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Annals of Medicine Dec 2023Obesity is a chronic disease characterised by excess adiposity, which impairs health. The high prevalence of obesity raises the risk of long-term medical complications... (Review)
Review
Obesity is a chronic disease characterised by excess adiposity, which impairs health. The high prevalence of obesity raises the risk of long-term medical complications including type 2 diabetes and chronic kidney disease. Several studies have focused on patients with obesity, type 2 diabetes and chronic kidney disease due to the increased prevalence of diabetic kidney disease. Several randomized controlled trials on sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 analogues, and bariatric surgery in diabetic kidney disease showed renoprotective effects. However, further research is critical to address the treatment of patients with obesity and chronic kidney disease to lessen morbidity.Key messageObesity is a driver of chronic kidney disease, and type 2 diabetes, along with obesity, accelerates chronic kidney disease.Several randomized controlled trials on sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 analogues, and bariatric surgery in diabetic kidney disease demonstrate the improvement of renal outcomes.There is a need to address the treatment of patients with obesity and CKD to lessen morbidity.
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Hypoglycemic Agents; Obesity; Renal Insufficiency, Chronic; Glucagon-Like Peptide 1; Glucose; Sodium
PubMed: 37086110
DOI: 10.1080/07853890.2023.2203517 -
Aging Nov 2023A ketogenic diet (KD) and β-hydroxybutyrate (βOHB) have been widely reported as effective therapies for metabolic diseases. β-Hydroxybutyrate dehydrogenase 1 (BDH1)...
A ketogenic diet (KD) and β-hydroxybutyrate (βOHB) have been widely reported as effective therapies for metabolic diseases. β-Hydroxybutyrate dehydrogenase 1 (BDH1) is the rate-limiting enzyme in ketone metabolism. In this study, we examined the BDH1-mediated βOHB metabolic pathway in the pathogenesis of diabetic kidney disease (DKD). We found that BDH1 is downregulated in the kidneys in DKD mouse models, patients with diabetes, and high glucose- or palmitic acid-induced human renal tubular epithelial (HK-2) cells. BDH1 overexpression or βOHB treatment protects HK-2 cells from glucotoxicity and lipotoxicity by inhibiting reactive oxygen species overproduction. Mechanistically, BDH1-mediated βOHB metabolism activates NRF2 by enhancing the metabolic flux of βOHB-acetoacetate-succinate-fumarate. Moreover, studies showed that adeno-associated virus 9-mediated BDH1 renal expression successfully reverses fibrosis, inflammation, and apoptosis in the kidneys of C57 BKS mice. Either βOHB supplementation or KD feeding could elevate the renal expression of BDH1 and reverse the progression of DKD. Our results revealed a BDH1-mediated molecular mechanism in the pathogenesis of DKD and identified BDH1 as a potential therapeutic target for DKD.
Topics: Animals; Humans; Mice; 3-Hydroxybutyric Acid; Antioxidants; Diabetes Mellitus; Diabetic Nephropathies; Kidney; NF-E2-Related Factor 2; Hydroxybutyrate Dehydrogenase
PubMed: 38015723
DOI: 10.18632/aging.205248 -
BMC Endocrine Disorders Jul 2023The higher prevalence of thyroid dysfunction in type 1 diabetes patients has been well established, whereas it is a matter of debate whether that is also observed in... (Observational Study)
Observational Study
BACKGROUND
The higher prevalence of thyroid dysfunction in type 1 diabetes patients has been well established, whereas it is a matter of debate whether that is also observed in type 2 diabetes patients. This study was conducted to reveal whether higher prevalence of thyroid dysfunction is observed in patients with type 2 diabetes.
METHODS
We examined thyroid functions and thyroid autoantibodies in 200 patients with type 2 diabetes and 225 controls, with 24 months follow up for those with type 2 diabetes.
RESULTS
Serum free triiodothyronine (fT3) levels and fT3/free thyroxine (fT4) ratio were significantly lower, while fT4 levels were significantly higher in patients with type 2 diabetes. The number of patients with thyroid dysfunction or patients positive for thyroid autoantibodies were not different between the two groups. The fT3/fT4 ratio was positively and negatively correlated with serum c-peptide and HbA1c levels, respectively, suggesting that the difference can be attributable to insulin resistance and diabetic control. In the follow-up observation, we found no significant correlation between basal thyrotropin (TSH), fT3, fT4 or fT3/fT4 ratio with the amounts of changes of HbA1c levels at 12 or 24 months after the basal measurements. There was a negative relationship between TSH levels and eGFR at baseline measurements, but TSH levels did not seem to predict future decline of eGFR levels. No relationship was observed between urine albumin/ g‧cre levels and thyroid function.
CONCLUSION
Thyroid dysfunction and thyroid autoantibodies were not different in prevalence between patients with type 2 diabetes and controls, although in patients with type 2 diabetes, the fT3/fT4 ratio was decreased. Basal thyroid function did not predict future diabetes control or renal function within 24 months of follow-up.
Topics: Humans; Autoantibodies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycated Hemoglobin; Glycemic Control; Thyroid Gland; Prospective Studies
PubMed: 37430240
DOI: 10.1186/s12902-023-01393-4 -
Inflammopharmacology Feb 2024Diabetic nephropathy (DN) is reported as one of the most serious microvascular diabetic complications and the trigger of end-stage renal disease (ESRD), underscoring the...
Diabetic nephropathy (DN) is reported as one of the most serious microvascular diabetic complications and the trigger of end-stage renal disease (ESRD), underscoring the concern of any therapeutic intervention directed at ameliorating the development and progression of DN. The current study explored the renoprotective impact of montelukast (Mon) against streptozotocin (STZ)-induced DN in rats compared to a standard anti-hyperglycemic insulin (Ins) treatment. Diabetes was induced by a single dose of STZ (55 mg/kg). Diabetic rats were treated with Mon (10 and 20 mg/kg, oral gavage) for eight weeks. Mon administration for 8 weeks after induction of diabetes conferred significant dose-dependent renoprotection, independent of blood glucose levels (unlike Ins), as evidenced by the improvement in serum creatinine, and blood urea nitrogen (BUN), and ameliorated STZ-induced renal necrotic, inflammatory alterations, and renal fibrosis. Additionally, Mon treatment in diabetic rats significantly restored redox hemostasis as evidenced by malondialdehyde (MDA) and total antioxidant capacity (TAC) levels; significantly reduced the renal expression of high mobility group box (HMGB) 1, toll-like receptor (TLR) 4, nuclear factor kappa B (NF-κB) (in the nucleus), NOD-like receptor family pyrin domain containing (NLRP) 3, and interleukin (IL)-1β. Moreover, Mon administration ameliorated the dysregulation in autophagy as evidenced by p62 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-II levels. In conclusion, the renoprotective effect of Mon is potentially associated with its modulatory effect on inflammatory cytokines, antioxidant properties, and autophagy.
Topics: Animals; Rats; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Diabetic Nephropathies; NF-kappa B; Streptozocin; HMGB1 Protein; Antioxidants; Diabetes Mellitus, Experimental; Toll-Like Receptor 4; Insulin; Acetates; Cyclopropanes; Quinolines; Sulfides
PubMed: 37498374
DOI: 10.1007/s10787-023-01301-1 -
Frontiers in Immunology 2023Diabetic nephropathy (DN) is one of the most common diabetic complications, which has become the primary cause of end-stage renal disease (ESRD) globally. Macrophage...
BACKGROUND
Diabetic nephropathy (DN) is one of the most common diabetic complications, which has become the primary cause of end-stage renal disease (ESRD) globally. Macrophage infiltration has been proven vital in the occurrence and development of DN. This study was designed to investigate the hub genes involved in macrophage-mediated inflammation of DN via bioinformatics analysis and experimental validation.
METHODS
Gene microarray datasets were obtained from the Gene Expression Omnibus (GEO) public website. Integrating the CIBERSORT, weighted gene co-expression network analysis (WGCNA) and DEGs, we screened macrophage M1-associated key genes with the highest intramodular connectivity. Subsequently, the Least Absolute Shrinkage and Selection Operator (LASSO) regression was utilized to further mine hub genes. GSE104954 acted as an external validation to predict the expression levels and diagnostic performance of these hub genes. The Nephroseq online platform was employed to evaluate the clinical implications of these hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to elucidate the dominant biological functions and signal pathways. Finally, we conducted experiments to verify the role of GBP2 in M1 macrophage-mediated inflammatory response and the underlying mechanism of this role.
RESULTS
Sixteen DEGs with the highest connectivity in M1 macrophages-associated module (paleturquoise module) were determined. Subsequently, we identified four hub genes through LASSO regression analysis, including CASP1, MS4A4A, CD53, and GBP2. Consistent with the training set, expression levels of these four hub genes manifested memorably elevated and the ROC curves indicated a good diagnostic accuracy with an area under the curve of greater than 0.8. Clinically, enhanced expression of these four hub genes predicted worse outcomes of DN patients. Given the known correlation between the first three hub genes and macrophage-mediated inflammation, experiments were performed to demonstrate the effect of GBP2, which proved that GBP2 contributed to M1 polarization of macrophages by activating the notch1 signaling pathway.
CONCLUSION
Our findings detected four hub genes, namely CASP1, MS4A4A, CD53, and GBP2, may involve in the progression of DN via pro-inflammatory M1 macrophage phenotype. GBP2 could be a promising prognostic biomarker and intervention target for DN by regulating M1 polarization.
Topics: Humans; Diabetic Nephropathies; Signal Transduction; Caspase 1; Inflammation; Macrophages; Diabetes Mellitus; GTP-Binding Proteins
PubMed: 37622120
DOI: 10.3389/fimmu.2023.1127612 -
Frontiers in Endocrinology 2023
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Hypoxia; Autophagy
PubMed: 38164495
DOI: 10.3389/fendo.2023.1349432 -
Frontiers in Endocrinology 2023Diabetic kidney disease (DKD) is a common disorder with numerous severe clinical implications. Due to a high level of fibrosis and inflammation that contributes to renal... (Review)
Review
Diabetic kidney disease (DKD) is a common disorder with numerous severe clinical implications. Due to a high level of fibrosis and inflammation that contributes to renal and cardiovascular disease (CVD), existing treatments have not effectively mitigated residual risk for patients with DKD. Excess activation of mineralocorticoid receptors (MRs) plays a significant role in the progression of renal and CVD, mostly by stimulating fibrosis and inflammation. However, the application of traditional steroidal MR antagonists (MRAs) to DKD has been limited by adverse events. Finerenone (FIN), a third-generation non-steroidal selective MRA, has revealed anti-fibrotic and anti-inflammatory effects in pre-clinical studies. Current clinical trials, such as FIDELIO-DKD and FIGARO-DKD and their combined analysis FIDELITY, have elucidated that FIN reduces the kidney and CV composite outcomes and risk of hyperkalemia compared to traditional steroidal MRAs in patients with DKD. As a result, FIN should be regarded as one of the mainstays of treatment for patients with DKD. In this review, the safety, efficiency, and potential mechanisms of FIN treatment on the renal system in patients with DKD is reviewed.
Topics: Humans; Diabetic Nephropathies; Cardiovascular Diseases; Inflammation; Fibrosis; Diabetes Mellitus
PubMed: 38174337
DOI: 10.3389/fendo.2023.1320603 -
International Journal of Molecular... Apr 2024Diabetes 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.... (Review)
Review
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.
Topics: Diabetic Nephropathies; Humans; Macrophages; Animals; Fibrosis
PubMed: 38673935
DOI: 10.3390/ijms25084350 -
Frontiers in Immunology 2024As the leading cause of chronic kidney disease, diabetic kidney disease (DKD) is an enormous burden for all healthcare systems around the world. However, its early...
BACKGROUND
As the leading cause of chronic kidney disease, diabetic kidney disease (DKD) is an enormous burden for all healthcare systems around the world. However, its early diagnosis has no effective methods.
METHODS
First, gene expression data in GEO database were extracted, and the differential genes of diabetic tubulopathy were obtained. Immune-related genesets were generated by WGCNA and immune cell infiltration analyses. Then, differentially expressed immune-related cuproptosis genes (DEICGs) were derived by the intersection of differential genes and genes related to cuproptosis and immune. To investigate the functions of DEICGs, volcano plots and GO term enrichment analysis was performed. Machine learning and protein-protein interaction (PPI) network analysis helped to finally screen out hub genes. The diagnostic efficacy of them was evaluated by GSEA analysis, receiver operating characteristic (ROC) curve, single-cell RNA sequencing and the Nephroseq website. The expression of hub genes at the animal level by STZ -induced and db/db DKD mouse models was further verified.
RESULTS
Finally, three hub genes, including , and that were up-regulated in both the test set GSE30122 and the validation set GSE30529, were screened. The areas under the curve (AUCs) of ROC curves of hub genes were 0.911, 0.935 and 0.922, respectively, and 0.946 when taking as a whole. Correlation analysis showed that the expression level of three hub genes demonstrated their negative relationship with GFR, while those of displayed a positive correlation with the level of serum creatinine. GSEA was enriched in inflammatory and immune-related pathways. Single-nucleus RNA sequencing indicated the main distribution of in podocyte and mesangial cells, the high expression of in leukocytes and the main localization of in the loop of Henle. In mouse models, all three hub genes were increased in both STZ-induced and db/db DKD models.
CONCLUSION
Machine learning was combined with WGCNA, immune cell infiltration and PPI analyses to identify three hub genes associated with cuproptosis, immunity and diabetic nephropathy, which all have great potential as diagnostic markers for DKD and even predict disease progression.
Topics: Animals; Mice; Diabetic Nephropathies; Follistatin-Related Proteins; Machine Learning; Area Under Curve; Databases, Factual; Diabetes Mellitus
PubMed: 38390317
DOI: 10.3389/fimmu.2024.1332279 -
Frontiers in Immunology 2023
Topics: Humans; Cardiovascular Diseases; Macrophages; Diabetic Nephropathies; Biochemical Phenomena
PubMed: 38173724
DOI: 10.3389/fimmu.2023.1352567