Spilanthes filicaulis (Schumach. & Thonn.) C.D. Adams leaves protects against streptozotocin-induced diabetic nephropathy.

BACKGROUND AND OBJECTIVE: Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. METHODS: Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. RESULTS: We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). CONCLUSION: Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways.

Spontaneous Akt2 deficiency in a colony of NOD mice exhibiting early diabetes.

Diabetes constitutes a major public health problem, with dramatic consequences for patients. Both genetic and environmental factors were shown to contribute to the different forms of the disease. The monogenic forms, found both in humans and in animal models, specially help to decipher the role of key genes in the physiopathology of the disease. Here, we describe the phenotype of early diabetes in a colony of NOD mice, with spontaneous invalidation of Akt2, that we called HYP. The HYP mice were characterised by a strong and chronic hyperglycaemia, beginning around the age of one month, especially in male mice. The phenotype was not the consequence of the acceleration of the autoimmune response, inherent to the NOD background. Interestingly, in HYP mice, we observed hyperinsulinemia before hyperglycaemia occurred. We did not find any difference in the pancreas' architecture of the NOD and HYP mice (islets' size and staining for insulin and glucagon) but we detected a lower insulin content in the pancreas of HYP mice compared to NOD mice. These results give new insights about the role played by Akt2 in glucose homeostasis and argue for the ß cell failure being the primary event in the course of diabetes.

Cyclophilin D knockout significantly prevents HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH.

A family of Peptidyl-prolyl isomerases (PPIases), called Cyclophilins, localize to numerous intracellular and extracellular locations where they contribute to a variety of essential functions. We previously reported that non-immunosuppressive pan-cyclophilin inhibitor drugs like reconfilstat (CRV431) or NV556 decreased multiple aspects of non-alcoholic fatty liver disease (NAFLD) in mice under two different non-alcoholic steatohepatitis (NASH) mouse models. Both CRV431 and NV556 inhibit several cyclophilin isoforms, among which cyclophilin D (CypD) has not been previously investigated in this context. It is unknown whether it is necessary to simultaneously inhibit multiple cyclophilin family members to achieve therapeutic benefits or if loss-of-function of one is sufficient. Furthermore, narrowing down the isoform most responsible for a particular aspect of NAFLD/NASH, such as hepatocellular carcinoma (HCC), would allow for more precise future therapies. Features of human diabetes-linked NAFLD/NASH can be reliably replicated in mice by administering a single high dose of streptozotocin to disrupt pancreatic beta cells, in conjunction with a high sugar, high fat, high cholesterol western diet over the course of 30 weeks. Here we show that while both wild-type (WT) and Ppif-/- CypD KO mice develop multipe severe NASH disease features under this model, the formation of HCC nodules was significantly blunted only in the CypD KO mice. Furthermore, of differentially expressed transcripts in a qPCR panel of select HCC-related genes, nearly all were downregulated in the CypD KO background. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NAFLD/NASH. This study highlights the impact of CypD loss-of-function on the development of HCC, one of the most severe disease outcomes.

Does diabetes affect breast cancer survival?

OBJECTIVES: The objective of this study is to investigate the influence of diabetes on breast cancer-specific survival among women with breast cancer in Aotearoa/New Zealand. METHODS: This study included women diagnosed with invasive breast cancer between 2005 and 2020, with their information documented in the Te Rehita Mate Utaetae-Breast Cancer Foundation National Register. Breast cancer survival curves for women with diabetes and those without diabetes were generated using the Kaplan-Meier method. The hazard ratio (HR) of breast cancer-specific mortality for women with diabetes compared to women without diabetes was estimated using the Cox proportional hazards model. RESULTS: For women with diabetes, the 5-year and 10-year of cancer-specific survival were 87% (95% CI: 85%-88%) and 79% (95% CI: 76%-81%) compared to 89% (95% CI: 89%-90%) and 84% (95% CI: 83%-85%) for women without diabetes. The HR of cancer-specific mortality for patients with diabetes compared to those without diabetes was 0.99 (95% CI: 0.89-1.11) after adjustment for patient demographics, tumor characteristics, and treatments. Age at cancer diagnosis and cancer stage had the biggest impact on the survival difference between the two groups. When stratified by cancer stage, the cancer-specific mortality between the two groups was similar. CONCLUSIONS: While differences in survival have been identified for women with diabetes when compared to women without diabetes, these are attributable to age and the finding that women with diabetes tend to present with more advanced disease at diagnosis. We did not find any difference in survival between the two groups due to differences in treatment.

LncRNA and mRNA expression characteristic and bioinformatic analysis in myocardium of diabetic cardiomyopathy mice.

BACKGROUND: Diabetic cardiomyopathy (DCM) is becoming a very well-known clinical entity and leads to increased heart failure in diabetic patients. Long non-coding RNAs (LncRNAs) play an important role in the pathogenesis of DCM. In the present study, the expression profiles of lncRNAs and mRNAs were illuminated in myocardium from DCM mice, with purpose of exploring probable pathological processes of DCM involved by differentially expressed genes in order to provide a new direction for the future researches of DCM. RESULTS: The results showed that a total of 93 differentially expressed lncRNA transcripts and 881 mRNA transcripts were aberrantly expressed in db/db mice compared with the controls. The top 6 differentially expressed lncRNAs like up-regulated Hmga1b, Gm8909, Gm50252 and down-regulated Msantd4, 4933413J09Rik, Gm41414 have not yet been reported in DCM. The lncRNAs-mRNAs co-expression network analysis showed that LncRNA 2610507I01Rik, 2310015A16Rik, Gm10503, A930015D03Rik and Gm48483 were the most relevant to differentially expressed mRNAs. CONCLUSION: Our results showed that db/db DCM mice exist differentially expressed lncRNAs and mRNAs in hearts. These differentially expressed lncRNAs may be involved in the pathological process of cardiomyocyte apoptosis and fibrosis in DCM.

Deficiency of lncRNA MERRICAL abrogates macrophage chemotaxis and diabetes-associated atherosclerosis.

Diabetes-associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of the aortic intima in Ldlr-/- mice on a high-fat, high-sucrose-containing (HFSC) diet identifies a macrophage-enriched nuclear long noncoding RNA (lncRNA), MERRICAL (macrophage-enriched lncRNA regulates inflammation, chemotaxis, and atherosclerosis). MERRICAL expression increases by 249% in intimal lesions during progression. lncRNA-mRNA pair genomic mapping reveals that MERRICAL positively correlates with the chemokines Ccl3 and Ccl4. MERRICAL-deficient macrophages exhibit lower Ccl3 and Ccl4 expression, chemotaxis, and inflammatory responses. Mechanistically, MERRICAL guides the WDR5-MLL1 complex to activate CCL3 and CCL4 transcription via H3K4me3 modification. MERRICAL deficiency in HFSC diet-fed Ldlr-/- mice reduces lesion formation by 74% in the aortic sinus and 86% in the descending aorta by inhibiting leukocyte recruitment into the aortic wall and pro-inflammatory responses. These findings unveil a regulatory mechanism whereby a macrophage-enriched lncRNA potently inhibits chemotactic responses, alleviating lesion progression in diabetes.

Implementation of a randomized mobile-technology lifestyle program in individuals with nonalcoholic fatty liver disease.

Identifying effective, feasible, low-cost interventions that promote sustainable lifestyle changes in nonalcoholic fatty liver disease (NAFLD) is a key unmet need. The aim of this study was to assess predictors of lifestyle practice patterns of NAFLD patients and evaluate the implementation of a mobile technology-based intervention. We prospectively enrolled adults with NAFLD (diagnosed by imaging or biopsy). Individuals with additional liver diseases or decompensated cirrhosis were excluded. Patient were randomized to usual care or a FitBit based program for 6-months. We obtained anthropometrics, labs, vibration controlled transient elastography (VCTE), health-related quality of life (HRQOL), physical activity, diet and motivation to change data. 70 patients were enrolled, 33% with cirrhosis. Median age was 52.1 years, 47% males, 83% white, body mass index 32.3, liver stiffness 7.6 kPa, controlled attenuation parameter 319 db/m, and 50% had diabetes. Baseline HRQOL was 5.4/7 and independently negatively correlated with level of concern about their disease and positively with physical function. Younger age was independently associated with unhealthy diets whereas diabetes was independently associated with unhealthy diets and higher VCTE kPa. 6-month follow-up data available on 31 patients showed trends in improvement in weight. In a cohort of NAFLD patients, we identified independent correlates of lifestyle behaviors and HRQOL. Implementation of interventions that improve physical function may improve HRQOL in NAFLD. Younger patients and those with diabetes appeared to have the greatest need for dietary interventions. Structured mobile technology lifestyle interventions using Fitbit and personalized coaching showed promise but require further validation with a focus on sustainability of intervention and improvement in outcomes.

Evaluation of renal tubular function by multiparametric functional MRI in early diabetes.

Purpose To evaluate the tubular function in an alloxan-induced type 1 diabetes mellitus (DM) rabbit model measured by renal oxygenation (R2*), oxygen extraction fraction (OEF), and renal blood flow (RBF) using blood oxygenation level dependent, asymmetric spin echo, and arterial spin labeling MRI. Methods Twenty-six rabbits were randomized into the 3-day DM group (n = 13) and the 7-day DM group (n = 13). We performed pairs of multiparametric MRIs (before and after furosemide injection) at baseline and 3/7 days post-DM, and scored pathological kidney injury. We performed statistical analyses using non-parametric, chi-square, and Spearman correlation tests. Results At baseline, medullary R2* significantly decreased by 24.97% and 16.74% in the outer and inner stripes of the outer medulla (OS and IS, p = 0.006 and 0.003, respectively) after furosemide administration. While the corresponding OEF decreased by 15.91% for OS and 16.67% for IS (both p = 0.003), and no significant change in medullary RBF was observed (p > 0.05). In the 3-day DM group, the decrease of medullary R2* and OEF post-furosemide became unremarkable, suggesting tubular dysfunction. We noticed similar changes in the 7-day DM group. Correlation analysis showed pathological tubular injury score significantly correlated with medullary ∆R2* (post-furosemide - pre-furosemide difference, r = 0.82 for OS and 0.82 for IS) and ∆OEF (r = 0.82 for OS and 0.82 for IS) (p < 0.001, respectively). Conclusion: The combination of medullary OEF and R2* in response to furosemide could detect renal tubular dysfunction in early DM.

LncRNA AA465934 Improves Podocyte Injury by Promoting Tristetraprolin-Mediated HMGB1 DownRegulation in Diabetic Nephropathy.

Although LncRNA AA465934 expression is reduced in high glucose (HG)-treated podocytes, its role in HG-mediated podocyte injury and diabetic nephropathy (DN) remains unknown. Herein, we investigated the role of AA465934 in HG-mediated podocyte injury and DN using a spontaneous type II diabetic nephropathy (T2DN) model. The model was created by injecting AA465934 overexpressed adeno-associated virus (AAV) or control into mice. The levels of renal function, proteinuria, renal structural lesions, and podocyte apoptosis were then examined. Furthermore, AA465934 and autophagy levels, as well as tristetraprolin (TTP) and high mobility group box 1 (HMGB1) expression changes were detected. We also observed podocyte injury and the binding ability of TTP to E3 ligase proviral insertion in murine lymphomas 2 (PIM2), AA465934, or HMGB1. According to the results, AA465934 improved DN progression and podocyte damage in T2DN mice. In addition, AA465934 bound to TTP and inhibited its degradation by blocking TTP-PIM2 binding. Notably, TTP knock-down blocked the ameliorating effects of AA465934 and TTP bound HMGB1 mRNA, reducing its expression. Overexpression of HMGB1 inhibited the ability of AA465934 and TTP to improve podocyte injury. Furthermore, AA465934 bound TTP, inhibiting TTP-PIM2 binding, thereby suppressing TTP degradation, downregulating HMGB1, and reversing autophagy downregulation, ultimately alleviating HG-mediated podocyte injury and DN. Based on these findings, we deduced that the AA465934/TTP/HMGB1/autophagy axis could be a therapeutic avenue for managing podocyte injury and DN.

Exosomes Derived from Adipose Stem Cells Enhance Angiogenesis in Diabetic Wound Via miR-146a-5p/JAZF1 Axis.

Chronic trauma in diabetes is a leading cause of disability and mortality. Exosomes show promise in tissue regeneration. This study investigates the role of exosomes derived from adipose stem cells (ADSC-Exos) in angiogenesis. MiRNA-seq analysis revealed significant changes in 47 genes in human umbilical vein endothelial cells (HUVECs) treated with ADSC-Exos, with miR-146a-5p highly expressed. MiR-146a-5p mimics enhanced the pro-angiogenic effects of ADSC-Exos, while inhibitors had the opposite effect. JAZF1 was identified as a direct downstream target of miR-146a-5p through bioinformatics, qRT-PCR, and dual luciferase assay. Overexpress of JAZF1 resulted in decreased proliferation, migration, and angiogenic capacity of HUVECs, and reduced VEGFA expression. This study proposes that ADSC-Exos regulate angiogenesis partly via the miR-146a-5p/JAZF1 axis.

Associations between thyroid hormones and appendicular skeletal muscle index, and hand grip strength in people with diabetes: The KAMOGAWA-A study.

AIM: To assess the effects of thyroid hormones on appendicular skeletal muscle index (SMI) and hand grip strength (HGS) in people with diabetes. METHODS: This cross-sectional cohort included 1,135 participants with diabetes admitted to 3 hospitals in Japan. Multiple regression analysis was performed to determine the associations among thyroid hormone levels, SMI, and HGS. RESULTS: Of the 1,135 participants, 480 were female. Their median (interquartile range) age, body mass index, durations of diabetes, and glycated haemoglobin levels were 68 years, 24.3 kg/m2, 10 years, and 7.6 %, respectively. The median (interquartile range) SMI (kg/m2) and hand grip strength of the cohort were 7.1 kg/m2 and 28.2 kg, respectively. Positive correlations between FT3 and the FT3/FT4 ratio with SMI and HGS was observed after adjusting for covariates in males. A negative correlation was found between the FT3/FT4 ratio and sarcopenia as a result of low SMI and low HGS in the male participants but not in females (p for interaction = 0.02). CONCLUSIONS: FT3/FT4 ratios may impact skeletal muscles in people with diabetes-particularly in males. Assessments of FT3/FT4 ratios may represent key indicators of muscle mass and strength in males.

The presence of exudative thickening of Bowman's capsule predict poor prognosis in diabetic kidney disease.

BACKGROUND: The relationship between Bowman's capsule thickening and progression of diabetic kidney disease (DKD) remains uncertain. METHODS: Renal biopsy specimens from 145 DKD patients and 20 control subjects were evaluated for Bowman's capsule thickness. Immunohistochemical staining assessed col4α2, laminin ß1, and albumin expression. In a discovery cohort of 111 DKD patients with eGFR ≥ 30 ml/min/1.73 m2, thickening was classified as fibrotic or exudative. The composite endpoint included CKD stage 5, dialysis initiation, and renal disease-related death. Prognosis was analyzed using Kaplan-Meier and Cox regression analyses. Two validation cohorts were included. RESULTS: Three types of thickening were observed: fibrotic, exudative, and periglomerular fibrosis. Parietal epithelial cell matrix protein accumulation contributed to fibrotic thickening, while albumin was present in exudative thickening. Bowman's capsule was significantly thicker in DKD patients (5.74 ± 2.09 µm) compared to controls (3.38 ± 0.43 µm, P < 0.01). In discovery cohort, the group of exudative thickning had a poorer prognosis(median time 20 months vs 57 months, P = 0.000). Cox multivariate analysis revealed that exudative thickening of Bowman's capsule were associated with a poor prognosis. The validation cohorts confirmed the result. CONCLUSIONS: Various mechanisms contribute to Bowman's capsule thickening in DKD. The proportion of exudative thickening may serve as a valuable prognostic indicator for DKD patients.

Diabetes Accelerates Steatohepatitis in Mice: Liver Pathology and Single-Cell Gene Expression Signatures.

Glucose lowering independently reduces liver fibrosis in human nonalcoholic fatty liver disease. This study investigated the impact of diabetes on steatohepatitis and established a novel mouse model for diabetic steatohepatitis. Male C57BL/6J mice were fed a 60% high-fat diet (HFD) and injected with carbon tetrachloride (CCl4) and streptozotocin (STZ) to induce diabetes. The HFD+CCl4+STZ group showed more severe liver steatosis, hepatocyte ballooning, and regenerative nodules compared with other groups. Diabetes up-regulated inflammatory cytokine-associated genes and increased the M1/M2 macrophage ratios in the liver. Single-cell RNA sequencing analysis of nonparenchymal cells in the liver showed that diabetes reduced Kupffer cells and increased bone marrow-derived recruited inflammatory macrophages, such as Ly6Chi-RM. Diabetes globally reduced liver sinusoidal endothelial cells (LSECs). Furthermore, genes related to the receptor for advanced glycation end products (RAGE)/Toll-like receptor 4 (TLR4) were up-regulated in Ly6Chi-RM and LSECs in mice with diabetes, suggesting a possible role of RAGE/TLR4 signaling in the interaction between inflammatory macrophages and LSECs. This study established a novel diabetic steatohepatitis model using a combination of HFD, CCl4, and STZ. Diabetes exacerbated steatosis, hepatocyte ballooning, fibrosis, regenerative nodule formation, and the macrophage M1/M2 ratios triggered by HFD and CCl4. Single-cell RNA sequencing analysis indicated that diabetes activated inflammatory macrophages and impairs LSECs through the RAGE/TLR4 signaling pathway. These findings open avenues for discovering novel therapeutic targets for diabetic steatohepatitis.

MX1 and UBE2L6 are potential metaflammation gene targets in both diabetes and atherosclerosis.

Background: The coexistence of diabetes mellitus (DM) and atherosclerosis (AS) is widespread, although the explicit metabolism and metabolism-associated molecular patterns (MAMPs) responsible for the correlation are still unclear. Methods: Twenty-four genetically wild-type male Ba-Ma mini pigs were randomly divided into five groups distinguished by different combinations of 90 mg/kg streptozotocin (STZ) intravenous injection and high-cholesterol/lipid (HC) or high-lipid (HL) diet feeding for 9 months in total. Pigs in the STZ+HC and STZ+HL groups were injected with STZ first and then fed the HC or HL diet for 9 months. In contrast, pigs in the HC+STZ and HL+STZ groups were fed the HC or HL diet for 9 months and injected with STZ at 3 months. The controls were only fed a regular diet for 9 months. The blood glucose and abdominal aortic plaque observed through oil red O staining were used as evaluation indicators for successful modelling of DM and AS. A microarray gene expression analysis of all subjects was performed. Results: Atherosclerotic lesions were observed only in the HC+STZ and STZ+HC groups. A total of 103 differentially expressed genes (DEGs) were identified as common between them. The most significantly enriched pathways of 103 common DEGs were influenza A, hepatitis C, and measles. The global and internal protein-protein interaction (PPI) networks of the 103 common DEGs consisted of 648 and 14 nodes, respectively. The top 10 hub proteins, namely, ISG15, IRG6, IRF7, IFIT3, MX1, UBE2L6, DDX58, IFIT2, USP18, and IFI44L, drive aspects of DM and AS. MX1 and UBE2L6 were the intersection of internal and global PPI networks. The expression of MX1 and UBE2L6 was 507.22 ± 342.56 and 96.99 ± 49.92 in the HC+STZ group, respectively, which was significantly higher than others and may be linked to the severity of hyperglycaemia-related atherosclerosis. Further PPI network analysis of calcium/micronutrients, including MX1 and UBE2L6, consisted of 58 and 18 nodes, respectively. The most significantly enriched KEGG pathways were glutathione metabolism, pyrimidine metabolism, purine metabolism, and metabolic pathways. Conclusions: The global and internal PPI network of the 103 common DEGs consisted of 648 and 14 nodes, respectively. The intersection of the nodes of internal and global PPI networks was MX1 and UBE2L6, suggesting their key role in the comorbidity mechanism of DM and AS. This inference was partly verified by the overexpression of MX1 and UBE2L6 in the HC+STZ group but not others. Further calcium- and micronutrient-related enriched KEGG pathway analysis supported that MX1 and UBE2L6 may affect the inflammatory response through micronutrient metabolic pathways, conceptually named metaflammation. Collectively, MX1 and UBE2L6 may be potential common biomarkers for DM and AS that may reveal metaflammatory aspects of the pathological process, although proper validation is still needed to determine their contribution to the detailed mechanism.

High CD133 expression in proximal tubular cells in diabetic kidney disease: good or bad?

BACKGROUND: Proximal tubular cells (PTCs) play a critical role in the progression of diabetic kidney disease (DKD). As one of important progenitor markers, CD133 was reported to indicate the regeneration of dedifferentiated PTCs in acute kidney disease. However, its role in chronic DKD is unclear. Therefore, we aimed to investigate the expression patterns and elucidate its functional significance of CD133 in DKD. METHODS: Data mining was employed to illustrate the expression and molecular function of CD133 in PTCs in human DKD. Subsequently, rat models representing various stages of DKD progression were established. The expression of CD133 was confirmed in DKD rats, as well as in human PTCs (HK-2 cells) and rat PTCs (NRK-52E cells) exposed to high glucose. The immunofluorescence and flow cytometry techniques were utilized to determine the expression patterns of CD133, utilizing proliferative and injury indicators. After overexpression or knockdown of CD133 in HK-2 cells, the cell proliferation and apoptosis were detected by EdU assay, real-time cell analysis and flow analysis. Additionally, the evaluation of epithelial, progenitor cell, and apoptotic indices was performed through western blot and quantitative RT-PCR analyses. RESULTS: The expression of CD133 was notably elevated in both human and rat PTCs in DKD, and this expression increased as DKD progressed. CD133 was found to be co-expressed with CD24, KIM-1, SOX9, and PCNA, suggesting that CD133+ cells were damaged and associated with proliferation. In terms of functionality, the knockdown of CD133 resulted in a significant reduction in proliferation and an increase in apoptosis in HK-2 cells compared to the high glucose stimulus group. Conversely, the overexpression of CD133 significantly mitigated high glucose-induced cell apoptosis, but had no impact on cellular proliferation. Furthermore, the Nephroseq database provided additional evidence to support the correlation between CD133 expression and the progression of DKD. Analysis of single-cell RNA-sequencing data revealed that CD133+ PTCs potentially play a role in the advancement of DKD through multiple mechanisms, including heat damage, cell microtubule stabilization, cell growth inhibition and tumor necrosis factor-mediated signaling pathway. CONCLUSION: Our study demonstrates that the upregulation of CD133 is linked to cellular proliferation and protects PTC from apoptosis in DKD and high glucose induced PTC injury. We propose that heightened CD133 expression may facilitate cellular self-protective responses during the initial stages of high glucose exposure. However, its sustained increase is associated with the pathological progression of DKD. In conclusion, CD133 exhibits dual roles in the advancement of DKD, necessitating further investigation.

Crosstalk among podocytes, glomerular endothelial cells and mesangial cells in diabetic kidney disease: an updated review.

Diabetic kidney disease (DKD) is a long-term and serious complication of diabetes that affects millions of people worldwide. It is characterized by proteinuria, glomerular damage, and renal fibrosis, leading to end-stage renal disease, and the pathogenesis is complex and involves multiple cellular and molecular mechanisms. Among three kinds of intraglomerular cells including podocytes, glomerular endothelial cells (GECs) and mesangial cells (MCs), the alterations in one cell type can produce changes in the others. The cell-to-cell crosstalk plays a crucial role in maintaining the glomerular filtration barrier (GFB) and homeostasis. In this review, we summarized the recent advances in understanding the pathological changes and interactions of these three types of cells in DKD and then focused on the signaling pathways and factors that mediate the crosstalk, such as angiopoietins, vascular endothelial growth factors, transforming growth factor-ß, Krüppel-like factors, retinoic acid receptor response protein 1 and exosomes, etc. Furthermore, we also simply introduce the application of the latest technologies in studying cell interactions within glomerular cells and new promising mediators for cell crosstalk in DKD. In conclusion, this review provides a comprehensive and updated overview of the glomerular crosstalk in DKD and highlights its importance for the development of novel intervention approaches.

Diabetic Cardiomyopathy and Cell Death: Focus on Metal-Mediated Cell Death.

Cardiac myocyte death is an essential initiator of the pathogenesis and progression of various etiological cardiomyopathies, including diabetic cardiomyopathy (DCM), a disease that has been reported since 1972. Cardiac cell death has been detected in the hearts of patients with diabetes and in animal models, and the role of cell death in the pathogenesis of DCM has been extensively investigated. The first review by the authors, specifically focusing on "Cell death and diabetic cardiomyopathy," was published in the journal, Cardiovascular Toxicology in 2003. Over the past two decades, studies investigating the role of cardiac cell death in the pathogenesis of DCM have gained significant attention, resulting in the discovery of several new kinds of cell death involving different mechanisms, including apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis. After the 20th anniversary of the review published in 2003, we now provide an update with a focus on the potential role of metal-mediated cell death, ferroptosis, and cuproptosis in the development of DCM in compliance with this special issue. The intent of our review is to further stimulate work in the field to advance the body of knowledge and continue to drive efforts to develop more advanced therapeutic approaches to prevent cell death, particularly metal-dependent cell death, and, ultimately, to reduce or prevent the development of DCM.

Brain alterations in regions associated with end-organ diabetic microvascular disease in diabetes mellitus: A UK Biobank study.

BACKGROUND: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC). METHODS: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. RESULTS: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). INTERPRETATION: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM.

Atherosclerosis and Hippocampal Volumes in Older Adults: The Role of Age and Blood Pressure.

BACKGROUND: Lower hippocampal volume is associated with late-life cognitive decline and is an important, but nonspecific marker for clinical Alzheimer's dementia. Cerebrovascular disease may also be associated with hippocampal volume. Here we study the role of intracranial large vessel disease (atherosclerosis) in association with hippocampal volume and the potential role of age, average late-life blood pressure across all visits, and other factors (sex, apolipoprotein ε4 [APOE ε4], and diabetes). METHODS AND RESULTS: Data came from 765 community-based older people (91 years old on average at death; 72% women), from 2 ongoing clinical-pathologic cohort studies. Participants completed baseline assessment, annual standardized blood pressure measurements, vascular risk assessment for diabetes, and blood draws to determine APOE genotype, and at death, brains were removed and underwent ex vivo magnetic resonance imaging and neuropathologic evaluation for atherosclerosis pathology and other cerebrovascular and neurodegenerative pathologies. Linear regression models examined the association of atherosclerosis and hippocampal to hemisphere volume ratio and whether age at death, blood pressure, and other factors modified associations. In linear regression models adjusted for demographics and neurodegenerative and other cerebrovascular pathologies, atherosclerosis severity was associated with a lower hippocampal to hemisphere volume ratio. In separate models, we found the effect of atherosclerosis on the ratio of hippocampal to hemisphere volume was attenuated among advanced age at death or having higher systolic blood pressure (interaction terms P≤0.03). We did not find confounding or interactions with sex, diabetes, or APOE ε4. CONCLUSIONS: Atherosclerosis severity is associated with lower hippocampal volume, independent of neurodegenerative and other cerebrovascular pathologies. Higher systolic blood pressures and advanced age attenuate associations.