in exosome applications for the diagnosis and treatment of various forms of kidney diseases over the past decades. We not only introduce the urinary and blood biomarkers linked to kidney diseases found within exosomes but also explore their therapeutic effects. Finally, we discuss existing challenges and future directions concerning the clinical applications of exosomes for diagnostic and therapeutic purposes.

In this editorial, we discussed the article published in the recent issue of the World Journal of Diabetes. To understand the effect of mizagliflozin on kidney injury induced by diabetes, we focused on the mechanisms by which high glucose triggers oxidative stress and contributes to kidney injury in diabetes. The high level of unmetabolized glucose reaching the kidney triggers glucose reabsorption by renal tubules, which elevates the cellular glucose level of renal cells. High glucose induces lactate dehydrogenase overexpression and thus shifts glucose metabolism, which causes mitochondrial dysfunction. Mitochondria generate approximately 90% of the reactive oxygen species in cells, whose dysfunction further alters glucose metabolism and enhances reactive oxygen species generation. Oxidative stress stimulates proinflammatory factor production and kidney inflammatory injury. Mizagliflozin decreases glucose reabsorption and thus ameliorates diabetes-induced kidney injury.

Diabetes is a chronic metabolic disease that is endemic worldwide and is characterized by persistent hyperglycemia accompanied by multiple severe complications, including cardiovascular disease, kidney dysfunction, neuropathy, and retinopathy. The pathogenesis of diabetes mellitus and its complications is multifactorial, involving various molecular and cellular pathways. In recent years, research has indicated that mechanisms of cell death play a significant role in the advancement of diabetes and its complications. PANoptosis is a complex phenomenon caused by three cell death pathways: programmed apoptosis, necroptosis and pyroptosis. The contribution of PANoptosis to diabetes and its complications remains incompletely understood. Non-coding RNA, an important molecule in gene expression regulation, has shown significant regulatory functions in a variety of diseases. This paper reviews the underlying mechanisms of diverse types of non-coding RNAs (including lncRNA, miRNA and circRNA) in regulating PANoptosis and their specific contributions in diabetes, aiming to explore how non-coding RNAs influence PANoptosis and their effects in diabetes.

Diabetic nephropathy (DN) is a significant driver of end-stage renal disease, requiring kidney replacement therapies such as transplantation and dialysis. Given the critical importance of understanding the onset and progression of DN, we sought to explore the expression levels of tumor necrosis factor (TNF) and related long noncoding RNAs (lncRNAs) in diabetic patients with and without DN, as well as in pre-diabetic individuals, compared to healthy controls. We further explored the involvement of TNF and TNF-related lncRNAs in high glucose (HG)-induced apoptosis of human embryonic kidney (HEK)-293 cells.

In the current cross-sectional investigation, we compare the expression levels of lncRNA myocardial infarction-associated transcript (MIAT), lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), and TNF in 50 healthy individuals, 50 people with prediabetes, 50 patients with type 2 diabetes mellitus (T2DM), and 50 patients with T2DM- DN. We cultured HEK293 cells in a HG condition (100 mM glucose) to establish a cellular model of DN, while HEK293 cells cultured in a normal-glucose environment (5 mM glucose) served as controls. We further assess apoptosis in HEK293 cells via flow cytometry analysis. Moreover, we evaluated the expression levels of lncRNA MIAT, lncRNA NEAT1, and TNF in HG and normal-glucose (NG) groups to investigate their potential involvement in HEK293 cell apoptosis and the pathogenesis of DN.

Our findings reveal a significant upregulation of lncRNA MIAT, lncRNA NEAT1, and TNF in T2DM and T2DM-associated DN groups compared to prediabetic individuals and healthy controls (p < 0.05). Furthermore, HG conditions significantly increased the apoptotic rate of HEK293 cells. Additionally, the expression levels of TNF, lncRNA MIAT, and lncRNA NEAT1 were increased in HEK-293 cells cultured in a HG.

In conclusion, our findings indicate a significant role for the TNF gene and associated lncRNAs, such as lncRNA MIAT and lncRNA NEAT1, in podocyte apoptosis and the development of DN.

Trigonella foenum-graecum L. (HLB) exhibits promising pharmacological properties for the treatment of type 2 diabetic nephropathy (DN). This study aims to enhance the understanding of HLB's pharmacodynamic effects and elucidate the mechanisms underlying its therapeutic potential in DN.

The pharmacodynamic effects of HLB were initially evaluated in a murine DN model through the oral administration of an aqueous extract of HLB. The primary bioactive constituents were subsequently identified using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Network pharmacology analysis was integrated with these data to uncover potential molecular targets of HLB in DN. Key renal metabolites were profiled using untargeted metabolomics, followed by metabolic pathway enrichment analysis conducted with the MetaboAnalyst 6.0 platform, which facilitated the identification of relevant metabolic pathways through which HLB modulates DN. Finally, quantitative real-time polymerase chain reaction (QRT-PCR) and Western blot (WB) techniques were employed to validate the expression levels of key genes and proteins, thereby confirming the molecular mechanisms underlying the effects of HLB in DN.

Animal experiments indicated that HLB significantly improved blood glucose regulation and renal function while reducing oxidative stress and abnormalities in lipid metabolism in diabetic mice. A total of 34 compounds and 159 potential therapeutic targets were identified as key active components of HLB. The untargeted metabolomics analysis revealed 61 critical metabolites, among which the PI3K-Akt-ERK signaling pathway-known to be involved in diabetes-was highlighted as a crucial pathway. QRT-PCR and WB analyses demonstrated that HLB upregulated the expression of MAPK1, MAPK3, AKT1, and PI3K.

These results suggest that HLB may alleviate DN by modulating oxidative stress and lipid metabolism. Its effects are likely mediated through the PI3K-Akt-ERK signaling pathway, along with the upregulation of MAPK1, MAPK3, AKT1, and PI3K expression. This study lays the groundwork for further investigations into the molecular mechanisms underlying HLB's action in DN.

To explore and validate the association between the oxidative balance and prevalence of diabetic kidney disease (DKD) and mortality in patients with diabetes.

A large and representative sample from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016 was analyzed to study the potential association between Oxidative Balance Score (OBS) and prognosis of DKD in adult diabetic patients. Weighted multivariate logistic regression analysis was conducted to examine the relationship between OBS and DKD risk. Subgroup analysis, sensitivity analysis, and mediation effect analysis were conducted to explore the effect of the covariates and assess the robustness of the findings. Mendelian randomization (MR) was employed to evaluate the correlated relationship between mitochondrial reactive oxygen species (ROS) levels and DKD at the genetic level.

The highest OBS quartile showed the most significant negative correlation with DKD compared to the lowest OBS quartile (OR = 0.62, 95% CI 0.41-0.92, P = 0.017). Higher OBS was associated with a reduced risk of DKD (OR = 0.96; 95% CI = 0.93, 0.98; P < 0.001) and mortality (P = 0.021 by log-rank) in diabetic patients. This association remained robust even after excluding individual OBS components. Subgroup analysis revealed the interaction of metabolic syndrome on OBS was significant. Mediation analyses revealed that OBS's effect on DKD was independent of blood uric acid and cholesterol. Restricted cubic spline (RCS) analysis indicated a typical L-shaped relationship between OBS and DKD risk. The physical activity was identified as the core variable predicting DKD risk by two machine learning algorithms. MR showed a potential correlated relationship between ROS and microalbuminuria in DKD.

The high level of oxidative balance score was negatively correlated with the risk of DKD and mortality in diabetic patients.

Type 1 diabetes mellitus is defined by the autoimmune destruction of pancreatic β cells, with diabetic nephropathy being a significant consequence. Recently, cuminaldehyde has been shown protective ability against various pathophysiology. However, its nephroprotective and anti-diabetic potential has not yet been fully understood. We, therefore, conducted the present study to evaluate the anti-hyperglycemic potential of cuminaldehyde in NRK52E cells without (control) or with high glucose medium to emulate hyperglycemic conditions. Cuminaldehyde pre-treatment at an optimal concentration of 175 μM prior to high glucose addition restricted excessive reactive oxygen species (ROS) production and maintained cellular morphology to almost normal. The inhibitor study using N-acetyl-l-cysteine confirmed that blocking of ROS assists NRK52E cells in evading apoptosis. In addition, hyperglycemia was induced in 6-week-old Swiss albino mice in this investigation through the intraperitoneal injection of streptozotocin (150 mg kg-1 body weight). Hyperglycemia increased the kidney-to-body weight ratio, lowered serum insulin levels, and led to significant renal tissue damage compared to control mice. Moreover, hyperglycemia disturbs cellular redox equilibrium by decreasing antioxidant enzyme functions and promoting inflammatory cytokines in kidney tissue. Administering cuminaldehyde at a dosage of 10 mg kg-1 body weight for 5 weeks daily after the onset of diabetes effectively ameliorated the aforementioned anomalies and reversed kidney damage by regulating inflammation-induced cell death. Overall, the research demonstrated that cuminaldehyde has hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties. We believe that after conducting extensive research, this unique molecule can be used in clinical trials against diabetic nephropathy in future.

The aim of this study is to explore the impact of blood lipids and statins on renal function and all-cause mortality in patients with diabetic nephropathy (DN). PubMed, Embase, Web of Science, and Cochrane Library were systematically searched until April 9, 2024, for relevant studies of blood lipids and statins on renal function and all-cause mortality in patients with DN. After the selection, total cholesterol levels (TC), total triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), serum creati-nine (SCR), end-stage renal disease (ESRD), and all-cause mortality indexes were extracted for finally meta-analysis. In total, 25 papers containing 21,411 patients with DN were finally included in this study. Levels of TC and LDL-C, which are continuous variables, were higher in DN patients who developed ESRD [TC/weighted mean difference (WMD) = 0.517, 95 % confidence interval (CI): (0.223, 0.812), p = 0.001; LDL-C/WMD = 0.449, 95%CI: (0.200, 0.698), p < 0.001]. In addition, this study also observed that statins may reduce UAE levels [WMD = -46.814, 95% CI: (-71.767, -21.861), p < 0.001]. Finally, the survey indicated that statins may be associated with an ESRD reduction [HR = 0.884, 95% CI: (0.784, 0.998), p = 0.045]. Blood lipids, particularly TC and LDL-C, may slow the progression of DN to ESRD. Besides, statins may protect the kidneys by lowering the excretion of UAE levels and reducing the risk of ESRD. Based on the above outcomes, the findings of this study provided robust evidence-based medical support for the future prevention, surveillance, and management of DN.

Diabetic nephropathy (DN) is one of the most feared complications of diabetes and key cause of end-stage renal disease (ESRD). Berberis integerrima has been widely used to treat diabetic complications, but exact molecular mechanism is yet to be discovered. Data on active ingredients of B. integerrima and target genes of both diabetic nephropathy and B.integerrima were obtained from public databases. Common results between B. integerrima and DN targets were used to create protein-protein interaction (PPI) network using STRING database and exported to Cytoscape software for the selection of hub genes based on degree of connectivity. Future, PPI network between constituents and overlapping targets was created using Cytoscape to investigate the network pharmacological effects of B. integerrima on DN. KEGG pathway analysis of core genes exposed their involvement in excess glucose-activated signaling pathway. Then, expression of core genes was validated through machine learning classifiers. Finally, PyRx and AMBER18 software was used for molecular docking and simulation. We found that Armepavine, Berberine, Glaucine, Magnoflorine, Reticuline, Quercetin inhibits the growth of diabetic nephropathy by affecting ICAM1, PRKCB, IKBKB, KDR, ALOX5, VCAM1, SYK, TBXA2R, LCK, and F3 genes. Machine learning revealed SYK and PRKCB as potential genes that could use as diagnostic biomarkers against DN. Furthermore, docking and simulation analysis showed the binding affinity and stability of the active compound with target genes. Our study revealed that B. integerrima has preventive effect on DN by acting on glucose-activated signaling pathways. However, experimental studies are needed to reveal biosafety profiles of B. integerrima in DN.Communicated by Ramaswamy H. Sarma.

Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear.

The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits.

Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin.

Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway.

Sigma-1 receptor (S1R) activation was recently identified as a promising target for preventing diabetic nephropathy (DN) by mitigating hypoxia, oxidative stress, and inflammation. This study aimed to investigate the potential reno-protective effect of the S1R agonist afobazole against streptozotocin (STZ)-induced DN in rats compared to metformin.

Rats were split into six groups: the normal control group; the diabetic control group received STZ (55 mg/kg i.p.); the other four groups received STZ and were treated with different doses of either afobazole (10, 15, and 20 mg/kg) or metformin (200 mg/kg). Metabolic parameters and renal function were assessed. Expression levels of oxidative stress markers and inflammatory cytokines were measured using ELISA, apoptosis-related proteins were evaluated using immunohistochemistry, and gene expression of S1R, Nrf2, NF-κB, and TLR-4 was determined. Histopathological analysis was performed on kidney tissues.

Both afobazole and metformin exerted hypoglycemic effects, alleviating renal injury, reducing blood urea nitrogen (BUN) and serum creatinine, and restoring oxidant/antioxidant balance in diabetic rats. Both treatments boosted renal S1R and Nrf2 levels, suppressed inflammatory proteins and cytokines, and reduced apoptotic features.

The study revealed that afobazole provided nephroprotection in STZ-induced DN through a hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic potential mediated by activating the S1R/Nrf2 antioxidant axis. The 15 mg/kg dose elicited the most pronounced nephroprotective effects, outperforming other treatment groups.

Diabetes mellitus represents a complicated metabolic condition marked by ongoing hyperglycemia arising from impaired insulin secretion, inadequate insulin action, or a combination of both. Mitochondrial dysfunction has emerged as a significant contributor to the aetiology of diabetes, affecting various metabolic processes critical for glucose homeostasis. This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics. Additionally, it discusses the clinical implications and complications of mitochondrial dysfunction in diabetes and its complications, diagnostic approaches for assessing mitochondrial function in diabetics, therapeutic strategies, future directions, and research opportunities.

To examine the relationship between grip strength (GS) and diabetic nephropathy (DN).

Data on patients with type 2 diabetes mellitus collected between 2011 and 2014 were obtained from National Health and Nutrition Examination Survey (NHANES). Demographic characteristics (sex, age, race, marital status, and educational level), clinical measures (smoking status, drinking status, body mass index [BMI], glycated hemoglobin [HbA1c], urinary albumin creatinine ratio [UACR], diabetes duration, and hypertension), and grip strength assessments were collected. The relationship between GS and DN was analyzed using a logistic regression model. Subgroup analyses were showed as forest plots, conducted while accounting for confounding variables. Restricted cubic splines were applied to investigate nonlinear correlations. A sensitivity analysis was conducted to assess the robustness of the findings.

This study included 1,539 participants. In the multivariate logistic regression model, the odds ratios (ORs) were 0.96 (95% CI, 0.94-0.98) in male and 0.94 (95% CI, 0.91-0.98) in female. Compared with those in the lowest quartiles, participants in the uppermost GS quartiles were less susceptible to DN in male [OR 0.35 (95% CI, 0.20-0.62)] and female [OR 0.37 (95% CI, 0.20-0.67)] (p for trend < 0.001). After adjusting for all variables, the ORs were 0.96 (95% CI, 0.94-0.98) in male and 0.94 (95% CI, 0.91-0.98) in female. Compared with those in the lowest quartiles, participants in the uppermost GS quartiles were less susceptible to DN in male [OR 0.35 (95% CI, 0.20-0.62)] (p for trend < 0.001) and female [OR 0.37 (95% CI, 0.20-0.67)] (p for trend < 0.001). Subgroup analysis demonstrated a reliable connection between GS and DN (all p for interaction > 0.05). We discovered a nonlinear relationship between GS and DN in both male and female participants (all p for nonlinearity < 0.05). More precisely, the data revealed L-shaped relationship and inverted-S relation in male and female participants, respectively.

The results of this cross-sectional study using NHANES data indicated a potential negative association between GS and DN. Additional extensive studies are necessary to elucidate these trends.

The circulating renin-angiotensin system (RAS) is an endocrine system with key functions in maintaining blood pressure, fluid volume, and electrolytes. The RAS in the kidney (intrarenal RAS) plays a critical role in the onset and progression of kidney diseases. However, the mechanism underlying the onset and progression of diabetic nephropathy in relation to the expression and secretion of angiotensinogen (AGT) in the kidneys remains unclear. In this review, we present an overview of the intrarenal RAS and its role in diabetic nephropathy, as well as reviewing the evidence for the use of urinary AGT as a biomarker of this system in diabetic nephropathy. We also describe the roles of isoflavones in the context of diabetic nephropathy. The considered studies show that the intrarenal RAS-especially AGT-plays a diversified role in diabetic nephropathy; for instance, the increase in AGT due to oxidative stress is suppressed by polyphenols with antioxidant capacity, which is thought to affect the progression of diabetic nephropathy. Therefore, clarification of how polyphenols affect the onset and progression of diabetic nephropathy may provide insights into new treatments for this illness.

To gain insight into the extent of oxidative stress and DNA damage in diabetic kidney disease (DKD), a serious complication of diabetes, we compared the levels of the oxidative stress-related metabolite 8-hydroxy-2'-deoxyguanosine (8-OHdG) in a case-control study accurately matching diabetic patients with and without renal complications.

We analyzed serum 8-OHdG in relation to clinical indicators of kidney function in a group of type-2 diabetes patients including 33 patients with DKD and 33 without DKD. Circulating levels of 8-OHdG were higher in patients with DKD than in those without (4.6 ± 0.7 ng/mL vs 4.0 ± 0.8 ng/mL, p = 0.002). In a logistic regression analysis adjusting for potential confounders, 8-OHdG was associated with DKD (OR: 2.90, 95%CI:1.15-7.34; p = 0.02) and in a linear regression model, a 1 ng/mL increase of this biomarker entailed a reduction of 11.5 mL/min/1.73 m2 in the renal filtration rate. Furthermore, an interaction analysis showed that glycated hemoglobin was a modifier of the relationship between 8-OHdG and study outcomes (p for effect modification = 0.02).

This study supports the role of oxidative stress in the pathogenesis of diabetic nephropathy and highlights the potential of serum 8-OHdG as a biomarker for assessing oxidative stress and DNA damage in patients with diabetes and renal complications.

The objective of the study was to explore the association between homocysteine (Hcy) levels and the risk of type 2 diabetic nephropathy (T2DN). PubMed, Web of Science, Cochrane Library, and Embase databases were searched to collect literature on the association between Hcy levels and the risk of T2DN. The retrieval period was from the establishment of the database to September 10, 2024. Stata 15.0 statistical software was used for data analysis. Type II diabetes without nephropathy was considered the control group, and microalbuminuria and macroalbuminuria were included in the experimental group. Fourteen articles were included in this meta-analysis. The results of the meta-analysis showed that compared with the control group, the level of Hcy in the T2DN group with microalbuminuria [Weighted mean difference (WMD)=2.50, 95% confidence interval (CI): 1.49-3.51, p<0.001] and the group with macroalbuminuria (WMD=3.38, 95% CI: 1.95-4.82) was significantly increased. Compared with the T2DN microalbuminuria group, the Hcy level in the T2DN macroalbuminuria group was considerably higher (WMD=2.12, 95% CI: 0.80-3.44, p<0.001). High homocysteine levels were associated with an increased risk of T2DN (OR=1.36, 95% CI: 1.20-1.54, p<0.001). In conclusion, circulating Hcy levels are significantly associated with the severity of T2DN. In addition, there was a significant association between high Hcy levels and an increased risk of T2DN.

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM) and stands out as the leading cause of end-stage renal disease worldwide. There is increasing evidence that mitochondrial dysfunction, including impaired mitochondrial biogenesis, dynamics, and oxidative stress, contributes to the development and progression of DKD. D-amino acids (D-AAs), which are enantiomers of L-AAs, have recently been detected in various living organisms and are acknowledged to play important roles in numerous physiological processes in the human body. Accumulating evidence demonstrates that D-AA levels in blood or urine could serve as useful biomarkers for reflecting renal function. The physiological roles of D-AAs are implicated in the regulation of cellular proliferation, oxidative stress, generation of reactive oxygen species (ROS), and innate immunity. This article reviews current evidence relating to D-AAs and mitochondrial dysfunction and proposes a potential interaction and contribution of the D-AAs-mitochondria axis in DKD pathophysiology and progression. This insight could provide novel therapeutic approaches for preventing or ameliorating DKD based on this biological axis.

Cardiovascular-kidney-metabolic (CKM) syndrome is a systemic clinical condition characterized by pathological and physiological interactions among metabolic abnormalities, chronic kidney disease, and cardiovascular diseases, leading to multi-organ dysfunction and a higher incidence of cardiovascular endpoints. Traditional approaches to managing CKM syndrome risk are inadequate in these patients, necessitating strategies targeting specific CKM syndrome risk factors. Increasing evidence suggests that addressing uremic toxins and/or pathways induced by uremic toxins may reduce CKM syndrome risk and treat the disease. This review explores the interactions among heart, kidney, and metabolic pathways in the context of uremic toxins and underscores the significant role of uremic toxins as potential therapeutic targets in the pathophysiology of these diseases. Strategies aimed at regulating these uremic toxins offer potential avenues for reversing and managing CKM syndrome, providing new insights for its clinical diagnosis and treatment.

The progression of diabetic kidney disease (DKD) affects the patient's kidney glomeruli and tubules, whose normal functioning is essential for maintaining normal calcium (Ca) and phosphorus (P) metabolism in the body. The risk of developing osteoporosis (OP) in patients with DKD increases with the aggravation of the disease, including a higher risk of fractures, which not only affects the quality of life of patients but also increases the risk of death.

To analyze the risk factors for the development of OP in patients with DKD and their correlation with Ca-P metabolic indices, fibroblast growth factor 23 (FGF23), and Klotho.

One hundred and fifty-eight patients with DKD who were admitted into the Wuhu Second People's Hospital from September 2019 to May 2021 were selected and divided into an OP group (n = 103) and a normal bone mass group (n = 55) according to their X-ray bone densitometry results. Baseline data and differences in Ca-P biochemical indices, FGF23, and Klotho were compared. The correlation of Ca-P metabolic indices with FGF23 and Klotho was discussed, and the related factors affecting OP in patients with DKD were examined by multivariate logistic regression analysis.

The OP group had a higher proportion of females, an older age, and a longer diabetes mellitus duration than the normal group (all P < 0.05). Patients in the OP group exhibited significantly higher levels of intact parathyroid hormone (iPTH), blood P, Ca-P product (Ca × P), fractional excretion of phosphate (FeP), and FGF23, as well as lower estimated glomerular filtration rate, blood Ca, 24-hour urinary phosphate excretion (24-hour UPE), and Klotho levels (all P < 0.05). In the OP group, 25-(OH)-D3, blood Ca, and 24-hour UPE were negatively correlated with FGF23 and positively correlated with Klotho. In contrast, iPTH, blood Ca, Ca × P, and FeP exhibited a positive correlation with FGF23 and an inverse association with Klotho (all P < 0.05). Moreover, 25-(OH)-D3, iPTH, blood Ca, FePO4, FGF23, Klotho, age, and female gender were key factors that affected the lumbar and left femoral neck bone mineral density.

The Ca-P metabolism metabolic indexes, FGF23, and Klotho in patients with DKD are closely related to the occurrence and development of OP.

Hyperglycemia in diabetes increases the generation of advanced glycation end products (AGEs) through non-enzymatic reactions. The interaction between AGEs and their receptors (RAGE) leads to oxidative and inflammatory stress, which plays a pivotal role in developing diabetic nephropathy. Syzygium cumini (SC) L. (DC.) homeopathic preparations viz. 200C, 30C, and mother tincture [MT] are used to treat diabetes. This study aimed to elucidate the regulatory effects of SC preparations (200C, 30C, and MT) on the nuclear factor erythroid 2-related factor 2 (Nrf2) - nuclear factor-κB (NF-κB) pathways and mitochondrial dysfunction in mitigating diabetic nephropathy (DN).

Streptozotocin-induced diabetic rats were treated with SC preparations (200C, 30C, MT; 1:20 dilution in distilled water; 600 μL/kg body weight) and metformin (45 mg/kg body weight) twice daily for 40 days. DN was evaluated through biochemical parameters and histological examination. Renal tissue lysates were analyzed for glycation markers. Protein and gene levels of Nrf2, NF-κB, and mitochondrial dysfunctional signaling were determined via western blotting and RT-qPCR. An immunohistochemical analysis of the kidneys was performed. In vitro, human serum albumin (HSA - 10 mg/ml) was glycated with methylglyoxal (MGO - 55 mM) in the presence of SC preparations (200C, 30C, MT) for eight days. Glycated samples (400 μg/mL) were incubated with renal cells (HEK-293) for 24 h. Further reactive oxygen species production, Nrf2 nuclear translocation, and protein or gene expression of Nrf2 and apoptosis markers were analyzed by western blotting, RT-qPCR, and flow cytometry. Molecular docking of gallic and ellagic acid with the HSA-MGO complex was performed.

In vivo experiments using streptozotocin-induced diabetic rats treated with SC preparations exhibited improved biochemical parameters, preserved kidney function, and reduced glycation adduct formation in a dose-dependent manner. Furthermore, SC preparations downregulated inflammatory mediators such as RAGE, NF-κB, vascular endothelial growth factor (VEGF), and Tumor necrosis factor α (TNF-α) while upregulating the Nrf2-dependent antioxidant and detoxification pathways. They downregulated B-cell lymphoma 2 (Bcl-2) associated X-protein (BAX), C/EBP homologous protein (CHOP), Dynamin-related protein 1 (DRP1), and upregulated BCL 2 gene expression. Notably, SC preparations facilitated nuclear translocation of Nrf2, leading to the upregulation of antioxidant enzymes and the downregulation of oxidative stress markers. Molecular docking studies revealed favorable interactions between gallic (-5.26 kcal/mol) and ellagic acid (-4.71 kcal/mol) with the HSA-MGO complex.

SC preparations mitigate renal cell apoptosis and mitochondrial dysfunction through Nrf2-dependent mechanisms.

Increasing evidence points toward an essential role for complement activation in the pathogenesis of diabetic kidney disease (DKD). However, the precise molecular mechanisms remain unclear, and the pathway predominantly contributing to complement activation in DKD is of particular interest. In this study, the glomerular proteome, especially the profiles of the complement proteins, was analyzed in kidney biopsies from 40 DKD patients and 10 normal controls using laser microdissection-assisted liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS). The glomerular abundances of three proteins related to classical pathway (CP) (C1q, C1r, C1s), five proteins related to alternative pathway (AP) (CFB, CFH, CFHR1, CFHR3, CFHR5), one common protein related to CP and lectin pathway (LP) (C4), and six proteins related to terminal complement pathway (C3, C5, C6, C7, C8, C9) were significantly increased in DKD. Notably, none of the proteins unique to the lectin complement pathway, including mannose-binding lectin (MBL) and its associated proteins, were detected in DKD glomeruli. Furthermore, the glomerular complement proteins of CP and AP were positively correlated with glomerular pathological grades and proteinuria, and negatively correlated with eGFR in DKD patients. Our results highlight a critical role for complement activation of the CP and AP, rather than the LP, in DKD progression.

To investigate the role of pyroptosis in diabetic nephropathy (DN) and identify potential biomarkers for diagnosis.

We analyzed the GEO dataset GSE96804 to identify differentially expressed genes (DEGs) related to pyroptosis in DN. The CIBERSORT method was used to assess M1 macrophage infiltration in the samples. Using weighted gene co-expression network analysis (WGCNA), we identified gene modules associated with M1 macrophages. The least absolute shrinkage and selection operator (LASSO) method was then applied to screen for key genes. The intersection of key genes identified by LASSO and the gene modules obtained from WGCNA resulted in the identification of ten hub genes as potential biomarkers for DN.

A total of 366 DEGs were identified, with 310 genes associated with pyroptosis. Increased M1 macrophage infiltration was observed in DN patients. Ten hub genes were identified as potential DN biomarkers: ECM1, LRP2BP, ALKBH7, CDH10, DUSP1, HSPA1A, LPL, NFIL3, PDK4, and TMEM150C.

This study highlights the importance of pyroptosis in DN pathophysiology and identifies 10 hub genes as potential biomarkers. These findings may contribute to improved diagnosis and treatment of DN.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus. Colquhounia Root Tablet (CRT), one of the Tripterygium wilfordii Hook F. (TwHF)-based therapeutics, has exhibited various functions in DN. However, the pharmacological mechanisms underlying its effects are still unclear. The bioactive compounds and targets of CRT were obtained from the TCMSP database, HERB-National Genomics Data Center, and SwissTargetPrediction database. The targets of DN were obtained from the DisGeNET database, Genecards database, and OMIM database. Potential therapeutic targets for CRT against DN were identified by intersecting the above targets. Protein-protein interaction (PPI), Gene ontology (GO) functional annotation, and Kyoto Encyclopedia of Genes Genomes (KEGG) enrichment analysis were performed to explore the underlying mechanism. Molecular docking assessed the binding ability between bioactive compounds and targets. Network pharmacology analysis predicted that the overlap between CRT and DN targets yielded 163 therapeutic targets. STAT3, IL1B, JUN, IL6, TNF, HIF1A, CASP3, PPARG, and BCL2 were identified as the core targets through PPI. KEGG enrichment analysis revealed that the AGEs/RAGE signaling was the prominent pathway for CRT against DN. Molecular docking indicated hypodiolide A had the lowest binding energy and the most stable binding affinity towards HIF1A. Furthermore, AGEs-induced human podocytes were treated with different concentrations of CRT to validate the predicted signaling pathway. Results showed that CRT exerted protective effects against podocyte injury, angiogenesis, and epithelial-mesenchymal transition (EMT) by regulating the AGEs/RAGE/RhoA/RCOK signaling pathway. However, in vivo studies are needed to reveal the safety and efficacy of CRT in DN.

Renal failure is typical chronic kidney disease that required peritoneal dialysis as the primary treatment, but current catheter devices lack functionality to monitor changes in chemical analytes during peritoneal dialysis. Fabrication of miniatured sensing modules with good electrochemical performance in tiny catheter devices is the key to realize the smart monitoring of peritoneal dialysis. In this work, a vertical graphene-based multiparametric sensing array (VG-MSA) is developed to continuously measure fluctuations of various analyte concentrations for peritoneal dialysis monitoring. Vertical graphene (VG) electrode with good electrochemical properties serves as the core module in VG-MSA, allowing the development of miniatured sensing modules with sufficient electrochemical performance. The VG-MSA enables sensitive and multiplexed measurement of dialysate components like metabolites (reactive oxygen species, uric acid, and glucose) and ions (K+, Ca2+, and H+). The VG-MSA is demonstrated to effectively detect biochemical signals in peritoneal dialysate in vivo on rat models. The VG-MSA catheter can be inserted into abdominal cavity, allowing full contact with dialysate for in situ, real-time, and continuous collection of biochemical information during peritoneal dialysis. The VG-MSA catheter device offers a valuable tool for monitoring dialysis quality and facilitating treatment adjustments, potentially as a promising platform for high-quality therapy of renal failure.

Recent research has suggested that adherence to plant-based dietary index (PDI) may reduce the risk of type 2 diabetes and related complications like diabetic nephropathy (DN). Therefore, the aim of this study was to investigate the possible association of PDI with the odds of DN.

We enrolled 105 eligible women with DN and 105 controls without DN (30-65 years). A 147-item food frequency questionnaire was used to evaluate an overall PDI, healthy plant-based dietary index (hPDI), and unhealthful PDI. Biochemical variables and anthropometric measurements were assessed for all patients using predefined protocols.

According to our final analyses, after controlling for potential confounders, participants with greater adherence to overall PDI (OR: 0.29; 95% CI: 0.15-0.56; P < .001) and hPDI (OR: 0.30; 95% CI: 0.15-0.56; P < .001) had 71% and 70% lower odds of DN compared to those with a low adherence, respectively. Conversely, subjects with a higher adherence to the unhealthful PDI had a positive association with increased odds of DN in the crude (OR = 5.00; 95% CI = 2.78-8.98; P < .001) and adjusted models (OR = 4.27; 95% CI = 2.24-8.14; P < .001), respectively.

The results of this study showed that greater adherence to overall PDI and hPDI was inversely associated with the odds of DN. However, further prospective studies are warranted to confirm these results.

Qikui granule (QKG), a hospital preparation of traditional Chinese medicine, has been widely used for diabetic kidney disease (DKD) in clinical practice. However, its holistic therapeutic effects and the underlying therapeutic mechanisms remain unclear. In the present study, the integrated analysis of network pharmacology, 16S rRNA sequencing, and non-targeted lipidomics was performed to explore the anti-DKD effects of QKG and the underlying mechanisms in db/db mouse DKD model. The results of the network pharmacology analysis identified the PI3K-AKT, EGFR, MAPK, JAK-STAT, FoxO, and AGE-RAGE signaling pathways as the potential molecular mechanisms responsible for the efficacy of QKG. Importantly, these signaling pathways were found to be closely related to lipid metabolism and gut microbiota. The therapeutic effectiveness of QKG against DKD was manifested by reducing body weight, alleviating oxidative stress, improving kidney function indicators, promoting the recovery of renal histopathological damage, and regulating the lipid metabolic profile of serum and kidney in db/db mice. A total of 26 lipid metabolites were identified as potential pharmacological biomarkers (PPBs) of QKG for the treatment of DKD, which were mainly involved in glycerophospholipid metabolism. Meanwhile, QKG could alleviate DKD-induced gut microbiota dysbiosis primarily by enriching Candidatus_Arthromitus, which showed a negative correlation with all 26 lipid PPBs as well as 5 biochemical parameters, including 2 oxidative stress factors and 3 kidney function indices. In conclusion, our findings suggest that QKG may upregulate the gut level of Candidatus_Arthromitus to suppress the abnormal activation of PI3K-AKT related signaling pathway, thereby reducing the levels of PC and LPC in the glycerophospholipid metabolism, to finally ameliorate the progression of DKD in db/db mice.

This study explores the application and advancements of precision nursing model (PNM) in hemodialysis for diabetic nephropathy patients. Diabetic nephropathy is a severe complication of diabetes, frequently leading to end-stage renal disease and necessitating long-term hemodialysis. The PNM aims to enhance treatment outcomes and patient quality of life through individualized care plans, multidisciplinary collaboration, and continuous quality improvement. Research indicates that this model significantly improves clinical indicators and patient satisfaction, demonstrating broad applicability. This paper provides a detailed overview of the definition, theoretical foundation, implementation strategies, and specific interventions of the PNM, and evaluates its effectiveness in hemodialysis. Additionally, it addresses the challenges faced in implementation and suggests future research directions. Emphasis is placed on the need for long-term studies, technological innovations, and cost-effectiveness analyses to further integrate precision nursing into clinical practice.

This study investigated the associations between non-insulin-based insulin resistance indices (METS-IR, TyG, TG/HDL, and TyG-BMI) and the risk of diabetic nephropathy (DN) in US adults with diabetes mellitus (DM).

This study was based on the 1999-2018 National Health and Nutrition Examination Survey (NHANES) database and included 6,891 patients with DM for cross-sectional analysis. Multivariate adjusted models and restricted cubic spline (RCS) models were employed to assess the association between the insulin resistance index and the risk of DN. Subgroup analyses were conducted to explore the impact of different population characteristics.

The results indicated that higher quartiles of METS-IR, TyG, TG/HDL, and TyG-BMI were associated with a significantly increased risk of DN. After adjusting for multiple covariates, including gender, age, and race, the associations between these indices and the risk of DN remained significant, with corresponding odds ratios (ORs) of 1.51 (95% confidence interval [CI]: 1.29-1.76), 2.06 (95% CI: 1.77-2.40), 1.61 (95% CI: 1.38-1.88), and 1.57 (95% CI: 1.35-1.84), with all P-values less than 0.001. RCS analysis indicated a nonlinear relationship between these indices and the risk of DN. The TyG index exhibited a highly consistent association with the risk of DN in all models.

Non-insulin-based insulin resistance indices are significantly associated with the risk of DN. The TyG index is a superior tool for assessing the risk of DN. These indices can assist in identifying patients at risk of DN, thereby enabling the implementation of more effective preventive and therapeutic strategies.

Background: The association between diabetic nephropathy and arterial elasticity and endothelial function is well established. In this study, we compared the effect of the combination of dulaglutide and dapagliflozin versus DPP-4 inhibitors on the endothelial glycocalyx, arterial stiffness, myocardial function, and albuminuria. Methods: Overall, 60 patients were randomized to combined dulaglutide and dapagliflozin treatment (n = 30) or DPP-4 inhibitors (DPP-4i, n = 30) (ClinicalTrials.gov: NCT06611904). We measured at baseline and 4 and 12 months post-treatment: (i) the perfused boundary region of the sublingual arterial microvessels, (ii) pulse wave velocity (PWV) and central systolic blood pressure (cSBP), (iii) global left ventricular longitudinal strain (GLS), and (iv) urine albumin-to-creatinine ratio (UACR). Results: After twelve months, dual therapy showed greater improvements vs. DPP-4i in PBR (2.10 ± 0.31 to 1.93 ± 0.23 μm vs. 2.11 ± 0.31 to 2.08 ± 0.28 μm, p < 0.001), UACR (326 ± 61 to 142 ± 47 mg/g vs. 345 ± 48 to 306 ± 60 mg/g, p < 0.01), and PWV (11.77 ± 2.37 to 10.7 ± 2.29 m/s vs. 10.64 ± 2.44 to 10.54 ± 2.84 m/s, p < 0.001), while only dual therapy showed improvement in cSBP (130.21 ± 17.23 to 123.36 ± 18.42 mmHg). These effects were independent of glycemic control. Both treatments improved GLS, but the effect of dual therapy was significantly higher compared to DPP-4i (18.19% vs. 6.01%, respectively). Conclusions: Twelve-month treatment with dulaglutide and dapagliflozin showed a greater improvement in arterial stiffness, endothelial function, myocardial function, and albuminuria than DPP-4is. Early initiation of combined therapy as an add-on to metformin should be considered in these patients.

Diabetic kidney disease (DKD) is a significant contributor to the development of end-stage renal disease and cardiovascular disease (CVD), with inflammation being a critical factor in its pathogenesis. The aim of this study is to examine the relationship between the neutrophil-to-lymphocyte ratio (NLR), a new inflammatory marker, and mortality from all causes and CVD in patients with DKD.

This multicenter, retrospective cohort study utilized data from the China Renal Data System (CRDS) on patients with DKD hospitalized between January 1, 2000, and February 28, 2023. The patients' demographic information, along with their initial clinical and laboratory results, were collected and recorded. Follow-up continued until July 1, 2023, and patients were categorized into two groups based on the median baseline NLR. The Cox proportional hazards regression, Restricted cubic spline (RCS) curves, The Kaplan-Meier curve, Fine-Gray competing risk model, Time-dependent ROC and subgroup analysis were used to analyze the association between all-cause mortality and CVD mortality in patients having DKD with varying NLR.

This study included 11,427 patients who had been clinically diagnosed with DKD. Baseline NLR was associated with C-reactive protein, procalcitonin, high-sensitivity C-reactive protein, plasma D-dimer, cystatin C, creatinine, urea nitrogen, brain natriuretic peptide, and eGFR. We selected the demographic characteristics, differential factors from univariate analysis, and clinically DKD-related laboratory indicators as covariates for Cox analysis. Results indicated that NLR was an independent risk factor for both all-cause and CVD mortality after adjusting for the relevant variables. The risk of all-cause death and CVD death in the high NLR group was 4.688 and 2.141 times higher, respectively, compared to the low NLR group (HR = 4.688, 95% CI 1.153-19.061, P = 0.031; HR = 2.141, 95% CI 1.257-3.644, P = 0.005). However, potential confounding factors and biases, such as unmeasured variables and the influence of treatment interventions, could not be fully accounted for.

NLR can independently predict the risk of all-cause and CVD mortality in patients with DKD. Identifying individuals with a high NLR and providing further intervention could be crucial measures to reduce both all-cause and CVD mortality. However, the results should be interpreted with caution due to the study's limitations.

Hyperglycemia, a hallmark of diabetes mellitus, significantly contributes to skeletal muscle atrophy, characterized by progressive muscle mass and strength loss. This review summarizes the mechanisms of hyperglycemia-induced muscle atrophy, examines clinical evidence, and discusses preventive and therapeutic strategies. A systematic search of electronic databases, including PubMed, Scopus, and Web of Science, was conducted to identify relevant papers on hyperglycemic skeletal muscle atrophy. Key mechanisms include insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction. Crucial molecular pathways involved are Phosphoinositide 3-kinase/Protein kinase B signaling, Forkhead box O transcription factors, the ubiquitin-proteasome system, and myostatin-mediated degradation. Hyperglycemia disrupts normal glucose and lipid metabolism, exacerbating muscle protein degradation and impairing synthesis. Clinical studies support the association between hyperglycemia and muscle atrophy, emphasizing the need for early diagnosis and intervention. Biomarkers, imaging techniques, and functional tests are vital for detecting and monitoring muscle atrophy in hyperglycemic patients. Management strategies focus on glycemic control, pharmacological interventions targeting specific molecular pathways, nutritional support, and tailored exercise regimens. Despite these advances, research gaps remain in understanding the long-term impact of hyperglycemia on muscle health and identifying novel therapeutic targets. The review aims to provide a comprehensive understanding of the mechanisms, clinical implications, and potential therapeutic strategies for addressing hyperglycemia-induced skeletal muscle atrophy.

This study aimed to demonstrate the protective effect of beta-carotene against STZ-induced DN in rats and explore the possible underlying mechanisms that may have mediated such condition.

Wistar rats were allocated into four groups. Normal group received distilled water for 3 weeks. The other three groups were rendered diabetic by an intraperitoneal dose of STZ (50 mg/kg), 48 h later, group 2: received the vehicle and served as control, groups (3 &4) received orally beta-carotene in doses of 10 and 20 mg/kg, respectively for 3 weeks. Then serum and renal tissue were collected for biochemical, molecular, immunohistopathological, and histopathological examination.

Beta-carotene ameliorated the reduction in body weight, reduced blood glucose, elevated serum insulin, reduced blood urea nitrogen, and serum creatinine levels. Beta-carotene elevated phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK)/AMPK, alleviated phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR, reduced interleukin 1 beta (IL-1β), increased Beclin 1, LC3II/LC3I, and reduced p62 renal contents. Moreover, it elevated renal SIRT1 gene expression and reduced renal tumor necrosis factor-alpha (TNF-α) and caspase-3 protein expressions.

Beta-carotene exerted renoprotective effect against STZ-induced DN and histopathological alterations through alleviating hyperglycemia, attenuating inflammation, activating AMPK/SIRT1/autophagy pathway, and combating apoptosis.

Diabetic nephropathy (DN) is a severe renal disorder that arises as a complication of diabetes. Liraglutide, an analogue of a glucagon-like peptide 1 (GLP-1) receptor agonist, has been shown to decrease diabetes-caused renal damage. Nevertheless, the complete understanding of the roles and mechanism remains unclear. In our study, diabetic rat models were created through a single intraperitoneal injection of streptozotocin (STZ). The level of fasting blood glucose, 24-h urine protein, serum creatinine (Scr) and blood urea nitrogen (BUN) were assessed. Periodic acid-Schiff (PAS) staining was applied to examine the pathological changes in renal tissues. Reactive oxygen species (ROS) formation was measured via dichloro-dihydro-fluorescein diacetate (DCFH-DA) probes. Western blot was conducted to examine the levels of oxidative stress-related and extracellular matrix (ECM)-associated proteins. The nuclear translocation of NRF2 was investigated through immunofluorescence and Western blot assays. We demonstrated that liraglutide attenuated DN-induced oxidative stress and ECM deposition in vitro and in vivo. Liraglutide exerted a reno-protective effect by promoting nuclear translocation of NRF2 in mesangial cells. ML385, an NRF2 inhibitor, counteracted the beneficial impact of liraglutide.