Association of the systemic immune-inflammation index (SII) and severity of diabetic ketoacidosis in patients with type 1 diabetes mellitus: a retrospective cohort study.

Background: Diabetic ketoacidosis (DKA) is the most serious metabolic complication of type 1 diabetes mellitus (T1DM). Insulin deficiency and inflammation play a role in the pathogenesis of DKA. The authors aimed to assess the systemic immune-inflammation index (SII) as a marker of severity among T1DM patients with DKA and without infection. Methods: The authors included T1DM patients older than or equal to 12 years hospitalized because of DKA. The authors excluded patients with infection or any condition that can change SII parameters or cause metabolic acidosis. The authors compared SII, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) between severe and non-severe DKA groups. The authors also assessed the need for an ICU, length of stay, and 90-day readmission rate between the groups. Results: The study included 241 patients with a median age of 17 (14, 24) years, and 44.8% were males. More patients with severe DKA (45%) required ICU admission (P<0.001). Median SII increased with DKA severity, and the difference was significant (P=0.033). No significant difference was observed as regards median NLR or PLR (P=0.380 and 0.852, respectively). SII, but not NLR or PLR, had a significant negative correlation with PH (r=-0.197, P=0.002) and HCO3 level (r=-0.144, P=0.026). Also, being in the highest SII quartile was an independent risk factor for DKA severity (OR, 2.522; 95% CI, 1.063-6.08; P=0.037). The authors estimated an SII cut-off value of 2524.24 to predict DKA severity with high specificity. Conclusion: Elevated SII is a risk factor for DKA severity in T1DM. It is better than NLR and PLR in prognosticating DKA patients. These findings highlight the role of inflammation in DKA. SII can help as a valuable and simple tool to assess DKA severity.

The Utilization of Topical Insulin for Ocular Surface Diseases: A Narrative Review.

Various etiologies, including diabetic keratopathy (DK), dry eye disease (DED), and neurotrophic keratopathy (NK), can disrupt corneal homeostasis, exacerbating corneal epithelial defects. Topical insulin has emerged as a promising therapy for promoting corneal wound healing and addressing underlying pathologies. This review systematically evaluates the efficacy of topical insulin across different corneal disorders. A literature review was conducted across the PubMed, Google Scholar, and Scopus research databases. The search resulted in a total of 19 articles, consisting of clinical trials, retrospective studies, and case reports. In DK, topical insulin accelerates corneal wound healing post-vitreoretinal surgery with lower concentrations showing higher outcomes when compared to conventional therapy, possibly due to improved epithelial stem cell migration. In comparison, the dry-eye disease results are inconclusive regarding patient-reported outcomes and corneal staining. For NK, topical insulin accelerates corneal wound healing and restores corneal nerve sensation. Other persistent epithelial defect (PED) etiologies that have been treated with topical insulin are infection, immune-mediated, mechanical and chemical trauma, and chronic ocular surface alterations. Although individual mechanisms for the benefits of topical insulin for each of these etiologies have not been studied, the literature demonstrates that topical insulin is efficacious for PEDs regardless of etiology. Future clinical trials need to be conducted to further evaluate optimal dosing, duration, and use of topical insulin for the restoration of the corneal surface.

Exosomes derived from umbilical cord-derived mesenchymal stem cells exposed to diabetic microenvironment enhance M2 macrophage polarization and protect against diabetic nephropathy.

The role of mesenchymal-stem-cell-derived exosomes (MSCs-Exo) in the regulation of macrophage polarization has been recognized in several diseases. There is emerging evidence that MSCs-Exo partially prevent the progression of diabetic nephropathy (DN). This study aimed to investigate whether exosomes secreted by MSCs pre-treated with a diabetic environment (Exo-pre) have a more pronounced protective effect against DN by regulating the balance of macrophages. Exo-pre and Exo-Con were isolated from the culture medium of UC-MSCs pre-treated with a diabetic mimic environment and natural UC-MSCs, respectively. Exo-pre and Exo-Con were injected into the tail veins of db/db mice three times a week for 6 weeks. Serum creatinine and serum urea nitrogen levels, the urinary protein/creatinine ratio, and histological staining were used to determine renal function and morphology. Macrophage phenotypes were analyzed by immunofluorescence, western blotting, and quantitative reverse transcription polymerase chain reaction. In vitro, lipopolysaccharide-induced M1 macrophages were incubated separately with Exo-Con and Exo-pre. We performed microRNA (miRNA) sequencing to identify candidate miRNAs and predict their target genes. An miRNA inhibitor was used to confirm the role of miRNAs in macrophage modulation. Exo-pre were more potent than Exo-Con at alleviating DN. Exo-pre administration significantly reduced the number of M1 macrophages and increased the number of M2 macrophages in the kidney compared to Exo-Con administration. Parallel outcomes were observed in the co-culture experiments. Moreover, miR-486-5p was distinctly expressed in Exo-Con and Exo-pre groups, and it played an important role in macrophage polarization by targeting PIK3R1 through the PI3K/Akt pathway. Reducing miR-486-5p levels in Exo-pre abolished macrophage polarization modulation. Exo-pre administration exhibited a superior effect on DN by remodeling the macrophage balance by shuttling miR-486-5p, which targets PIK3R1.

Electrical Stimulating Redox Membrane Incorporated with PVA/Gelatin Nanofiber for Diabetic Wound Healing.

Chronic wounds adversely affect the quality of life. Although electrical stimulation has been utilized to treat chronic wounds, there are still limitations to practicing it due to the complicated power system. Herein, an electrostimulating membrane incorporated with electrospun nanofiber (M-sheet) to treat diabetic wounds is developed. Through the screen printing method, the various alternate patterns of both Zn and AgCl on a polyurethane substrate, generating redox-mediated electrical fields are introduced. The antibacterial ability of the patterned membrane against both E. coli and S. aureus is confirmed. Furthermore, the poly(vinyl alcohol) (PVA)/gelatin electrospun fiber is incorporated into the patterned membrane to enhance biocompatibility and maintain the wet condition in the wound environment. The M-sheet can improve cell proliferation and migration in vitro and has an immune regulatory effect by inducing the polarization of macrophage to the M2 phenotype. Finally, when applied to a diabetic skin wound model, the M-sheet displays an accelerated wound healing rate and enhances re-epithelialization, collagen synthesis, and angiogenesis. It suggests that the M-sheet is a simple and portable system for the spontaneous generation of electrical stimulation and has great potential to be used in the practical wound and other tissue engineering applications.

Synthesis, anti-diabetic profiling and molecular docking studies of 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones.

Aim: To synthesize novel more potent anti-diabetic agents. Methodology: A simple cost effective Hantzsch's synthetic strategy was used to synthesize 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones. Results: Fifteen new 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones were established to check their anti-diabetic potential. From alpha(α)-amylase inhibition, anti-glycation and anti-oxidant activities it is revealed that most of the compounds possess good anti-diabetic potential. All tested compounds were found to be more potent anti-diabetic agents via anti-glycation mode. The results of α-amylase and anti-oxidant inhibition revealed that compounds are less active against α-amylase and anti-oxidant assays. Conclusion: This study concludes that introduction of various electron withdrawing groups at the aryl ring and substitution of different functionalities around thiazolone nucleus could help to find out better anti-diabetic drug.

Diabetes is a most spreading chronicle disease effecting millions of peoples across the globe every year and this number increases day by day. To cure the human population from this dilemma, we had synthesized, characterized and evaluated the anti-diabetic behavior of our synthesized compounds. α-Amylase, in vitro anti-glycation and anti-oxidant assays were performed to find out good lead for Diabetes Mellitus. All tested compounds were found to be excellent anti-glycating agents with IC₅₀ values far better than standard amino-guanidine (IC₅₀ = 3.582 ± 0.002 µM). Compound 4m was most efficient glycation inhibitor (IC₅₀ = 1.095 ± 0.002 µM). Cytotoxicity of all compounds was determined with in vitro hemolytic assay and found all compounds safe and bio-compatible to humans at all tested concentrations. The inhibition potential was also examined with theoretical docking studies to support our experimental results against human pancreatic alpha-amylase (HPA) and human serum albumin (HSA) proteins. All compounds showed excellent binding affinity with HSA active pockets however, only compound 4h and 4k binding affinity was good with HPA.

Exploring the Possible Link Between Diabetic Ketoacidosis, Glucose-6-Phosphate Dehydrogenase Deficiency, and Methemoglobinemia.

One of the most widespread enzymopathies affecting human beings is glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is brought on by inherited mutations in the X-linked gene. Red blood cells (RBCs) with a G6PD deficiency are more sensitive to oxidative assault and consequently to hemolysis. There are more than 200 known G6PD mutations, of which around half are polymorphic and thus prevalent in a variety of populations. We present a case of diabetic ketoacidosis (DKA), with severe hemolytic anemia and methemoglobinemia. The patient was admitted to the intensive care unit, treated for DKA, and received a blood transfusion. In addition, the patient presented with high methemoglobin levels and features of severe hemolytic anemia from the onset, which made the diagnostic consideration of G6PD highly likely. Accordingly, the patient was treated with several doses of ascorbic acid instead of methylene blue. In a nutshell, a patient with DKA who has hemolytic anemia has to have it properly evaluated and controlled. The link between methemoglobinemia, G6PD deficiency, and DKA should be recognized by medical professionals, particularly when oxygen saturation gaps are found.

Convergence of Crisis: A Case Report of Diabetic Ketoacidosis Masking an Impending Thyroid Storm and Periodic Paralysis.

Diabetic ketoacidosis (DKA) is an extreme complication of diabetes mellitus characterized by hyperglycemia, metabolic acidosis, and ketonemia. Thyroid storm, a potentially life-threatening manifestation of thyrotoxicosis, presents with a multitude of symptoms, including hyperthermia, tachycardia, and altered mental status. Periodic paralysis can be precipitated by different metabolic disturbances, including thyrotoxicosis, and may lead to extreme episodes of muscle weakness and paralysis. We present a case of a 41-year-old female with a history of type 1 diabetes mellitus and hyperthyroidism, who presented with DKA complicated by an impending thyroid storm and likely periodic paralysis exacerbated due to hypokalemia. Prompt recognition and aggressive management of each component of this triad were essential for a positive patient outcome. This case highlights the importance of a broad and comprehensive approach to managing complex metabolic emergencies, particularly in patients with multiple comorbidities. Our patient presented to the emergency department with symptoms of severe vomiting, shortness of breath, and altered mental status. Laboratory investigations revealed metabolic derangements consistent with DKA, alongside impending thyrotoxicosis and hypokalemia-induced periodic paralysis. Management involved aggressive fluid resuscitation, insulin therapy, anti-thyroid medications, and potassium supplementation, with a multidisciplinary approach to stabilize the patient's condition.

Neutrophil-to-Lymphocyte Ratio as a Marker for Cardiac Autonomic Neuropathy in Egyptian Patients With Type 2 Diabetes: A Cross-Sectional Study.

OBJECTIVE: Cardiac autonomic neuropathy (CAN) is one of the most serious complications of diabetes. This study aimed to analyze the correlation between neutrophil-to-lymphocyte ratio (NLR) and CAN in patients with type 2 diabetes (T2D) using 24-hour Holter ECG and to assess the relationship between NLR and severity of diabetic peripheral neuropathy (DPN). SUBJECTS & METHODS:  This cross-sectional study included 90 T2D patients with DPN confirmed by nerve conduction study (NCS). A 24-hour Holter ECG was done to detect the decrease in heart rate variability (HRV). Laboratory parameters, including fasting blood glucose, creatinine, cholesterol, triglyceride, and glycosylated hemoglobin (HbA1c) levels, as well as CBC, neutrophils, lymphocytes, NLR, and platelet-to-lymphocyte ratio (PLR), were calculated accordingly. An albumin-to-creatinine ratio (ACR) test was done and the estimated glomerular filtration rate (eGFR) was calculated. Chronic kidney disease was diagnosed by the presence of albuminuria (≥30 mg/g creatinine) and/or eGFR less than 60. RESULTS: Based on the 24-hour Holter ECG, 25 patients out of 90 (27.7%) had CAN. On comparing both the CAN and non-CAN groups, the CAN group had higher HbA1C (p = 0.005), higher NLR (p = 0.014), and higher neutrophils (p = 0.10). Also, PLR was higher in the CAN group than in the non-CAN group, but this was not statistically significant (p = 0.180). Receiver operator characteristic curve analysis revealed that NLR with a cutoff of 1.7 succeeded in detecting patients with CAN. CONCLUSION: NLR can be used as an inexpensive and accessible marker to detect patients with diabetes at risk for developing CAN.

Health transition and eye care policy planning for people with diabetic retinopathy in south Asia.

The prevalence of type 2 diabetes (T2D), associated systemic disorders, diabetic retinopathy (DR) and current health policies in south Asian countries were analysed to assess country-specific preparedness to meet the 2030 Sustainable Development Goals. The south Asian countries were classified by human development index, socio-demographic index, multidimensional poverty indices, and eye health resources for epidemiological resource-level analysis. In south Asia, the prevalence of diagnosed and undiagnosed T2D in adults aged 40 years or above, was higher in Pakistan (26.3%) and Afghanistan (71.4%), respectively; India has the highest absolute number of people with DR, and Afghanistan has the highest prevalence of DR (50.6%). In this region, out-of-pocket spending is high (∼77%). This Health Policy is a situational analysis of data available on the prevalence of DR and common eye diseases in people with T2D in south Asia and available resources to suggest tailored health policies to local needs. The common issues in the region are insufficient human resources for eye health, unequal distribution of available workforce, and inadequate infrastructure. Addressing these challenges of individuals with T2D and DR, a 10-point strategy is suggested to improve infrastructure, augment human resources, reduce out-of-pocket spending, employ targeted screening, and encourage public-private partnerships.

Dysregulated Urinary Extracellular Vesicle Small RNAs in Diabetic Nephropathy: Implications for Diagnosis and Therapy.

Background: Diabetic nephropathy (DN) represents a major chronic kidney disorder and a leading cause of end-stage renal disease (ESRD). Small RNAs have been showing great promise as diagnostic markers as well as drug targets. Identifying dysregulated micro RNAs (miRNAs) could help in identifying disease biomarkers and investigation of downstream interactions, shedding light on the molecular pathophysiology of DN. In this study, we analyzed small RNAs within human urinary extracellular vesicles (ECVs) from DN patients using small RNA next-generation sequencing. Method: In this cross-sectional study, urine samples were collected from 88 participants who were divided into 3 groups: type 2 diabetes (T2D) with DN (T2D + DN, n = 20), T2D without DN (T2D - DN, n = 40), and healthy individuals (n = 28). The study focused on isolating urinary ECVs to extract and sequence small RNAs. Differentially expressed small RNAs were identified, and a functional enrichment analysis was conducted. Results: The study revealed a distinct subset of 13 miRNAs and 10 Piwi-interacting RNAs that were significantly dysregulated in urinary ECVs of the DN group when compared to other groups. Notably, miR-151a-3p and miR-182-5p exhibited a unique expression pattern, being downregulated in the T2D - DN group, and upregulated in the T2D + DN group, thus demonstrating their effectiveness in distinguishing patients between the 2 groups. Eight driver genes were identified PTEN, SMAD2, SMAD4, VEGFA, CCND2, CDK6, LIN28B, and CHD1. Conclusion: Our findings contribute valuable insights into the pathogenesis of DN, uncovering novel biomarkers and identifying potential therapeutic targets that may aid in managing and potentially decelerating the progression of the disease.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This research advances our understanding of DN by highlighting the role of disulfidptosis and identifying potential biomarkers for early detection and personalized treatment.

Risk factors for 30-day hospital readmission in patients with diabetic foot.

INTRODUCTION: Diabetic foot (DF) is part of the natural history of diabetes mellitus, ulceration being a severe complication with a prevalence of approximately 6.3 %, which confers a significant economic burden. Hospital readmission in the first thirty (30) days is considered a measure of quality of healthcare and it's been identified that the most preventable causes are the ones that occur in this period. This study seeks to identify the risk factors associated with readmission of patients with DF. METHODS: A case-control study was done by performing a secondary analysis of a database. Descriptive statistics were used for all variables of interest, bivariate analysis to identify statistically significant variables, and a logistic regression model for multivariate analysis. RESULTS: 575 cases were analyzed (113 cases, 462 controls). A 20 % incidence rate of 30-day readmission was identified. Statistically significant differences were found in relation to the institution of attention (Hospital Universitario de la Samaritana: OR 1.9, p value < 0.01, 95 % CI 1.2-3.0; Hospital Universitario San Ignacio: OR 0.5, p value < 0.01, 95 % CI 0.3-0.8) and the reasons for readmission before 30 days, especially due to surgical site infection (SSI) (OR 7.1, p value < 0.01, 95 % CI 4.1-12.4), sepsis (OR 8.4, p value 0.02, 95 % CI 1.2-94.0), dehiscence in amputation stump (OR 16.4, p value < 0.01, 95 % CI 4.2-93.1) and decompensation of other pathologies (OR 3.5, p value < 0.01, 95 % CI 2.1-5.7). CONCLUSION: The hospital readmission rate before 30 days for our population compares to current literature. Our results were consistent with exacerbation of chronic pathologies, but other relevant variables not mentioned in other studies were the hospital in which patients were taken care of, the presence of SSI, sepsis, and dehiscence of the amputation stump. We consider thoughtful and close screening of patients at risk in an outpatient setting might identify possible readmissions.

Mesenchymal stem cells ameliorate inflammation and pyroptosis in diabetic cardiomyopathy via the miRNA-223-3p/NLRP3 pathway.

BACKGROUND: Diabetic cardiomyopathy (DCM) stands as the primary cause of heart failure and mortality among patients with diabetes. Nevertheless, conventional treatment approaches are limited in their ability to effectively prevent myocardial tissue damage itself. Mesenchymal stem cell (MSC) therapy exhibits immense potential for treating DCM; however, the precise mechanisms involved in regulating inflammatory responses and pyroptosis processes, an emerging form of cellular death, within myocardial cells remain elusive. Hence, it is imperative to further elucidate the precise underlying mechanisms to facilitate the clinical implementation of MSC therapy. METHODS: In vivo, we established a DCM mouse model by administering streptozotocin and fed the mice a high-glucose and high-fat diet, followed by MSC therapy. Cardiac function and myocardial injury were evaluated through echocardiography and histological analysis. Furthermore, the levels of inflammation and pyroptosis were assessed using ELISA, Western blotting, and qRT-PCR. In vitro experiments involved inducing H9C2 myocardial cell damage with high glucose treatment, followed by coculture with MSCs to investigate their role in modulating inflammation and pyroptosis mechanisms. RESULTS: MSCs can maintain cardiac function and alleviate myocardial injury in mice with DCM. Moreover, they effectively suppress the activation of NLRP3 and reduce the release of inflammatory factors (such as IL-1ß and ROS), thereby further downregulating the expression of pyroptosis-related proteins including NLRP3, Caspase-1, and GSDMD. Additionally, we experimentally validated that MSCs exert their therapeutic effects by promoting the expression of miR-223-3p in cardiac myocytes; however, this effect can be reversed by an miR-223-3p inhibitor. CONCLUSION: MSCs effectively mitigate the release of inflammatory factors and cell lysis caused by pyroptosis through the regulation of the miR-223-3p/NLRP3 pathway, thereby safeguarding cardiomyocytes against damage in DCM. This mechanism establishes a novel theoretical foundation for the clinical treatment of cardiac conditions utilizing MSCs.

Kidney tea [Orthosiphon aristatus (Blume) Miq.] improves diabetic nephropathy via regulating gut microbiota and ferroptosis.

Introduction: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Due to its complex pathogenesis, new therapeutic agents are urgently needed. Orthosiphon aristatus (Blume) Miq., commonly known as kidney tea, is widely used in DN treatment in China. However, the mechanisms have not been fully elucidated. Methods: We used db/db mice as the DN model and evaluated the efficacy of kidney tea in DN treatment by measuring fasting blood glucose (FBG), serum inflammatory cytokines, renal injury indicators and histopathological changes. Furthermore, 16S rDNA gene sequencing, untargeted serum metabolomics, electron microscope, ELISA, qRT-PCR, and Western blotting were performed to explore the mechanisms by which kidney tea exerted therapeutic effects. Results: Twelve polyphenols were identified from kidney tea, and its extract ameliorated FBG, inflammation and renal injury in DN mice. Moreover, kidney tea reshaped the gut microbiota, reduced the abundance of Muribaculaceae, Lachnoclostridium, Prevotellaceae_UCG-001, Corynebacterium and Akkermansia, and enriched the abundance of Alloprevotella, Blautia and Lachnospiraceae_NK4A136_group. Kidney tea altered the levels of serum metabolites in pathways such as ferroptosis, arginine biosynthesis and mTOR signaling pathway. Importantly, kidney tea improved mitochondrial damage, increased SOD activity, and decreased the levels of MDA and 4-HNE in the renal tissues of DN mice. Meanwhile, this functional tea upregulated GPX4 and FTH1 expression and downregulated ACSL4 and NCOA4 expression, indicating that it could inhibit ferroptosis in the kidneys. Conclusion: Our findings imply that kidney tea can attenuate DN development by modulating gut microbiota and ferroptosis, which presents a novel scientific rationale for the clinical application of kidney tea.

Segmentation of retinal microaneurysms in fluorescein fundus angiography images by a novel three-step model.

Introduction: Microaneurysms serve as early signs of diabetic retinopathy, and their accurate detection is critical for effective treatment. Due to their low contrast and similarity to retinal vessels, distinguishing microaneurysms from background noise and retinal vessels in fluorescein fundus angiography (FFA) images poses a significant challenge. Methods: We present a model for automatic detection of microaneurysms. FFA images were pre-processed using Top-hat transformation, Gray-stretching, and Gaussian filter techniques to eliminate noise. The candidate microaneurysms were coarsely segmented using an improved matched filter algorithm. Real microaneurysms were segmented by a morphological strategy. To evaluate the segmentation performance, our proposed model was compared against other models, including Otsu's method, Region Growing, Global Threshold, Matched Filter, Fuzzy c-means, and K-means, using both self-constructed and publicly available datasets. Performance metrics such as accuracy, sensitivity, specificity, positive predictive value, and intersection-over-union were calculated. Results: The proposed model outperforms other models in terms of accuracy, sensitivity, specificity, positive predictive value, and intersection-over-union. The segmentation results obtained with our model closely align with benchmark standard. Our model demonstrates significant advantages for microaneurysm segmentation in FFA images and holds promise for clinical application in the diagnosis of diabetic retinopathy. Conclusion: The proposed model offers a robust and accurate approach to microaneurysm detection, outperforming existing methods and demonstrating potential for clinical application in the effective treatment of diabetic retinopathy.

Strategies to address diabetic kidney disease burden in Mexico: a narrative review by the Mexican College of Nephrologists.

Chronic kidney disease (CKD) is a growing global public health challenge worldwide. In Mexico, CKD prevalence is alarmingly high and remains a leading cause of morbidity and mortality. Diabetic kidney disease (DKD), a severe complication of diabetes, is a leading determinant of CKD. The escalating diabetes prevalence and the complex regional landscape in Mexico underscore the pressing need for tailored strategies to reduce the burden of CKD. This narrative review, endorsed by the Mexican College of Nephrologists, aims to provide a brief overview and specific strategies for healthcare providers regarding preventing, screening, and treating CKD in patients living with diabetes in all care settings. The key topics covered in this review include the main cardiometabolic contributors of DKD (overweight/obesity, hyperglycemia, arterial hypertension, and dyslipidemia), the identification of kidney-related damage markers, and the benefit of novel pharmacological approaches based on Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA). We also address the potential use of novel therapies based on Mineralocorticoid Receptor Antagonists (MRAs) and their future implications. Emphasizing the importance of multidisciplinary treatment, this narrative review aims to promote strategies that may be useful to alleviate the burden of DKD and its associated complications. It underscores the critical role of healthcare providers and advocates for collaborative efforts to enhance the quality of life for millions of patients affected by DKD.

Downregulation of the (pro)renin receptor alleviates ferroptosis-associated cardiac pathological changes via the NCOA 4-mediated ferritinophagy pathway in diabetic cardiomyopathy.

Ferroptosis, characterized by the accumulation of reactive oxygen species and lipid peroxidation, is involved in various cardiovascular diseases. (Pro)renin receptor (PRR) in performs as ligands in the autophagic process, and its function in diabetic cardiomyopathy (DCM) is not fully understood. We investigated whether PRR promotes ferroptosis through the nuclear receptor coactivator 4 (NCOA 4)-mediated ferritinophagy pathway and thus contributes to DCM. We first established a mouse model of DCM with downregulated and upregulated PRR expression and used a ferroptosis inhibitor. Myocardial inflammation and fibrosis levels were then measured, cardiac function and ferroptosis-related indices were assessed. In vitro, neonatal rat ventricular primary cardiomyocytes were cultured with high glucose and transfected with recombinant adenoviruses knocking down or overexpressing the PRR, along with a ferroptosis inhibitor and small interfering RNA for the ferritinophagy receptor, NCOA4. Ferroptosis levels were measured in vitro. The results showed that the knockdown of PRR not only alleviated cardiomyocyte ferroptosis in vivo but also mitigated the HG-induced ferroptosis in vitro. Moreover, administration of Fer-1 can inhibit HG-induced ferroptosis. NCOA4 knockdown blocked the effect of PRR on ferroptosis and improved cell survival. Our result indicated that inhibition of PRR and NCOA4 expression provides a new therapeutic strategy for the treatment of DCM. The effect of PRR on the pathological process of DCM in mice may be in promoting cardiomyocyte ferroptosis through the NCOA 4-mediated ferritinophagy pathway.

A cross sectional pilot study utilising STrain Analysis and Mapping of the Plantar Surface (STAMPS) to measure plantar load characteristics within a healthy population.

BACKGROUND: No in-shoe systems, measuring both components of plantar load (plantar pressure and shear stress) are available for use in patients with diabetes. The STAMPS (STrain Analysis and Mapping of the Plantar Surface) system utilises digital image correlation (DIC) to determine the strain sustained by a deformable insole, providing a more complete understanding of plantar shear load at the foot-surface interface. RESEARCH QUESTIONS: What is the normal range and pattern of strain at the foot-surface interface within a healthy population as measured by the STAMPS system? Is STAMPS a valid tool to measure the effects of plantar load? METHODS: A cross-sectional study of healthy participants was undertaken. Healthy adults without foot pathology or diabetes were included. Participants walked 20 steps with the STAMPS insole in a standardised shoe. Participants also walked 10 m with the Novel Pedar® plantar pressure measurement insole within the standardised shoe. Both measurements were repeated three times. Outcomes of interest were global and regional values for peak resultant strain (SMAG) and peak plantar pressure (PPP). RESULTS: In 18 participants, median peak SMAG and PPP were 35.01 % and 410.6kPa respectively. The regions of the hallux and heel sustained the highest SMAG (29.31 % (IQR 24.56-31.39) and 20.50 % (IQR 15.59-24.12) respectively) and PPP (344.8kPa (IQR 268.3 - 452.5) and 279.3kPa (IQR 231.3-302.1) respectively). SMAG was moderately correlated with PPP (r= 0.65, p < 0.001). Peak SMAG was located at the hallux in 55.6 % of participants, at the 1st metatarsal head (MTH) in 16.7 %, the heel in 16.7 %, toes 3-5 in 11.1 % and the MTH2 in 5.6 %. SIGNIFICANCE: The results demonstrate the STAMPS system is a valid tool to measure plantar strain. Further studies are required to investigate the effects of elevated strain and the relationship with diabetic foot ulcer formation.

The circ_0003928/miR-31-5p/MAPK6 cascade affects high glucose-induced inflammatory response, fibrosis and oxidative stress in HK-2 cells.

BACKGROUND: Diabetic nephropathy (DN) is a severe diabetic complication disorder. Circular RNAs (circRNAs) actively participate in DN pathogenesis. In this report, we sought to define a new mechanism of circ_0003928 in regulating high glucose (HG)-induced HK-2 cells. METHODS: To construct a DN cell model, we treated HK-2 cells with HG. Cell viability and apoptosis were detected by CCK-8 and flow cytometry, respectively. The inflammatory cytokines were quantified by ELISA. Protein analysis was performed by immunoblotting, and mRNA expression was detected by quantitative PCR. The circ_0003928/miR-31-5p and miR-31-5p/MAPK6 relationships were validated by RNA pull-down and luciferase assays. RESULTS: HG promoted HK-2 cell apoptosis, fibrosis and oxidative stress. Circ_0003928 and MAPK6 levels were enhanced and miR-31-5p level was decreased in HK-2 cells after HG treatment. Circ_0003928 disruption promoted cell growth and inhibited apoptosis, inflammatory response, fibrosis and oxidative stress in HG-induced HK-2 cells. Circ_0003928 targeted miR-31-5p, and MAPK6 was a target of miR-31-5p. Circ_0003928 regulated MAPK6 expression through miR-31-5p. The functions of circ_0003928 disruption in HG-induced HK-2 cells were reversed by miR-31-5p downregulation or MAPK6 upregulation. CONCLUSION: Circ_0003928 exerts regulatory impacts on HG-induced apoptosis, inflammation, fibrosis and oxidative stress in human HK-2 cells by the miR-31-5p/MAPK6 axis.

No Differences in Kidney Function Decline Between People With Type 2 Diabetes Starting a Sodium-Glucose Cotransporter 2 Inhibitor or a Glucagon-like Peptide-1 Receptor Agonist: A Real-world Retrospective Comparative Observational Study.

PURPOSE: Diabetic nephropathy represents the leading cause of end-stage kidney disease in developed countries. Cardiovascular outcome trials have found that in participants who received a glucagon-like peptide-1 receptor agonist (GLP1RA) and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), the risk of incidence and progression of diabetic nephropathy in type 2 diabetes mellitus was reduced. The aim of this study was to compare the decline in estimated glomerular filtration rate (eGFR) among people taking a GLP1RA with that among people taking an SGLT2i in a real-world setting. METHODS: Data for 478 patients with type 2 diabetes mellitus who initiated therapy with a GLP1RA (n = 254) or an SGLT2i (n = 224) between January 1, 2018 and December 31, 2021 were extracted. The primary outcome was any reduction ≥30% in eGFR after the start of therapy. Weight loss and drug discontinuation were also assessed. FINDINGS: Over a median follow-up of 24 months, an eGFR reduction ≥30% occurred in 34 of 254 patients (13.4%) starting a GLP1RA and in 26 of 223 patients (11.6%) starting an SGLT2i (hazard ratio = 0.89; 95% CI, 0.54-1.49; P = 0.67). Median eGFR change over the whole follow-up was similar between groups (SGLT2i: median, -2 mL/min/1.73 m2; 25th, 75th percentile, -13, 8 mL/min/1.73 m2; GLP1RA: median, 0 mL/min/1.73 m2; 25th, 75th percentile, -10, 7 mL/min/1.73 m2; P = 0.54). No worsening of kidney function was observed, even when considering the ratio eGFR mean. The value of eGFR at baseline indicated a statistically significant indirect correlation with the observed absolute value of eGFR change over the follow-up (ρ = -0.36; P < 0.001). The difference in eGFR changes over time observed by eGFR categories was statistically significant (P = 0.0001) in both treatment groups. No significant differences in weight loss and drug discontinuations were observed between groups. IMPLICATIONS: Although acting on different molecular mechanisms, both GLP1RA and SGLT2i might have similar effects on eGFR decline in diabetes, as suggested by the results of the present study conducted in a real-world setting. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.