Severe Microvascular Complications Research Articles

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.

Management of Microcomplications of Diabetes Mellitus: Challenges, Current Trends, and Future Perspectives in Treatment

Diabetes mellitus is a chronic metabolic disorder characterized by high blood sugar levels, which can lead to severe health issues if not managed effectively. Recent statistics indicate a significant global impact, with 463 million adults diagnosed worldwide and this projected to rise to 700 million by 2045. Type 1 diabetes is an autoimmune disorder where the immune system attacks pancreatic beta cells, reducing insulin production. Type 2 diabetes is primarily due to insulin resistance. Both types of diabetes are linked to severe microvascular and macrovascular complications if unmanaged. Microvascular complications, such as diabetic retinopathy, nephropathy, and neuropathy, result from damage to small blood vessels and can lead to organ and tissue dysfunction. Chronic hyperglycemia plays a central role in the onset of these complications, with prolonged high blood sugar levels causing extensive vascular damage. The emerging treatments and current research focus on various aspects, from insulin resistance to the intricate cellular damage induced by glucose toxicity. Understanding and intervening in these pathways are critical for developing effective treatments and managing diabetes long term. Furthermore, ongoing health initiatives, such as increasing awareness, encouraging early detection, and improving treatments, are in place to manage diabetes globally and mitigate its impact on health and society. These initiatives are a testament to the collective effort to combat this global health challenge.

Protective Effects of Bioactive Compound-Derived Nanoparticle Against Diabetic Retinopathy Through the Modulation of the NF-κB Signaling Pathway.

Diabetic retinopathy is a prevalent and severe microvascular complication of diabetes, often causing visual impairment and blindness in adults. This condition significantly impacts the quality of life for many diabetes patients worldwide. Berberine (BBR), a bioactive compound known for its effects on blood glucose levels, has shown promise in managing diabetic complications. However, the exact mechanism of how BBR influences the development of diabetic retinopathy remains unclear. In this study, we focused on synthesizing a formulation derived from BBR and assessing its protective effects against diabetic retinopathy. The formulation was created using a green synthesis method and thoroughly characterized. In vitro studies demonstrated the antioxidant activity of the formulation against 2,2-diphenyl-1-picryl-hydrazyl-hydrate. We also examined the NF-κB signaling pathway at a molecular level using real-time polymerase chain reaction. To mimic diabetic retinopathy in a controlled setting, a diabetic rat model was established through streptozotocin injection. The rats were divided into normal, diabetic, and treatment groups. The treatment group received the formulated treatment via intragastric administration for several weeks, while the other groups received normal saline. Evaluation of histopathological characteristics and microstructural changes in the retina using hematoxylin and eosin staining revealed that the bioactive compound-derived nanoparticle exhibited favorable biological, chemical, and physical properties. Treatment with the formulation effectively reduced oxidative stress induced by diabetes and inhibited the NF-κB signaling pathway in the diabetic rat model. Under high glucose conditions, oxidative stress was heightened, leading to mitochondria-dependent cell apoptosis in Müller cells via the activation of the NF-κB signaling pathway. The bioactive compound-derived formulation counteracted these effects by decreasing IκB phosphorylation, preventing NF-κB nuclear translocation, and deactivating the NF-κB signaling pathway. Furthermore, treatment with the bioactive compound-derived formulation mitigated retinal micro- and ultrastructural changes associated with diabetic retinopathy. These results indicate that the formulation protects against diabetic retinopathy by suppressing oxidative stress, reducing cell apoptosis, and deactivating the NF-κB signaling pathway. This suggests that the bioactive compound-derived formulation could be a promising therapeutic option for diabetic retinopathy.

Systemic administration of miR-451 improves autophagy response in an accelerated mouse model of diabetic kidney disease

Diabetic kidney disease (DKD) is a common and severe microvascular complication of both type 1 and type 2 diabetes mellitus. It is the most common cause of end stage renal disease in the United States. Autophagy is a highly conserved pathway that recycles damaged organelles and macromolecules to maintain intracellular homeostasis. There is mounting evidence highlighting the role of autophagy in diabetic kidney disease. MicroRNAs (miRNA) affect the transcription of several genes involved in the development and progression of DKD, regulating key pathways and processes, including fibrotic signaling and autophagy. Thus, the dysregulation of miRs exacerbates kidney injury in the diabetic setting. Previous work from our group suggests that chronic systemic inhibition of miR-451 exacerbates fibrosis in the kidney of an obese insulin resistant mouse model (tallyHo/Jng), indicating a potential renoprotective role for miR-451 in the diabetic kidney. However, few studies have investigated this protective role of miR-451 in the diabetic kidney. This study aimed to understand the renoprotective effects of miR-451 in an accelerated mouse model of DKD. BTBR ob/ob mice rapidly develop morphological renal lesions characteristic of both early and advanced human DKD, with proteinuria typically beginning at 4-weeks of age. 12-week old male black and tan, brachyuric (BTBR) ob/ob mice and BTBR wild-type mice were treated with commercially available miR-451 mimics (2mg/kg/bw; n=3/treatment group; treatment groups: WT, BTBR ob/ob, WT+miR-451, and BTBR ob/ob+miR-451) 1X per week for 3-consective weeks. Spot urine was collected weekly until the end of study. Random blood glucose was measured by tail prick weekly. Mice were humanely euthanized, and kidneys and blood harvested at the end of the treatment period. Western blotting of whole kidney homogenate was performed following a standard protocol. Data was analyzed using students t-test or ANOVA, where appropriate, p<0.05 considered significant. Albumin: creatinine ratio was four times higher (p=0.01) in BTBR ob/ob mice beginning at 5 weeks. Treatment with miR-451 mimics had no significant effect on body weight in either group. Blood glucose was significantly higher in miR-451 treated and untreated BTBR ob/ob mice at 12-weeks (425± 33.1 mg/dL; p=0.04) and 13-weeks (383± 25.3 mg/dL; p=0.007). However, blood glucose decreased significantly from week 13 (554.7± 10.8 mg/dL) to week 14(289± 13.3 mg/dL; p=0.0002) in BTBR ob/ob miR-451 treated mice. Western blot analysis of MiR-451 mimic treated BTBR ob/ob and WT mice whole kidney homogenate revealed a 91% (p=0.02) and 95% (p=0.01) reduction, respectively, in YWHAZ (a predicted miR-451 target). Conversely, western blot analysis of autophagy related proteins revealed a 68% (p=0.01) increase in ATG101 and a 44% increase in Beclin-1 in miR-451 mimic treated BTBR ob/ob mice. Collectively, the findings of this study suggest that miR-451 may offer protection in the diabetic kidney via autophagic signaling and improved blood glucose control. GHUCCTS KL2 Scholar Program (Award Number: KL2TR001432) The Charles and Mary Latham Fund Howard University Department of Medicine Start-Up Funds; Howard University Bridge Fund and Pilot Study Awards. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Advances in Research Related to MicroRNA for Diabetic Retinopathy.

Diabetic retinopathy (DR) is a severe microvascular complication of diabetes and is one of the primary causes of blindness in the working-age population in Europe and the United States. At present, no cure is available for DR, but early detection and timely intervention can prevent the rapid progression of the disease. Several treatments for DR are known, primarily ophthalmic treatment based on glycemia, blood pressure, and lipid control, which includes laser photocoagulation, glucocorticoids, vitrectomy, and antivascular endothelial growth factor (anti-VEGF) medications. Despite the clinical efficacy of the aforementioned therapies, none of them can entirely shorten the clinical course of DR or reverse retinopathy. MicroRNAs (miRNAs) are vital regulators of gene expression and participate in cell growth, differentiation, development, and apoptosis. MicroRNAs have been shown to play a significant role in DR, particularly in the molecular mechanisms of inflammation, oxidative stress, and neurodegeneration. The aim of this review is to systematically summarize the signaling pathways and molecular mechanisms of miRNAs involved in the occurrence and development of DR, mainly from the pathogenesis of oxidative stress, inflammation, and neovascularization. Meanwhile, this article also discusses the research progress and application of miRNA-specific therapies for DR.

Association between Lipoprotein(a) and diabetic nephropathy in patients with type 2 diabetes.

Diabetic nephropathy (DN) is one of the most prevalent and severe microvascular complications of type 2 diabetes (T2DM). However, little is currently known about the pathogenesis and its associated risk factors in DN. The present study aims to investigate the potential risk factors of DN in patients with T2DM. A total of 6,993 T2DM patients, including 5,089 participants with DN and 1,904 without DN, were included in this cross-sectional study. Comparisons between the two groups (DN vs. non-DN) were carried out using Student's t-test, Mann-Whitney U-test, or Pearson's Chi-squared test. Spearman's correlation analyses were performed to assess the correlations of serum lipids and indicators of renal impairment. Logistic regression models were applied to assess the relationship between blood lipid indices and the presence of DN. T2DM patients with DN were older, and had a longer duration of diagnosed diabetes compared to those without DN. Of note, the DN patients also more likely develop metabolic disorders. Among all serum lipids, Lipoprotein(a) [Lp(a)] was the most significantly correlated indicators of renal impairment. Moreover, univariate logistic regression showed that elevated Lp(a) level was associated with an increased risk of DN. After adjusted for confounding factors, including age, gender, duration of T2DM, BMI, SBP, DBP and lipid-lowering drugs usage, Lp(a) level was independently positively associated with the risk of DN [odds ratio (OR):1.115, 95% confidence interval (CI): 1.079-1.151, P=6.06×10-11]. Overall, we demonstrated that serum Lp(a) level was significantly positively associated with an increased risk of DN, indicating that Lp(a) may have the potential as a promising target for the diagnosis and treatment of diabetic nephropathy.

Cell and molecular targeted therapies for diabetic retinopathy.

Diabetic retinopathy (DR) stands as a prevalent complication in the eye resulting from diabetes mellitus, predominantly associated with high blood sugar levels and hypertension as individuals age. DR is a severe microvascular complication of both type I and type II diabetes mellitus and the leading cause of vision impairment. The critical approach to combatting and halting the advancement of DR lies in effectively managing blood glucose and blood pressure levels in diabetic patients; however, this is seldom achieved. Both human and animal studies have revealed the intricate nature of this condition involving various cell types and molecules. Aside from photocoagulation, the sole therapy targeting VEGF molecules in the retina to prevent abnormal blood vessel growth is intravitreal anti-VEGF therapy. However, a substantial portion of cases, approximately 30-40%, do not respond to this treatment. This review explores distinctive pathophysiological phenomena of DR and identifiable cell types and molecules that could be targeted to mitigate the chronic changes occurring in the retina due to diabetes mellitus. Addressing the significant research gap in this domain is imperative to broaden the treatment options available for managing DR effectively.

Colquhounia root tablet improves diabetic kidney disease by regulating epithelial-mesenchymal transition via the PTEN/PI3K/AKT pathway.

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes mellitus that can lead to end-stage renal disease. Colquhounia root tablet (CRT) has shown therapeutic potential in treating DKD, but its efficacy and underlying mechanisms remain to be elucidated. A randomized controlled clinical trial was conducted on 61 DKD patients. The treatment group received CRT in addition to standard therapy, while the control group received standard therapy alone. Treatment efficacy and adverse events were evaluated after 3months. Additionally, in vitro experiments using human renal tubular epithelial cells (HK-2) were performed to investigate the effect of CRT on high glucose (HG)-induced epithelial-mesenchymal transition (EMT) and the involvement of the PTEN/PI3K/AKT signaling pathway. CRT treatment significantly improved proteinuria and increased the effective treatment rate in DKD patients compared to the control group, with no significant difference in adverse events. Moreover, CRT reversed HG-induced EMT in HK-2 cells, as evidenced by the downregulation of α-SMA and upregulation of E-cadherin at both mRNA and protein levels. Mechanistically, CRT increased PTEN expression and inhibited the PI3K/AKT pathway, similar to the effects of the PI3K inhibitor LY29400. The combination of CRT and LY29400 further enhanced PTEN mRNA expression under HG conditions. CRT effectively improves proteinuria in DKD patients and ameliorates HG-induced EMT in HK-2 cells. The underlying mechanism may involve the upregulation of PTEN and subsequent inhibition of the PI3K/AKT signaling pathway. These findings provide new insights into the therapeutic potential of CRT for DKD treatment.

To study the role of hematological biomarkers in type 2 diabetes patients with diabetic retinopathy

Abstract Background: Diabetic retinopathy (DR) is the most common and severe microvascular complication of diabetes mellitus (DM). It is the leading cause of irreversible blindness, and the prevalence is expected to double by 2030. Aim of this study was to compare the hematological biomarkers in diabetics with and without retinopathy. And also, as the grade of retinopathy increased. Methods: The study comprised three groups: DR (n = 66), NDR (n = 33), and controls (n = 33). Detailed workup included HbA1c levels, platelet indices (mean platelet volume (MPV), platelet distribution width (PDW), platelet count, and plateletcrit. Results: The mean age was 54 years. The mean duration of DM was 10 and 4 years in the DR and NDR groups, respectively. MPV values were significantly higher in the DR group (10.77 ± 1.2) than NDR (9.2 ± 1.1) and least in controls (8.3 ± 0.89) (P = 0.00). These values increased significantly with increasing severity of retinopathy (P = 0.04). There was a 6.13 times increased risk of developing diabetic retinopathy with increased mean platelet volume (MPV). Mean PDW was significantly higher in the DR group (19.22 ± 2.5) than NDR (13.89 ± 2.9) and least in controls (11.3 ± 2.5) (P = 0.00). These values increased significantly with increasing severity of retinopathy (P = 0.00). Other markers were not significant. Conclusion: MPV and PDW are important biomarkers which can predict the development and severity of retinopathy. Therefore, it is suggested that platelet indices be routinely done in diabetic workup. Furthermore, these are conveniently obtained from automated cell counters.

Роль самоконтроля гликемии у подростков с сахарным диабетом 1-го типа: клинический разбор

Type 1 diabetes mellitus (dm) is a disease characterized by chronic hyperglycemia and the development and progression of severe microvascular complications. The results of the AdVAnce, Accord and VAdT large-scale research studies have definitely proved that glycemic control plays a role in prevention of the dm microvascular complications. A number of studies have shown that glycemic variability parameters play a separate role in prediction of diabetic retinopathy, nephropathy and cardiovascular complications. Adolescents with type 1 dm are characterized by the labile disease course and the tendency to develop hypoglycemia and ketoacidosis. modern approach to type 1 dm management, especially in adolescents, includes the need for mandatory self-monitoring of blood glucose (BG). Adolescents with type 1 dm are unable to achieve target glucose levels themselves at home without BG monitoring. Glycemic control in type 1 dm should be accurate, simple and convenient, allowing patients to adjust insulin therapy for dm on their own. Selection of BG monitor is one of the main aspects of self-monitoring of BG. From the doctor's point of view, compliance with accuracy standards is the most important criterion for choosing the glucose meter, while from the patient’s perspective it is convenience and ease of use. With improvements in technology, the accuracy of BG measurement increases, the self-monitoring of BG procedure gets simpler, which results in higher adherence to treatment and treatment efficacy. It is impossible to achieve and maintain target BG levels without active full-fledged participation of patient with type 1 dm, self-monitoring of BG using the advanced, accurate and convenient for patient glucose meter, such as contour Plus one.

Identification of necroptosis-related features in diabetic nephropathy and analysis of their immune microenvironent and inflammatory response.

Background: Diabetic nephropathy (DN) was considered a severe microvascular complication of diabetes, which was recognized as the second leading cause of end-stage renal diseases. Therefore, identifying several effective biomarkers and models to diagnosis and subtype DN is imminent. Necroptosis, a distinct form of programmed cell death, has been established to play a critical role in various inflammatory diseases. Herein, we described the novel landscape of necroptosis in DN and exploit a powerful necroptosis-mediated model for the diagnosis of DN. Methods: We obtained three datasets (GSE96804, GSE30122, and GSE30528) from the Gene Expression Omnibus (GEO) database and necroptosis-related genes (NRGs) from the GeneCards website. Via differential expression analysis and machine learning, significant NRGs were identified. And different necroptosis-related DN subtypes were divided using consensus cluster analysis. The principal component analysis (PCA) algorithm was utilized to calculate the necroptosis score. Finally, the logistic multivariate analysis were performed to construct the necroptosis-mediated diagnostic model for DN. Results: According to several public transcriptomic datasets in GEO, we obtained eight significant necroptosis-related regulators in the occurrence and progress of DN, including CFLAR, FMR1, GSDMD, IKBKB, MAP3K7, NFKBIA, PTGES3, and SFTPA1 via diversified machine learning methods. Subsequently, employing consensus cluster analysis and PCA algorithm, the DN samples in our training set were stratified into two diverse necroptosis-related subtypes based on our eight regulators' expression levels. These subtypes exhibited varying necroptosis scores. Then, we used various functional enrichment analysis and immune infiltration analysis to explore the biological background, immune landscape and inflammatory status of the above subtypes. Finally, a necroptosis-mediated diagnostic model was exploited based on the two subtypes and validated in several external verification datasets. Moreover, the expression level of our eight regulators were verified in the singe-cell level and glomerulus samples. And we further explored the relationship between the expression of eight regulators and the kidney function of DN. Conclusion: In summary, our necroptosis scoring model and necroptosis-mediated diagnostic model fill in the blank of the relationship between necroptosis and DN in the field of bioinformatics, which may provide novel diagnostic insights and therapy strategies for DN.

Tiliroside from Potentilla chinensis attenuates oxidative stress and accumulation of ECM in mesangial cells under high glucose via activating Nrf2

Diabetic nephropathy (DN) is one of the severe microvascular complications of diabetes mellitus and it was proved activation of nuclear factor erythroid 2-related factor 2 (Nrf2) could attenuate DN. To find Nrf2 activators, we explored tiliroside identified from Potentilla chinensis using mesangial cells under high glucose. The results showed tiliroside ameliorated oxidative stress via reducing the overproduction of ROS and MDA as well as enhancing the decreased activity of superoxide dismutase, catalase, and glutathione peroxidase. Meanwhile, tiliroside attenuated the accumulation of extracellular matrix (ECM) including collagen IV, laminin and fibronectin resulting from high glucose through down-regulating transforming growth factor β1 and connective tissue growth factor. Further investigations revealed activation of Nrf2 by tiliroside was involved in the effects against oxidative stress and accumulation of ECM, and the activation of Nrf2 was dependent on the interaction between Kelch-like ECH-associated protein-1 (Keap1) and tiliroside to disrupt the Keap1-Nrf2 complex.

Research progress on extracellular vesicles in the renal tubular injury of diabetic kidney disease.

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes and is a chronic progressive condition. It is also a common cause of end-stage renal disease (ESRD), which is characterized by proteinuria or a progressive decline in the glomerular filtration rate. Due to their dependence on high-energy and aerobic metabolism, renal tubules are more susceptible to the metabolic disturbances associated with DKD, leading to inflammation and fibrosis. Consequently, tubular injury has become a recent research focus, and significant advancements have been made in studying the role of extracellular vesicles in DKD-associated tubular injury. This review aimed to elucidate the mechanisms and potential applications of different types of extracellular vesicles in tubular injury in DKD to provide new insights for the prevention and treatment of DKD.

Determinants and Stratification of Microvascular Complications of Type 2 Diabetes Mellitus.

Background Diabetes mellitus (DM) is a prevalent metabolic disorder characterized by high blood sugar levels. It is classified into type 1 (T1DM) and type 2 (T2DM), which have different mechanisms and complications. The global prevalence of diabetes, particularly T2DM, has increased significantly in recent decades, leading to a need for standardized data collection of macrovascular and microvascular complications to track disease progression and guide treatment options. This study aims to assess and correlate the prevalence and severity of microvascular complications in patients with T2DM. Methodology This observational, cross-sectional study was conducted at Poonam Multispeciality Hospital in Ahmedabad, India. A total of 4,123 diabetic patients admitted to the hospital were included. Information on sociodemographics and medical history was collected using standardized forms. Fundus photography and fluorescein angiography were performed to assess diabetic retinopathy, and estimated glomerular filtration rate and albumin-to-creatinine ratio were measured to evaluate renal function. Neurological examinations were conducted to score diabetic neuropathy. Chi-square tests were used to determine associations between medical history with diabetic retinopathy and nephropathy, and t-tests were used to compare diabetic neuropathy scores. Kendall's Tau correlation was used to determine correlations between diabetic retinopathy and nephropathy. P-values <0.05 were considered statistically significant. Results The overall prevalence of diabetic retinopathy, nephropathy, and neuropathy was 37.5%. Of the patients included, 47.9% had diabetic nephropathy and 28.9% had diabetic neuropathy. A significant association was observed between the severity of diabetic retinopathy and age, body mass index, duration of diabetes, and hemoglobin A1c (HbA1C) levels. Similarly, significant associations were found between these factors and the severity of diabetic nephropathy. Unpaired t-tests revealed significant differences in diabetic neuropathy examination scores based on the duration of diabetes and Hba1C levels. Moreover, correlation analysis indicated a low, positive correlation between diabetic retinopathy and diabetic nephropathy. Conclusions This study provides insights into the prevalence, severity, and associations of microvascular complications in patients with T2DM, contributing to the understanding and management of these conditions. Additionally, the research revealed a direct association between diabetic retinopathy and different stages of chronic kidney disease determined by the Kidney Disease Improving Global Outcome guidelines.

The roles of gut microbiota and its metabolites in diabetic nephropathy.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes, which increases the risk of renal failure and causes a high global disease burden. Due to the lack of sustainable treatment, DN has become the primary cause of end-stage renal disease worldwide. Gut microbiota and its metabolites exert critical regulatory functions in maintaining host health and are associated with many pathogenesis of aging-related chronic diseases. Currently, the theory gut-kidney axis has opened a novel angle to understand the relationship between gut microbiota and multiple kidney diseases. In recent years, accumulating evidence has revealed that the gut microbiota and their metabolites play an essential role in the pathophysiologic processes of DN through the gut-kidney axis. In this review, we summarize the current investigations of gut microbiota and microbial metabolites involvement in the progression of DN, and further discuss the potential gut microbiota-targeted therapeutic approaches for DN.

855-P: Evolution of KT-A112, an AAV-Mediated Gene Therapy for the Treatment of Type 1 Diabetes

Type 1 Diabetes (T1D) is a chronic, life-threatening autoimmune disorder characterized by profound insulin deficiency that results from progressive destruction of insulin-producing pancreatic β-cells. For over a century, exogenous insulin delivery was the only option to help T1D patients manage persistent hyperglycemia and reduce the risk of severe microvascular and macrovascular complications. Recent exploratory treatments use complex cell-based therapies requiring long-term immunosuppression. This abstract describes a unique AAV-mediated gene therapy approach to drive skeletal muscle expression of human glucokinase (GcK) and human insulin (INS). One-time IM administration to the quadriceps, gastrocnemius and tibialis anterior muscles of STZ-induced diabetic mice resulted in dose-related increases of pharmacologically active INS at fasting levels (~1 ng/mL) and human C-peptide that decreased fed and fasted blood glucose, lowered HbA1c by &amp;gt;5% at the highest dose, and reduced AUCGlu upon oral glucose challenge. Elevated triglycerides seen in control STZ-treated animals were normalized. No hypoglycemia or other adverse effects were observed through 8 weeks. No immunosuppression was required. Next steps in evaluation of KT-A112 involve a rolling dose-escalation study in STZ-treated NHPs. Disclosure C.Smith: Consultant; Horizon Therapeutics plc, Employee; Kriya Therapeutics. F.Bosch: None. M.Rhodes: None. W.W.Harrington: Consultant; Kriya Therapeutics. M.Stone: None. U.Karadge: None. J.Liu: None. W.J.Quinn: Employee; Kriya Therapeutics. A.Bassiri: None. J.Mallory: Employee; Kriya Therapeutics. V.Jimenez: None.

ADAM metallopeptidase domain 10 knockdown enables podocytes to resist high glucose stimulation by inhibiting pyroptosis via MAPK pathway.

Diabetic nephropathy (DN) is a common severe microvascular complication of diabetes mellitus, and podocyte damage occurs in the early stages of DN. The urine of patients with various types of glomerular disease presents increased levels of ADAM metallopeptidase domain 10 (ADAM10). The present study aimed to explore the role of ADAM10 in podocyte damage. Therefore, the expression of ADAM10 in high glucose (HG)-stimulated podocytes was measured by reverse transcription-qPCR and western blot. Moreover, the effects of ADAM10 knockdown on podocyte inflammation and apoptosis were determined by ELISA, western blot and TUNEL assay after confirming the efficacy of cell transfection. Subsequently, the effects of ADAM10 knockdown on the MAPK pathway and pyroptosis were assessed by western blot. Through performing the aforementioned experiments, the role of the MAPK pathway in the regulatory effects of ADAM10 was then investigated by pretreating podocytes with pathway agonists. ADAM10 expression was upregulated in HG-stimulated podocytes, while ADAM10 knockdown suppressed inflammation, apoptosis and pyroptosis of HG-stimulated podocytes and inhibited the activation of the MAPK signaling pathway. However, when podocytes were pretreated with pathway agonists (LM22B-10 or p79350), the aforementioned effects of ADAM10 knockdown were suppressed. The present study demonstrated that ADAM10 knockdown suppressed the inflammation, apoptosis and pyroptosis of HG-stimulated podocytes by blocking the MAPK signaling pathway.

Youth-Onset Type 2 Diabetes: Burden of Complications and Socioeconomic Cost

With the rise in prevalence of youth-onset type 2 diabetes (T2DM), it is imperative to understand the clinical burden of the disease and the socioeconomic burden this disease imposes. We review the most recent data on youth-onset T2DM, including its pathophysiology, complications, and treatment. We also review existing data to determine the socioeconomic burden of youth-onset T2DM. The incidence of youth-onset T2DM is rising, and significantly accelerated following the COVID-19 pandemic. Youth with T2DM are more frequently from families of racial/ethnic minorities and lower socioeconomic status. Youth-onset T2DM has more rapid disease progression compared to adult-onset type 2 diabetes. It results in earlier and more severe microvascular and macrovascular complications compared to both adult-onset T2DM and youth-onset type 1 diabetes (T1DM). While there is a lack of data describing the socioeconomic cost of youth-onset T2DM, based on extrapolation from analyses of the burden of T2DM in adults and T1DM in youth, we propose that youth-onset T2DM has higher direct and indirect costs than adult-onset T2DM. Youth-onset T2DM presents a significant clinical and socioeconomic burden due to its aggressive presentation and earlier appearance of complications. Additional research is needed regarding the cost of illness in this population.

Associations between the polymorphisms of main components in PI3K/Akt pathway and risk of diabetic kidney disease: A meta-analysis.

Diabetic kidney disease (DKD) is a severe microvascular complication frequently associated with type 1 and type 2 diabetes mellitus. The objective of this work was to evaluate the relevance of PI3K/Akt pathway polymorphisms and DKD susceptibility by a meta-analysis. Case-control studies related to the relationship between PI3K/Akt pathway polymorphisms and DKD risk were searched from Pubmed, Embase, Cochrane Library, SINOMED, CNKI, and Wanfang databases. Statistical analysis and heterogeneity test were conducted by Review Manager 5.4. Totally, 52 eligible studies were enrolled, including seven single nucleotide polymorphisms (SNPs) for four genes in the PI3K/AKT pathway (GNB3: rs5443; eNOS: rs1799983, rs869109213, rs2070744; IL-6: rs1800795, rs1800796; TNFα: rs1800629). The "M" allele of eNOS rs1799983 was related to the increased risk of DKD under random effects model, especially in Asian population (Overall:M vs. W: I2 = 75%, OR=1.29, 95%CI 1.07-1.56; MM + WM vs. WW: I2 = 75%, OR=1.50, 95%CI 1.21-1.86). The "M" allele of eNOS rs869109213 was implicated with higher prevalence of DKD under random effects model, especially in Asian population (Overall:M vs. W: I2 = 63%, OR=1.43, 95%CI 1.22-1.68; MM + WM vs. WW: I2 = 50%, OR=1.36, 95%CI 1.16-1.58; MM vs. WM + WW: I2 = 59%, OR=2.20, 95%CI 1.41-3.43). The "M" allele of eNOS rs2070744 was implicated with higher prevalence of DKD under random effects model, especially in Indian population (Overall: M vs. W: I2 = 47%, OR=1.35, 95%CI 1.15-1.59; MM + WM vs. WW: I2 = 45%, OR=1.32, 95%CI 1.07-1.62; MM vs. WM + WW: I2 = 65%, OR=2.29, 95%CI 1.39-3.77). The "M" allele of IL-6 rs1800796 was predominately associated with higher DKD risks under random effects model, especially in Asian population (Overall: M versus W: I2 = 23%, OR=1.49, 95%CI 1.21-1.84; MM + WM vs. WW: I2 = 1%, OR=1.43, 95%CI 1.15-1.77; MM + WM vs. WW: I2 = 71%, OR=2.77, 95%CI 1.09-7.06). This meta-analysis indicated that polymorphisms in the PI3K/Akt pathway in eNOS rs1799983, rs869109213, rs2070744, and IL-6 rs1800796 were related to the increased risk of DKD.

A review of the hybrid description of diabetes mellitus

Elevated blood sugar levels, which are either brought on by inadequate insulin synthesis by the pancreas or byincorrect insulin usage by the body, characterize diabetes mellitus, a chronic metabolic disease. Diabetes mellituscan cause renal failure, and those with the condition are at least 10 times more likely to have to amputate a foot dueto diabetes than those without it. High blood sugar levels are thought to contribute to kidney and heart problems.A rapid rate of beta cell malfunction and sequences resulting from an absolute lack of insulin hormone secretionmay be used to describe type 1 diabetes mellitus. Type 1 diabetes mellitus often manifests itself in young patients,although it may also affect adults. Diabetic neuropathy, one of the most severe microvascular complications ofdiabetes mellitus, is characterized by a metabolic-vascular disorder that compromises the structure and functionof peripheral somatic or autonomic nerves without inducing inflammation. Dehydration brought on by osmoticdiuresis, which impacts hyperviscosity and a hypercoagulable condition, and elevated blood glucose levels aretypical symptoms of a hyperosmolar hyperglycemic state. People with type 1 diabetes are 12 times more likelythan those with type 2 diabetes to develop diabetic nephropathy.