Severe Diabetic Complications Research Articles

Prevalence of self-reported symptoms of diabetic autonomic dysfunction in the North Denmark Region: a population-based survey.

Diabetic autonomic neuropathy is a severe complication of diabetes, estimated to affect up to 44% in type 1 diabetes (T1D) and 73% in type 2 diabetes (T2D) based on clinical studies. Currently, the assessment of diabetic autonomic neuropathy is not implemented in Denmark's clinical guidelines, complicating the estimation of the true prevalence. Thus, this study investigated the prevalence of self-reported symptoms of autonomic dysfunction in people living with diabetes in the North Denmark Region using the Composite Autonomic Symptoms Score (COMPASS)-31 questionnaire. In 2022, all adults with T1D or T2D in the North Denmark Region (n = 29,155) were identified using The National Health Insurance Service Registry and invited to an online survey including the Danish version of COMPASS-31. The prevalence and associated 95% confidence intervals (CI) for symptomatic autonomic dysfunction were determined using a cut-off value of 16. In total, 7,377 completed COMPASS-31, of which 82.4% reported having T2D and 13.7% T1D. The prevalence of symptomatic autonomic dysfunction was 36.8% (95% CI: 34-40) after a median of 26 years with diabetes for T1D and 44.2% (95% CI: 43-45) after a median of 10 years for T2D. Pupillary and orthostatic intolerance were the most frequent moderate to severe symptoms, respectively (38.4% and 24.0% in T1D and 32.8% and 26.3% in T2D). Symptoms of autonomic dysfunction are very common in individuals with diabetes living in the North Denmark Region, emphasizing the unmet need for regular testing to increase awareness and allow for adequate management, ultimately reducing the morbidity of diabetes.

Impaired Iron-Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM), a severe complication of diabetes, is characterized by mitochondrial dysfunction, oxidative stress, and DNA damage. Despite its severity, the intrinsic factors governing cardiomyocyte damage in DCM remain unclear. It is hypothesized that impaired iron-sulfur (Fe-S) cluster synthesis plays a crucial role in the pathogenesis of DCM. Reduced S-sulfhydration of cysteine desulfurase (NFS1) is a novel mechanism that contributes to mitochondrial dysfunction and PARthanatos in DCM. Mechanistically, hydrogen sulfide (H2S) supplementation restores NFS1 S-sulfhydration at cysteine 383 residue, thereby enhancing Fe-S cluster synthesis, improving mitochondrial function, increasing cardiomyocyte viability, and alleviating cardiac damage. This study provides novel insights into the interplay between Fe-S clusters, mitochondrial dysfunction, and PARthanatos, highlighting a promising therapeutic target for DCM and paving the way for potential clinical interventions to improve patient outcomes.

The association of the perioperative neutrophil-to-lymphocyte ratio with wound healing in patients with Wagner grade 3 and 4 diabetic foot ulcers after tibial cortex transverse transport surgery: a prospective observational cohort study

BackgroundDiabetic foot ulcers (DFUs) are severe complications of diabetes, involving multiple etiological factors including neuropathy, vascular insufficiency, and impaired wound healing. The global burden of DFUs is substantial, with significant morbidity and high management costs. Recent advancements have introduced the tibial cortex transverse transport (TTT) technique, which has shown promising results in the management of severe DFUs by promoting angiogenesis and immunomodulation.MethodsThis prospective cohort study enrolled patients with Wagner grade 3 and 4 DFUs, treated using the TTT technique from May 2022 to September 2023 at MianYang Central Hospital. The study assessed the influence of TTT on the perioperative neutrophil-to-lymphocyte ratio (NLR), an established biomarker of systemic inflammation, and its correlation with wound healing outcomes.ResultsA total of 82 patients were enrolled, with 66 completing the study. The survival analysis revealed that patients with a lower preoperative NLR experienced significantly faster wound healing compared with a high NLR (log rank test P< 0.05; hazard ratio (HR) = 0.46; 95% CI: 0.26–0.83). The optimal NLR cutoff values (4.25) were established to predict wound healing times for DFUs. The median NLR was significantly different before TTT surgery, 3 days after TTT surgery, and 1 month after TTT surgery (P<0.05).ConclusionThe TTT technique significantly influences the perioperative NLR and is associated with improved wound healing in DFU patients. The perioperative NLR serves as an effective predictive biomarker for wound healing outcomes, highlighting the significance of interventions targeting NLR values in perioperative management strategies and postoperative monitoring protocols for the treatment of diabetic foot ulcers (DFUs) in clinical practice.

Asiaticoside improves diabetic nephropathy by reducing inflammation, oxidative stress, and fibrosis: An in vitro and in vivo study

BACKGROUND Diabetic nephropathy (DN) is a severe microvascular complication of diabetes characterized by inflammation, oxidative stress, and renal fibrosis. Asiaticoside (AC) exhibits anti-inflammatory, antioxidant, and anti-fibrotic properties, suggesting potential therapeutic benefits for DN. This study aimed to investigate the protective effects of AC against DN and elucidate the underlying mechanisms involving the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) antioxidant pathway. AIM To investigate the renoprotective effects of AC against DN and elucidate the role of the NRF2/HO-1 pathway. METHODS The effects of AC on high glucose (HG)-induced proliferation, inflammation, oxidative stress, and fibrosis were evaluated in rat glomerular mesangial cells (HBZY-1) in vitro . A streptozotocin-induced DN rat model was established to assess the in vivo impact of AC on renal injury, inflammation, oxidative stress, and fibrosis. The involvement of the NRF2/HO-1 pathway was examined using pharmacological inhibition studies in the cell model. RESULTS AC inhibited HG-induced HBZY-1 cell proliferation and significantly improved various indicators of DN in rats, including reduced body weight, and elevated blood glucose, serum creatinine, blood urea nitrogen, and 24-h urine protein. Both in vitro and in vivo studies demonstrated that AC decreased inflammation and oxidative stress by reducing interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, reactive oxygen species, and malondialdehyde levels while increasing superoxide dismutase activity. Additionally, AC suppressed the expression of fibrogenic markers such as collagen I, collagen IV, and fibronectin. AC activated NRF2 expression in the nucleus and increased HO-1 and NAD(P)H dehydrogenase (Quinone) 1 protein expression in renal tissues and HG-induced HBZY-1 cells. CONCLUSION AC improves DN by reducing inflammation, oxidative stress, and fibrosis through the activation of the NRF2/HO-1 signaling pathway. These findings not only highlight AC as a promising therapeutic candidate for DN but also underscore the potential of targeting the NRF2/HO-1 pathway in developing novel treatments for other chronic kidney diseases characterized by oxidative stress and inflammation.

High glucose- or AGE-induced oxidative stress inhibits hippocampal neuronal mitophagy through the Keap1–Nrf2–PHB2 pathway in diabetic encephalopathy

Diabetic encephalopathy (DE) is a severe complication of diabetes, but its pathogenesis remains unclear. This study aimed to investigate the roles and underlying mechanisms of high glucose (HG)- and advanced glycosylation end product (AGE)-induced oxidative stress (OS) in the cognitive decline in DE. The DE mouse model was established using a high-fat diet and streptozotocin, and its cognitive functions were evaluated using the Morris Water Maze, novel object recognition, and Y-maze test. The results revealed increased reactive oxygen species (ROS) generation, mitophagy inhibition, and decreased prohibitin 2 (PHB2) expression in the hippocampal neurons of DE mice and HG- or AGE-treated HT-22 cells. However, overexpression of PHB2 reduced ROS generation, reversed mitophagy inhibition, and improved mitochondrial function in the HG- or AGE-treated HT-22 cells and ameliorated cognitive decline, improved mitochondrial structural damage, and reversed mitophagy inhibition of hippocampal neurons in DE mice. Further analysis revealed that the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the HG- or AGE-mediated downregulation of PHB2 in HT-22 cells. These results demonstrate that HG- or AGE-induced OS inhibits the mitophagy of hippocampal neurons via the Keap1–Nrf2–PHB2 pathway, thereby contributing to the cognitive decline in DE.

Dihydrolipoamide S-acetyltransferase activation alleviates diabetic kidney disease via AMPK-autophagy axis and mitochondrial protection

Diabetic kidney disease (DKD), a severe complication of diabetes marked by deregulated glucose metabolism, remains enigmatic in its pathogenesis. Herein, we delved into the functional role of Dihydrolipoamide S-acetyltransferase (DLAT), a pivotal E2 component of the pyruvate dehydrogenase complex (PDC), in the context of DKD. Our findings revealed a downregulation of DLAT in the kidneys of diabetic patients, correlating inversely with kidney function. Parallel downregulation was observed in both high-fat diet/streptozotocin (HFD/STZ) and db/db mouse models, as well as in human proximal tubular epithelial cells (HK-2) cultured under hyperglycemic conditions. To further elucidate the role of endogenous DLAT in DKD, we employed genetic ablation of Dlat in mouse models. Dlat haploinsufficient mice exhibited exacerbated renal dysfunction, structural damage, fibrosis, and mitochondrial dysfunction under DKD conditions. Consistent with these findings, modulation of DLAT expression in HK-2 cells highlighted its influence on fibrosis, with overexpression attenuating Fibronectin and Collagen I levels, while downregulation exacerbated fibrosis. Mechanistically, we discovered that DLAT activates mitochondria autophagy through the Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, thereby mitigating mitochondrial dysfunction associated with DKD progression. Inhibition of AMPK abrogated the protective effects of DLAT against mitochondrial dysfunction and DKD. Notably, we identified Hyperforin (HPF), a phytochemical, as a potential therapeutic agent. HPF activates DLAT and AMPK, subsequently ameliorating renal dysfunction, injuries, and fibrosis in both in vivo and in vitro models. In summary, our study underscores the pivotal role of DLAT and AMPK in kidney health and highlights the therapeutic potential of HPF in treating DKD.

Akkermansia muciniphila administration ameliorates streptozotocin-induced hyperglycemia and muscle atrophy by promoting IGF2 secretion from mouse intestine.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that can lead to severe diabetic complications. While the changes and correlations between gut microbiota and the pathogenesis of T1DM have been extensively studied, little is known about the benefits of interventions on gut bacterial communities, particularly using probiotics, for this disease. In the present study, we reported that the mice surviving after 5 months of streptozotocin (STZ) injection had reduced blood glucose level and recovered gut microbiota with increased Akkermansia muciniphila proportion. Gavage of heat-killed A. muciniphila increases the diversity of gut microbiota and elevated immune and metabolic signaling pathways in the intestine. Mechanistically, A. muciniphila treatment promoted the secretion of insulin-like growth factor 2 (IGF2) which subsequently activated IGF2 signaling in skeletal muscles and enhanced muscle and global metabolism. Our results suggest that the administration of heat-killed A. muciniphila could be a potential therapeutic strategy for T1DM and its associated hyperglycemia.

THE EFFECTS OF EXERCISE INTENSITY ON METABOLIC HEALTH IN PATIENTS WITH NAFLD AND TYPE 2 DIABETES: A COMPARATIVE STUDY

Introduction: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are chronic metabolic disorders that are increasingly prevalent globally, posing significant health challenges. Both conditions are linked to obesity, insulin resistance, and sedentary lifestyles, leading to severe complications such as cardiovascular diseases and liver cirrhosis. Exercise is a crucial lifestyle modification that improves metabolic health in these conditions, but the optimal exercise intensity remains debated. This study investigates the effects of different exercise intensities on metabolic health in patients with NAFLD and T2DM to provide insights for tailored exercise prescriptions. Materials and Methods: This randomized controlled trial involved 100 participants with NAFLD and T2DM, divided into two groups: MICT and HIIT, over 12 weeks. Participants were adults aged 30-65 years with confirmed NAFLD and T2DM, and a sedentary lifestyle. Exclusion criteria included other liver diseases, uncontrolled hypertension, severe diabetic complications, recent participation in a structured exercise program, and contraindications to exercise. Participants were randomly assigned to MICT or HIIT, with exercise sessions supervised by certified physiologists. Primary outcomes were liver fat content and insulin sensitivity, while secondary outcomes included lipid profiles, inflammatory markers, feasibility, and safety. Results: A total of 100 participants (50 per group) completed the study with comparable baseline characteristics. Both groups showed significant reductions in liver fat content and improvements in insulin sensitivity, with HIIT showing greater reductions (p=0.01 for liver fat, p=0.02 for insulin sensitivity). HIIT also led to more significant improvements in triglycerides, LDL, HDL, and inflammatory markers compared to MICT. Adherence rates were high in both groups, although slightly lower in the HIIT group, and dropout rates were comparable. Conclusion: Both MICT and HIIT significantly improve metabolic health in patients with NAFLD and T2DM, with HIIT yielding superior outcomes in reducing liver fat, improving insulin sensitivity, enhancing lipid profiles, and decreasing inflammatory markers. These findings support incorporating HIIT into exercise regimens for this population, highlighting its potential for greater metabolic health benefits. Future research should explore the long-term sustainability and broader applicability of HIIT and strategies to enhance adherence and safety.

Reference gene panel for urinary exosome-based molecular diagnostics in patients with kidney disease.

Kidney disease is a severe complication of diabetes that often leads to end-stage renal disease. Early diagnosis is crucial for prevention or delay. However, the current diagnostic methods, with their limitations in detecting the disease in its early stages, underscore the urgency and importance of finding new solutions. miRNAs encapsulated inside urinary exosomes (UEs) have potential as early biomarkers for kidney diseases. The need for reference miRNAs for accurate interpretation currently limits their translational potential. To identify consistently expressing reference miRNAs from UEs of controls and patients with type 2 diabetesmellitus (T2DM) and biopsy-confirmed kidney diseases. miRNA profiling was performed on UEs from 31 human urine samples using a rigorous and unbiased method. The UEs were isolated from urine samples collected from healthy individuals (n = 6), patients with T2DM (n = 13), and T2DM patients who also had kidney diseases (including diabetic nephropathy, n = 5; membranous nephropathy, n = 5; and IgA nephropathy, n = 2) through differential ultracentrifugation. After characterizing the UEs, miRNA expression profiling using microarray technology was conducted. Microarray data analysis identified 14 miRNAs that were consistently expressed in UEs from 31 human samples, representing various kidney conditions: diabetic controls, diabetic nephropathy, membrane nephropathy, IgA nephropathy, and healthy controls. Through in silico analysis, we determined that 10 of these miRNAs had significant potential to serve as reference genes in UEs. We identified uniformly expressing UE miRNAs that could serve as reference genes kidney disease biomarkers.

Identification of mitochondria-related genes as diagnostic biomarkers for diabetic nephropathy and their correlation with immune infiltration: New insights from bioinformatics analysis

BackgroundDiabetic nephropathy (DN) is a common and severe microvascular complication of diabetes. Mitochondrial dysfunction and immune inflammation are important factors in the pathogenesis of DN. However, the specific mechanisms and their intricate interactions in DN remain unclear. Besides, there are no effective specific predictive or diagnostic biomarkers for DN so far. Therefore, this study aims to elucidate the role of mitochondrial-related genes and their possibility as predictive or diagnostic biomarkers, as well as their crosstalk with immune infiltration in the progression of DN. MethodsBased on the GEO database and limma R package, the differentially expressed genes (DEGs) of DN were identified. Mitochondrial-related DEGs (MitoDEGs) were then obtained by intersecting these DEGs with mitochondria-related genes from the MitoCarta 3.0 database. Subsequently, the candidate hub genes were further screened by gene co-expression network analysis (WGCNA), and verified mRNA levels of these genes by real-time quantitative PCR (qRT-PCR) in high-glucose-treated human proximal tubular (HK-2) cells. The verified hub genes were utilized to construct a combined diagnostic model for DN, with its diagnostic efficacy assessed across the GSE30122 and GSE96804 datasets. Additionally, the immune infiltration pattern in DN was assessed with the CIBERSORT algorithm, and the Nephroseq v5 database was used to analyze the correlation between hub genes and clinical features of DN. ResultsSeven mitochondria-related candidate hub genes were screened from 56 MitoDEGs. Subsequently, the expression levels of six of them, namely EFHD1, CASP3, AASS, MPC1, NT5DC2, and BCL2A1, exhibited significant inter-group differences in the HK-2 cell model. The diagnostic model based on the six genes demonstrated good diagnostic efficacy in both training and validation sets. Furthermore, correlation analysis indicated that EFHD1 and AASS, downregulated in DN, are positively correlated with eGFR and negatively with serum creatinine. Conversely, CASP3, NT5DC2, and BCL2A1, upregulated in DN, show opposite correlations. In addition, spearman analysis revealed that the six hub genes were significantly associated with the infiltration of immune cells, including M1 and M2 macrophages, mast cells, resting NK cells, gamma delta T cells, and follicular helper T cells. ConclusionThis study elucidated the characteristics of mitochondria-related genes and their correlation with immune cell infiltration in DN, providing new insights for exploring the pathogenesis of DN and facilitating the identification of new potential biomarkers and therapeutic targets.

Photothermal and Antibacterial PDA@Ag/SerMA Microneedles for Promoting Diabetic Wound Repair.

Diabetic foot ulcer (DFU) is a common and severe complication of diabetes characterized by wound neuropathy, ischemia, and susceptibility to infection, making its treatment difficult. Dressings are commonly used in treating diabetic wounds; however, they have disadvantages, including lack of flexibility and mechanical strength, lack of coagulation activity, resistance to biodegradation, and low drug delivery efficiency. Developing more effective strategies for diabetic wound treatment has become a new focus. Microneedles (MN) can be used as a drug delivery platform for DFU wounds, allowing safe, effective, painless and minimally invasive medication administration through the skin. Herein, PDA@Ag/SerMA microneedles were prepared by combining the photothermal properties of polydopamine (PDA), the antimicrobial properties of argentum (Ag), and the ability of sericin methacryloyl (SerMA) to promote cell mitosis to accelerate wound healing and treat diabetic ulcer wounds. The results revealed that PDA@Ag/SerMA microneedles exhibited approximately 100% antimicrobial efficacy against Staphylococcus aureus and Escherichia coli under 808 nm near-infrared (NIR) irradiation. Furthermore, the wound healing rate of mice reached 95% within 12 days, which demonstrated the excellent antibacterial properties and wound healing efficacy of PDA@Ag/SerMA microneedles at cellular and animal levels, providing a potential solution for treating DFU.

Deep learning-powered segmentation and classification of diabetic retinopathy for enhanced diagnostic precision

This study addresses the critical challenge of diabetic retinopathy (DR), a severe complication of diabetes that potentially leads to blindness. We introduce a novel approach to DR detection using transfer learning, leveraging a single fundus photograph to automatically identify the disease’s stage. DR progresses through four stages, posing challenges for early detection, with existing methods often inefficient and prone to disagreements among clinicians. The proposed approach demonstrated in the APTOS 2019 Blindness Detection Competition employs convolutional neural networks (CNNs) and achieved a high quadratic weighted kappa score of 0.92546, highlighting its effectiveness in automatic DR detection and emphasizing the need for timely intervention. This paper first reviews related work, spanning classical computer vision methods to deep learning approaches, with a focus on CNNs. Transfer learning with CNN architectures is explored, showcasing promising results from various studies. Identifying two critical gaps in existing literature, the research emphasizes the need for comprehensive exploration into integrating pre-trained large language models (LLMs) with segmented image inputs for generating test/treatment recommendations. In addition, understanding the dynamic interactions among integrated components, including lesion segmentations, disease classification, and LLMs within web applications, remains essential. The objectives of the study include developing a comprehensive DR detection methodology, exploring and implementing model integration, evaluating performance through competition ranking, contributing significantly to DR detection methodologies, and identifying research gaps. The study encompasses revolutionizing DR detection by integrating cutting-edge technologies, focusing on transfer learning and various model integrations within web applications. The methodology covers data pre-processing, augmentation, segmentation using U-Net neural network architecture, and a detailed training process. The U-Net model demonstrates efficient segmentation of retinal structures with high accuracy and an impressive frames-per-second rate. The results highlight the model’s effectiveness in segmenting blood vessels, hard exudates, soft exudates, hemorrhages, microaneurysms, and the optical disc, with high Jaccard, F1, recall, precision, and accuracy scores. These findings underscore the model’s potential to enhance diagnostic capabilities in retinal pathology assessment, promising improved patient outcomes through timely diagnosis and intervention in combating DR.

The role of SLC7A11 in diabetic wound healing: novel insights and new therapeutic strategies.

Diabetic wounds are a severe complication of diabetes, characterized by persistent, non-healing ulcers due to disrupted wound-healing mechanisms in a hyperglycemic environment. Key factors in the pathogenesis of these chronic wounds include unresolved inflammation and antioxidant defense imbalances. The cystine/glutamate antiporter SLC7A11 (xCT) is crucial for cystine import, glutathione production, and antioxidant protection, positioning it as a vital regulator of diabetic wound healing. Recent studies underscore the role of SLC7A11 in modulating immune responses and oxidative stress in diabetic wounds. Moreover, SLC7A11 influences critical processes such as insulin secretion and the mTOR signaling pathway, both of which are implicated in delayed wound healing. This review explores the mechanisms regulating SLC7A11 and its impact on immune response, antioxidant defenses, insulin secretion, and mTOR pathways in diabetic wounds. Additionally, we highlight the current advancements in targeting SLC7A11 for treating related diseases and conceptualize its potential applications and value in diabetic wound treatment strategies, along with the challenges encountered in this context.

Effect of frailty on effectiveness and safety of GLP-1 receptor agonists versus SGLT2 inhibitors in people with type 2 diabetes in Taiwan: a retrospective, nationwide, longitudinal study

GLP-1 receptor agonists and SGLT2 inhibitors are increasingly being used in people with type 2diabetes on the basis of findings from randomised clinical trials; however, little is known of whether clinical outcomes are affected by frailty in real-world settings. We aimed to compare the clinical effectiveness and safety of GLP-1 receptor agonists and SGLT2 inhibitors in managing type 2diabetes, with a specific focus on stratifying people by their frailty status. In this retrospective, nationwide, longitudinal study, we identified people (aged ≥20years) with type 2 diabeteswho newly initiated either a GLP-1 receptor agonist or an SGLT2 inhibitor during the period Jan 1, 2017to Dec 31, 2019 from the Taiwan National Health Insurance database. Individuals were excluded if they had been diagnosed with cancer, received dialysis for kidney failure, or had prescriptions for a GLP-1 receptor agonist or an SGLT2 inhibitor, within 1year before the index date. Mortality data were collected from the Taiwan National DeathRegistry. Eligible individuals were categorised into three frailty subgroups-fit, mild frailty, and moderate or severe frailty-on the basis of the multimorbidity frailty index. Propensity score matching (1:1) was used to balance covariates between recipients of GLP-1 receptor agonists and SGLT2 inhibitors among each frailty subgroup. Clinical outcomes of interest included three-point major adverse cardiovascular events (non-fatal acute myocardial infarction, non-fatal stroke, and fatal cardiovascular disease), all-cause mortality, hospitalisation for heart failure, dialysis or renal transplant, severe diabetic foot complications, retinopathy, hospitalisation for severe hyperglycaemia, and hospitalisation for severe hypoglycaemia. The association between the use of a GLP-1 receptor agonist versus an SGLT2 inhibitor and the risk of the outcomes of interest among each frailty subgroup was examined using a subdistribution hazard model. We identified 320 210people with type 2diabetes, of whom 280 163 met the eligibility criteria, who initiated either a GLP-1 receptor agonist (n=22 968; mean age 57·7years [SD 13·9], 11 338 [49·4%] were female, and 11 630 [50·6%] were male) or SGLT2 inhibitor (n=257 195; mean age 58·8years [12·3], 107 988 [42·0%] were female, and 149 207 [58·0%] were male) during 2017-19. After matching, 11 882, 7210, and 3414pairs of GLP-1 receptor agonist and SGLT2 inhibitor users were assigned in the fit, mild frailty, and moderate or severe frailty subgroups. All clinical outcomes were comparable between users of GLP-1 receptor agonists and SGLT2 inhibitors among each frailty subgroup, except fora higher risk of hospitalisation for severe hyperglycaemia with GLP-1 receptor agonists than withSGLT2 inhibitors in the mild frailty subgroup (subdistribution hazard ratio 1·25 [95% CI 1·13-1·38]; p<0·0001) and a higher risk of dialysis or renal transplant with GLP-1 receptor agonists than with SGLT2 inhibitors in the fit (2·43 [1·82-3·23]; p<0·0001), mild frailty (3·93 [3·03-5·09]; p<0·0001), and moderate or severe frailty (2·60 [2·03-3·31]; p<0·0001) subgroups. Formulating clear and updated guidelines on the use of GLP-1 receptor agonists and SGLT2 inhibitors according to frailty status could improve management of type 2diabetes. Ministry of Education, Taiwan.

Predictors of Diabetic Retinopathy in Type 2 Diabetes: A Cross-Sectional Study.

Type 2 diabetes mellitus (T2DM) represents one of the most impacting health issues of the modern era, as it is associated with an extensive range of comorbidities. Diabetic retinopathy (DR) is one the utmost severe diabetes complications as it is one of the major causes of vision loss among these patients. Our present research aims to evaluate the most frequent risk factors related to the occurrence of DR in T2DM patients. This study consisted of a research group of 302 participants, priorly diagnosed with T2DM, that were evaluated for the most important risk factors related to the occurrence of DR. Patients had a median age of 64 years, 48% of them being women, with a 12-year median duration of DM and presenting a deficient glycaemic control echoed by a median HbA1C value of 7.5%. From the total number of participants, the total prevalence of DR in different stages of severity was 34.8% with a 95% CI. Statistically significant values were found regarding DM duration (p = 0.007), HbA1c > 7.2% (p = 0.001) and patients aged over 67 years (p = 0.0035), all these parameters being directly linked to DR. Older patients with T2DM that have a longer disease duration and simultaneous comorbidities present a higher risk of DR development, consequently a stringent management of these pathologies is needed.

Artemisia vulgaris Extract as a Novel Therapeutic Approach for Reversing Diabetic Cardiomyopathy in a Rat Model.

Diabetic cardiomyopathy, a severe diabetic complication, impairs heart function, leading to heart failure. Treatment that effectively addresses this condition without causing side effects is urgently needed. Current anti-hyperglycemic therapies are expensive, has side effects and do not effectively prevent cardiac remodeling. Therefore, it is important to explore natural products that may have the potential to reverse cardiac remodeling. That is why the aim of the current study was to determine the left ventricular remodeling potential of the methanolic extract of Artemisia vulgaris in a diabetic cardiomyopathy rat model. Following the initial comprehensive phytochemical evaluation of plant phenolic and flavonoid content, which showed strong anti-hyperglycemic and antioxidant activities, an extract of Artemisia vulgaris was administered in an in vivo experiment. Diabetic cardiomyopathy was induced in Wistar albino rats according to previously described protocols in the literature, and the effect of treatment was checked by serum and histopathological analysis after 45 days. Artemisia vulgaris treatment significantly (p ≤ 0.05) reduced fasting blood glucose (108.5 ± 1.75 mg/dL), glycated hemoglobin (4.03 ± 0.12 %), serum glucose (116.66 ± 3.28 mg/dL), insulin (15.66 ± 0.66 ng/mL), total oxidant status (54.66 ± 3.22 µmol H2O2Equiv.L-1), Malondialdehyde (0.20 ± 0.01 mmol/L), total cholesterol (91.16 ± 3.35 mg/dL), triglycerides (130.66 ± 3.15 mg/dL), low-density lipids (36.57 ± 1.02 mg/dL), sodium (140 ± 3.21 mmol/L), calcium (10.44 ± 0.24 mmol/L), creatine kinase MB (1227.5 ± 17.89 IU/L), lactate dehydrogenase (1300 ± 34.64 IU/L), C-reactive protein (30 ± 0.57 pg/mL), tumor necrosis factor-α (58.66 ± 1.76 pg/mL), atrial natriuretic peptide (2.53 ± 0.04 pg/mL), B-type natriuretic peptide (10.66 ± 0.44 pg/mL), aspartate aminotransferase (86.5 ± 4.99 U/L), Alanine Transaminase (55.33 ± 2.90 U/L), urea (25.33 ± 1.15 mg/dL) and creatinine (0.64 ± 0.02 mg/dL) but significantly increased (p ≤ 0.05) total antioxidant capacity (1.73 ± 0.07 mmol Trolox Equil./L), high-density lipids (40 ± 1.59 mg/dL) and potassium (3.82 ± 0.04 mmol/L) levels. ECG and histopathology confirmed the significant improvement in remodeling and the reversal of structural changes in the heart and pancreas. In conclusion, Artemisia vulgaris possesses significant left ventricular remodeling potential in course of diabetes-induced cardiomyopathy.

Whole-exome and whole-genome sequencing of 1064 individuals with type 1 diabetes reveals novel genes for diabetic kidney disease

Aims/hypothesisDiabetic kidney disease (DKD) is a severe diabetic complication that affects one third of individuals with type 1 diabetes. Although several genes and common variants have been shown to be associated with DKD, much of the predicted inheritance remains unexplained. Here, we performed next-generation sequencing to assess whether low-frequency variants, extending to a minor allele frequency (MAF) ≤10% (single or aggregated) contribute to the missing heritability in DKD.MethodsWe performed whole-exome sequencing (WES) of 498 individuals and whole-genome sequencing (WGS) of 599 individuals with type 1 diabetes. After quality control, next-generation sequencing data were available for a total of 1064 individuals, of whom 541 had developed either severe albuminuria or end-stage kidney disease, and 523 had retained normal albumin excretion despite a long duration of type 1 diabetes. Single-variant and gene-aggregate tests for protein-altering variants (PAV) and protein-truncating variants (PTV) were performed separately for WES and WGS data and combined in a meta-analysis. We also performed genome-wide aggregate analyses on genomic windows (sliding window), promoters and enhancers using the WGS dataset.ResultsIn the single-variant meta-analysis, no variant reached genome-wide significance, but a suggestively associated common THAP7 rs369250 variant (p=1.50 × 10−5, MAF=49%) was replicated in the FinnGen general population genome-wide association study (GWAS) data for chronic kidney disease and DKD phenotypes. The gene-aggregate meta-analysis provided suggestive evidence (p<4.0 × 10−4) at four genes for DKD, of which NAT16 (MAFPAV≤10%) and LTA (also known as TNFβ, MAFPAV≤5%) are replicated in the FinnGen general population GWAS data. The LTA rs2229092 C allele was associated with significantly lower TNFR1, TNFR2 and TNFR3 serum levels in a subset of FinnDiane participants. Of the intergenic regions suggestively associated with DKD, the enhancer on chromosome 18q12.3 (p=3.94 × 10−5, MAFvariants≤5%) showed interaction with the METTL4 gene; the lead variant was replicated, and predicted to alter binding of the MafB transcription factor.Conclusions/interpretationOur sequencing-based meta-analysis revealed multiple genes, variants and regulatory regions that were suggestively associated with DKD. However, as no variant or gene reached genome-wide significance, further studies are needed to validate the findings.Graphical

Global trends in publications regarding macrophages-related diabetic foot ulcers in the last two decades.

Diabetic foot ulcers (DFUs) are one of the most severe and popular complications of diabetes. The persistent non-healing of DFUs is the leading cause of ampu-tation, which causes significant mental and financial stress to patients and their families. Macrophages are critical cells in wound healing and perform essential roles in all phases of wound healing. However, no studies have been carried out to systematically illustrate this area from a scientometric point of view. Although there have been some bibliometric studies on diabetes, reports focusing on the investigation of macrophages in DFUs are lacking. To perform a bibliometric analysis to systematically assess the current state of research on macrophage-related DFUs. The publications of macrophage-related DFUs from January 1, 2004, to December 31, 2023, were retrieved from the Web of Science Core Collection on January 9, 2024. Four different analytical tools: VOSviewer (v1.6.19), CiteSpace (v6.2.R4), HistCite (v12.03.07), and Excel 2021 were used for the scientometric research. A total of 330 articles on macrophage-related DFUs were retrieved. The most published countries, institutions, journals, and authors in this field were China, Shanghai Jiao Tong University of China, Wound Repair and Regeneration, and Aristidis Veves. Through the analysis of keyword co-occurrence networks, historical direct citation networks, thematic maps, and trend topics maps, we synthesized the prevailing research hotspots and emerging trends in this field. Our bibliometric analysis provides a comprehensive overview of macrophage-related DFUs research and insights into promising upcoming research.

Unveiling diabetic nephropathy: a novel diagnostic model through single-cell sequencing and co-expression analysis.

Diabetic nephropathy (DN) is a severe complication of diabetes that affects the kidneys. Disulfidptosis, a newly defined type of programmed cell death, has emerged as a potential area of interest, yet its significance in DN remains unexplored. This study utilized single-cell sequencing data GSE131882 from GEO database combined with bulk transcriptome sequencing data GSE30122, GSE30528 and GSE30529 to investigate disulfidptosis in DN. Single-cell sequencing analysis was performed on samples from DN patients and healthy controls, focusing on cell heterogeneity and communication. Weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA) were employed to identify disulfidptosis-related gene sets and pathways. A diagnostic model was constructed using machine learning techniques based on identified genes, and immunocorrelation analysis was conducted to explore the relationship between key genes and immune cells. PCR validation was performed on blood samples from DN patients and healthy controls. The study revealed significant disulfidptosis heterogeneity and cell communication differences in DN. Specific targets related to disulfidptosis were identified, providing insights into the pathogenesis of DN. The diagnostic model demonstrated high accuracy in distinguishing DN from healthy samples across multiple datasets. Immunocorrelation analysis highlighted the complex interactions between immune cells and key disulfidptosis-related genes. PCR validation supported the differential expression of model genes VEGFA, MAGI2, THSD7A and ANKRD28 in DN. This research advances our understanding of DN by highlighting the role of disulfidptosis and identifying potential biomarkers for early detection and personalized treatment.

Advancements, Challenges, and clinical implications of integration of metabolomics technologies in diabetic nephropathy

BackgroundDiabetic nephropathy (DN), a severe complication of diabetes, involves a range of renal abnormalities driven by metabolic derangements. Metabolomics, revealing dynamic metabolic shifts in diseases like DN and offering insights into personalized treatment strategies, emerges as a promising tool for improved diagnostics and therapies. MethodsWe conducted an extensive literature review to examine how metabolomics contributes to the study of DN and the challenges associated with its implementation in clinical practice. We identified and assessed relevant studies that utilized metabolomics methods, including nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) to assess their efficacy in diagnosing DN. ResultsMetabolomics unveils key pathways in DN progression, highlighting glucose metabolism, dyslipidemia, and mitochondrial dysfunction. Biomarkers like glycated albumin and free fatty acids offer insights into DN nuances, guiding potential treatments. Metabolomics detects small-molecule metabolites, revealing disease-specific patterns for personalized care. ConclusionMetabolomics offers valuable insights into the molecular mechanisms underlying DN progression and holds promise for personalized medicine approaches. Further research in this field is warranted to elucidate additional metabolic pathways and identify novel biomarkers for early detection and targeted therapeutic interventions in DN.