Diabetic Vascular Complications Research Articles

A new mechanism of arterial calcification in diabetes: interaction between H3K18 lactylation and CHI3L1.

Metabolic changes are an important characteristic of vascular complications in diabetes. The accumulation of lactate in the microenvironment can promote VSMC calcification in diabetes, although the specific mechanism remains to be fully elucidated. In this study, we explored the characteristics of lactylation in diabetic arterial calcification and the underlying molecular mechanism. We found that in high-glucose calcified VSMC, the overall lactylationlevel was significantly increased. Mass spectrometry analysis revealed significant upregulation of H3 histone lactylation. After site-specific point-mutation at K18 to simulate the delactylation modification, VSMC calcification was significantly reduced. Through a combination of H3K18la ChIP-seq, RNA-seq, H3K18la ChIP-qPCR and point-mutation experiments, we confirmed that H3K18la can upregulate CHI3L1. CHI3L1 knockout significantly alleviated VSMC osteogenic phenotype transformation and mouse arterial calcification. RNA-seq analysis of the downstream molecular signaling showed that CHI3L1 activates the IL-13-IL-13Ra2-JAK1-STAT3 pathway. Targeted inhibition of IL-13Ra2 reduced VSMC calcification. We conclude that in a diabetic calcification environment, the H3 histone K18 site undergoes lactylation modification in VSMCs, upregulating CHI3L1, which in turn regulates the IL-13-IL-13Ra2-JAK1-STAT3 signaling pathway, ultimately exacerbating arterial calcification. Our study elucidates the epigenetic mechanism by which lactate promotes arterial calcification in diabetes.

Gut Microbiota and Their Metabolites as Modulators of Vascular Complications in Diabetes

Review Gut Microbiota and Their Metabolites as Modulators of Vascular Complications in Diabetes Meng Duan 1,2,3,†, Jielu Wen 1,2,†, Anning Chen 1,2,† and Sifan Chen 1,2,* 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510000, China 2 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, China 3 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510000, China * Correspondence: chensf26@mail.sysu.edu.cn † These authors contributed equally to this work. Received: 8 November 2024; Revised: 29 November 2024; Accepted: 24 December 2024; Published: 7 January 2025 Abstract: With the global rise in population and aging, along with the increasing burden of overweight and obesity, the prevalence of diabetes is expected to surge dramatically. Microvascular and macrovascular complications are the leading causes of death among patients with type 2 diabetes. Recent advancements have provided evidence suggesting that gut microbiota directly or indirectly regulate vascular function. This review focuses on the complex interactions between gut microbiota and its metabolites and vascular complications of diabetes. In particular, we highlight the novel therapeutic effects of interventions such as probiotics, dietary modifications, and fecal microbiota transplantation in improving gut microbiota composition and reducing the risk of vascular complications in diabetes. These findings not only provide new insights into the pathological mechanisms of diabetic vascular complications but also reveal ideas for guiding the formulation of future treatment strategies.

The Putative Antidiabetic Effect of Hypericum perforatum on Diabetes Mellitus.

Diabetes mellitus (DM), a global disease that significantly impacts public health, has become increasingly common over time. In this review, we aim to determine the potential benefits of St. John's Wort (SJW) as an adjunct therapy for DM. We gathered information from studies conducted in vitro, in vivo, and in humans. In vitro studies investigated the concentrations of SJW extracts capable of inhibiting certain enzymes or factors involved in the inflammatory pathway, such as the β-signal transducer and activator of transcription 1, nuclear factor κB, methylglyoxal, and oxidative stress (OS). The extract was found to have positive effects on OS and anti-inflammatory properties in DM, suggesting it could serve as a protective agent against diabetic vascular complications, cell damage, and apoptosis. According to in vivo research, the essential components of the extract can stimulate thermogenesis in adipose tissue, inhibit several key inflammatory signaling pathways, and delay the early death of pancreatic β cells, all of which contribute to combating obesity. The extract may also help treat prediabetes and significantly reduce neuropathic pain. Human studies have also confirmed some of these results. However, some of the plant's side effects need further investigation through clinical research before it can be used to treat DM.

Aberrant STING activation promotes macrophage senescence by suppressing autophagy in vascular aging from diabetes.

Diabetic vascular aging is driven by macrophage senescence, which propagates senescence-associated secretory phenotypes (SASP), exacerbating vascular dysfunction. This study utilized a type 2 diabetes mellitus (T2DM) mouse model induced by streptozotocin injection and a high-fat diet to investigate the role of STING in macrophage senescence. Vascular aging markers and senescent macrophages were assessed invivo, while invitro, high glucose treatment induced macrophage senescence, enhancing senescence in co-cultured vascular smooth muscle cells. Mechanistic studies revealed that STING activation inhibits autophagy by phosphorylating ULK1 at S757, accelerating senescence. Pharmacological modulation showed that the STING inhibitor H-151 alleviates, while the agonist DMXAA enhances, senescence. These findings highlight the STING-autophagy axis as a critical driver of macrophage senescence, offering insights into the molecular mechanisms of diabetic vascular aging and identifying potential therapeutic targets to mitigate vascular complications in diabetes.

Danggui Liuhuang Decoction Ameliorates Endothelial Dysfunction by Inhibiting the JAK2/STAT3 Mediated Inflammation

Ethnopharmacological relevanceVascular endothelial dysfunction (VED) is recognized as a key triggering diabetic vascular complications. Danggui Liuhuang Decoction (DGLHD) has shown potential in mitigating these complications. However, the clinical efficacy of DGLHD in enhancing endothelial function, as well as the molecular mechanisms underlying its alleviation of Type 2 Diabetes-Related Vascular Endothelial Dysfunction (T2DM-VED), remains insufficiently understood. Aim of the studyThis study aims to validate the therapeutic efficacy of DGLHD in ameliorating T2DM-VED through clinical research. Furthermore it seeks to analyze the pharmacodynamic basis and molecular mechanisms of DGLHD, elucidating the biological processes through which DGLHD alleviates VED in type 2 diabetes mellitus (T2DM). Materials and methodsPatients diagnosed with "Yin deficiency with hyperactive fire syndrome", who are at a high risk for atherosclerotic cardiovascular disease (ASCVD) associated with T2DM, were recruited for this study. The effect of DGLHD on vascular endothelial function in T2DM was assessed by measuring the levels of pro-inflammatory factors through enzyme-linked immunosorbent assay (ELISA) and flow-mediated dilation (FMD). The primary components of DGLHD were analyzed using the UHPLC-Q-Exactive Orbitrap system. Potential therapeutic targets of DGLHD were predicted using network pharmacology and molecular docking analysis. To validate the mechanism of DGLHD on T2DM-VED, endothelial injury and inflammation cell models were established using human umbilical vein endothelial cells (HUVECs). A mouse model of diabetic endothelial injury was also developed to observe the effects of DGLHD on pro-inflammatory factors and vascular endothelial factors were observed through immunohistochemistry. Additionally, the effects on the JAK2/STAT3 signaling pathway were observed through Western blot experiments. ResultsDGLHD was found to contain 201 active components. Network pharmacology analysis indicated that the treatment of T2DM-VED with DGLHD is associated with modulation of the JAK2/STAT3 signaling pathway. Molecular docking analysis demonstrated that small molecules in DGLHD interact with JAK2 and STAT3. Our clinical study demonstrated that DGLHD significantly reduces the levels of pro-inflammatory factors and improves FMD readings in diabetic patients, thereby alleviating T2DM-VED. DGLHD was shown to inhibit the phosphorylation of JAK2 and STAT3, which blocks the JAK2/STAT3 signaling pathway transmission, reducing the release of pro-inflammatory and vascular endothelial growth factors, and preventing the inflammatory response in vivo and in vitro. ConclusionThis study demonstrates the potential efficacy of DGLHD in improving endothelial function in T2DM patients at high risk for ASCVD. By inhibiting the JAK2/STAT3 signaling pathway, DGLHD effectively reduces the release of pro-inflammatory factors and vascular endothelial growth factors, alleviating VED.

N 6-Methyladenosine Demethylase FTO Controls Macrophage Homeostasis in Diabetic Vasculopathy.

Diabetic vasculopathy, encompassing complications such as diabetic retinopathy, represents a significant source of morbidity, with inflammation playing a pivotal role in the progression of these complications. This study investigates the influence of m6A modification and the m6A demethylase FTO on macrophage polarization and its subsequent effects on diabetic microvasculopathy. We found that diabetes induces a shift in macrophage polarization towards a pro-inflammatory M1 phenotype, which is associated with a reduction in m6A modification levels. Notably, FTO emerges as a critical regulator of m6A under diabetic conditions. In vitro experiments reveal that FTO not only modulates macrophage polarization but also mediates their interactions with vascular endothelial cells. In vivo experiments demonstrate that FTO deficiency exacerbates retinal inflammation and microvascular dysfunction in diabetic retinas. Mechanistically, FTO stabilizes mRNA through an m6A-YTHDF2-dependent pathway, thereby activating the PI3K/AKT signaling cascade. Collectively, these findings position FTO as a promising therapeutic target for the management of diabetic vascular complications.

The Pathophysiology and Vascular Complications of Diabetes in Chronic Kidney Disease: A Comprehensive Review.

The coexistence of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) represents a significant global health challenge, contributing to substantial morbidity, mortality, and economic burden. T2DM is the leading cause of CKD, and CKD exacerbates diabetes-related complications, creating a bidirectional relationship driven by oxidative stress, inflammation, and endothelial dysfunction. Diabetic kidney disease (DKD), affecting some individuals with T2DM, accelerates progression to end-stage renal disease (ESRD) and increases cardiovascular mortality. Microvascular complications, including nephropathy, retinopathy, and neuropathy, and macrovascular complications, such as coronary artery disease and stroke, are prevalent in this population, further diminishing the quality of life. The pathophysiology underlying these complications is multifaceted. Hyperglycemia-induced oxidative stress and inflammation drive kidney damage and systemic vascular complications, while CKD alters glucose metabolism and antidiabetic drug pharmacokinetics. Endothelial dysfunction exacerbates vascular complications through impaired nitric oxide production and heightened thrombogenicity. Emerging insights into genetic and epigenetic mechanisms, including DNA methylation and mitochondrial dysfunction, have highlighted new therapeutic targets. Management strategies emphasize early screening, glycemic control, and a multidisciplinary approach integrating lifestyle modifications, pharmacotherapy, and patient education. Interventions targeting oxidative stress, inflammation, and endothelial dysfunction have shown promise in mitigating disease progression. Current evidence on the interconnected mechanisms driving DKD and associated vascular complicationshighlights the critical need for proactive, patient-centered management and further research into innovative diagnostic and therapeutic approaches to address this global health challenge.

Frequency of undiagnosed hypertension among diabetic patients with micro vascular complications.

To determine the frequency of undiagnosed hypertension among the diabetic patients with micro vascular complications. This is a descriptive case series conducted at Department of Medicine, Ghurki Trust Teaching Hospital, in this six month stud which enrolled 213 patients between 18-60 years from March 28, 2021 to September 28, 2021, having diabetes with microvascular complications. These patients were not previously diagnosed as hypertensives. Patient was diagnosed as hypertensive if SBP or DBP was ≥l40 or ≥90 mmHg respectively. The frequency of undiagnosed hypertension was noted and compared across various subgroups of patients. The mean age of the patients was 49.3±9.7 years. The mean BMI of these patients was 28.3±3.5 Kg/m2 and 67 (31.5%) patients were obese. The mean duration of disease was 8.2±3.9 years. Majority (62.4%) of the patients had diabetic retinopathy while 37.6% patients had diabetic nephropathy. Undiagnosed hypertension was observed in 42 (19.7%) patients with diabetic micro vascular complications. The frequency of undiagnosed hypertension was significantly higher among obese as compared to non-obese patients (28.4% vs. 15.8%; p-value=0.032). There was no statistically significant difference in the frequency of undiagnosed hypertension across various subgroups based on patient's age (p-value=0.750), gender (p-value=0.902), type of micro vascular complication (p value=0.783) and duration of diabetes (p-value=0.763). In the present study, a substantial proportion of patients with diabetic micro vascular complications suffered undiagnosed hypertension which is alarming and advocates routine blood pressure monitoring of such patients so that timely identification and anticipated management of underlying hypertension may improve the outcome of such cases in future clinical practice.

Sestrin2 Suppression Promotes Endothelial-Mesenchymal Transition and Exacerbates Methylglyoxal-Induced Endothelial Dysfunction.

Sestrin2 (SESN2) is a stress-inducible protein known for its cytoprotective functions, but its role in diabetic vascular complications remains unclear. This study investigated the impact of SESN2 on methylglyoxal (MGO)-induced endothelial-mesenchymal transition (EndMT). Human endothelial cells were transfected with SESN2 siRNA duplexes to silence SESN2 expression, followed by MGO treatment. SESN2 knockdown significantly exacerbated MGO-induced oxidative stress, as evidenced by the reduced expression of antioxidant markers. Furthermore, SESN2 silencing enhanced the inflammatory response to MGO, demonstrated by the increased levels of pro-inflammatory cytokines. Notably, SESN2 deficiency promoted EndMT, a key process in diabetes-induced cardiovascular complications, as shown by the increased expression of mesenchymal markers and the decreased expression of endothelial markers. These findings suggest that SESN2 plays a critical protective role in endothelial cells against MGO-induced damage. The study provides novel insights into the molecular mechanisms underlying diabetic cardiovascular complications and identifies SESN2 as a potential therapeutic target for preventing endothelial dysfunction in diabetes. Our results indicate that SESN2 downregulation may contribute to the pathogenesis of diabetic vascular complications by promoting EndMT, increased oxidative stress, and inflammation.

Alternative splicing: Therapeutic target for vasculopathy in diabetic complications.

It is becoming increasingly evident that diabetic vascular complications seriously threaten human health. The most prevalent microvascular complications include kidney disease, retinal disease, cardiovascular diseases and amputation. Conventional treatments can only relieve the progression of the diseases, and is no longer appropriate for the long-term management of diabetic patients. Exploring a novel therapeutic regimens and improvements in management of Diabetic Complications is required. Alternative splicing has been found to play a crucial role in the occurrence and treatment of diseases, including the destruction and generation of blood vessels in diabetes. Alternative splicing is an important factor in the high complexity of multicellular eukaryotic transcriptome, and angiogenesis, which is an important process controlled by alternative splicing mechanism. This review mainly introduces the current understanding of alternative splicing and the role that alternative splicing plays in the diabetic complications, with a special focus on vascular system. In this study, we summarized alternative splicing in relation to diabetes complications and the pathogenesis of diabetic vasculopathy. It discussed potential treatment strategies for correcting aberrant splicing and suggested novel approaches for addressing diabetes complications.

Low-magnitude high-frequency vibration ameliorates high glucose-induced endothelial injury by restoring mitochondrial function via AMPK/mTOR pathway

ABSTRACT High glucose-induced dysfunction of endothelial cells is a critical and initiating factor in the genesis of diabetic vascular complications. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical intervention. It has been reported that it exhibits protective effects on high glucose-induced osteoblast dysfunction, but little was known on diabetic vascular complications. In this work, we aim to clarify the role of LMHFV on high glucose-induced endothelial dysfunction and hypothesized that the protective effects functioned through adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. We cultured primary murine aortic endothelial cells (MAECs) in normal or HG medium, respectively, before exposing to LMHFV. The tube formation, paracellular permeability assay, and aortic ring sprouting assay showed that the high glucose injured-function of MAECs was improved after LMHFV treatment. The intracellular ROS generation analysis, mitochondrial complex I activities measurement, ATP measurement and mitochondrial membrane potential (MMP), and mitochondrial ROS generation analysis of MAECs indicated that mitochondrial function was restored by LMHFV loading in a high glucose environment. Mechanically, western blot assays showed that AMPK phosphorylation was promoted and mTOR was inhibited in LMHFV-induced endothelial function restoration. After the administration of the AMPK inhibitor, Compound C, these protective effects resulting from LMHFV are reversed. These findings suggest that LMHFV plays a significant role in protecting endothelial cells’ function and mitochondrial function in high glucose-induced injured MAECs via AMPK/mTOR signalling.

Development of a hamster model of spontaneous hypertriglyceridemia in diabetes.

Hypertriglyceridemia (HTG) often accompanies diabetes and is considered a risk factor for diabetic vascular complications. However, inducing diabetic HTG typically requires high-fat diets in certain animal models. Leveraging our newly developed LDL receptor knockout hamster model, which exhibits features akin to human lipid metabolism, we sought to determine whether these animals would develop HTG without dietary manipulations in diabetes. Diabetes was induced via intraperitoneal injection of STZ in wild type and heterozygous LDL receptor deficient hamsters. Blood glucose, triglyceride, and cholesterol were measured over 60 days. Plasma TG clearance was determined via olive oil gavage. The effect of insulin on diabetic HTG was assessed on Day 60 post-diabetes induction. Blood glucose increased over threefold, while plasma insulin decreased to 30% of controls after STZ injection in both wild type and heterozygous hamsters by Day 7, remaining stable for 60 days. Plasma TG in wild-type hamsters remained unchanged at Day 7 post-STZ injection but increased slightly thereafter. Conversely, heterozygous hamsters exhibited severe HTG by Day 7 until the end of the study. Olive oil gavage revealed much slower plasma triglyceride clearance in heterozygous hamsters compared to WT animals, despite significantly reduced lipoprotein lipase activity in post-heparin plasma in both animals. Hyperglycemia and HTG in heterozygous hamsters were reversed to pre-diabetic levels following intraperitoneal insulin administration. In conclusion, severe HTG in diabetic heterozygous LDL receptor deficient hamsters developed spontaneously and was insulin-dependent. Thus, this hamster model holds promise for effectively studying the complications associated with human diabetic HTG.

Molecular Insights and Pharmacotherapy of Diabetic Neuropathy

Background: Diabetes mellitus is a chronic disorder of energy metabolism caused by lack or decrease in the effectiveness of insulin, and is characterised by an abnormally elevated blood glucose concentrations and the development of macrovascular, microvascular and/or neuropathic complications. Diabetic neuropathy (DN) is one of the most debilitating outcomes of diabetes mellitus, and may cause pain, decreased mobility as well as amputation. Diabetes can damage the peripheral nervous system (PNS), through the induction of de-myelination in neurones, precipitated by chronic hyperglycaemia-induced oxidative stress, and causing a condition that involves the upper and lower limbs. Objective: The study discussed the risk factors for insulin resistance and pre-diabetes, type II diabetes mellitus and vascular complications, cellular and molecular basis of DN, physiopathological mechanisms, and the pharmacological treatment of DN. Method: The study examined journal articles and standard textbooks, as it relates to diabetes mellitus and its complications. Search for articles on DN was carried out in the literature. These were identified and reviewed for selection using chemical abstracts service, pubmed, google scholar, crossreference, web of science, pubmed central free article, and scopus. The key words used for search were: diabetic neuropathy; diabetic peripheral neuropathy; peripheral neuropathy; microvascular complications of diabetes mellitus; and neuromuscular complications of diabetes mellitus. Result & Discussion: Two hundred and fifty (250) articles and other works were identified, while ninety-seven (97) articles and non-journal materials were extracted and reviewed, taking into account the criteria for selection. Studies done in the last 4.5 decades were included, while works written on other languages, outside English were excluded. Findings indicate that DN is a complex disorder that affects the peripheral and/or cranial nerves, which is caused by unattended or poorly attended, long-term increase in blood glucose concentrations. It relatively manifests early, affecting a significant proportion of the micro-blood vessels in the middle-aged and elderly diabetic patients. DN causes numbness, loss of sensation, and sometimes pain in the feet, legs, arms or hands. Hyperglycaemia causes the activation and inhibition of several molecular pathways that are crucial for homeostasis in neuronal and neuroglial cells. Conclusion: DN is the commonest complication of diabetes mellitus. It has no known definitive therapy. Treatment is essentially symptomatic with huge economic and psychological burden, hence the rationale for a cost effective and targeted therapies. Achieving euglycaemia using anti-diabetic regimens (i.e., insulin and oral hypoglycaemic agents), foot care, changes in feeding habits and lifestyle modification are critical to holistically address the problem.

Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy

Metabolic disorder significantly contributes to diabetic vascular complications, including diabetic retinopathy, the leading cause of blindness in the working-age population. However, the molecular mechanisms by which disturbed metabolic homeostasis causes vascular dysfunction in diabetic retinopathy remain unclear. O-GlcNAcylation modification acts as a nutrient sensor particularly sensitive to ambient glucose. Here, we observe pronounced O-GlcNAc elevation in retina endothelial cells of diabetic retinopathy patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase effectively mitigates vascular dysfunction. Mechanistically, we find that Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are O-GlcNAcylated in diabetic retinopathy. We identify threonine 383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at serine 397, leading to its stabilization and activation, thereby promoting vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. This work emphasizes the critical role of the O-GlcNAc-Hippo axis in the pathogenesis of diabetic retinopathy and suggests its potential as a therapeutic target.

STING-mediated DNA damage response in diabetes-induced vascular complications

Abstract Background Hyperglycemia drives endothelial dysfunction, a key factor in the development of diabetes vascular complications. The stimulator of interferon genes (STING) signal, plays a crucial role in the immune system and is implicated in the pathogenesis of inflammatory diseases. Therefore we investigated the role of STING in endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Methods and Results Diabetes was induced by single-dose administration of STZ in 8-week-old C57BL/6 and Sting-/- mice. STZ injection promoted the expression of STING and DNA damage markers in the aorta of C57BL/6 mice. Genetic deletion of STING ameliorated endothelial dysfunction as determined by vascular reactivity assay (P < 0.001) and increased aortic eNOS phosphorylation (P < 0.05) in STZ-injected mice. Stimulation of STING agonist (cGAMP), or mtDNA increased inflammatory molecules expression (e.g., VCAM1 and IFNB) and decreased eNOS phosphorylation in HUVECs. In ex-vivo experiments, cGAMP significantly impaired endothelial function which was ameliorated in the presence of an STING inhibitor or a neutralizing IFN-β antibody. Furthermore, the administration of STING inhibitor ameliorated endothelial dysfunction in STZ-induced diabetic mice (P < 0.01). Conclusion The DNA damage response regulated by STING aggravated diabetes-induced endothelial dysfunction. STING signaling may be a potential therapeutic target for diabetic vascular complications.

Homoplantaginin alleviates high glucose-induced vascular endothelial senescence by inhibiting mtDNA-cGAS-STING pathway via blunting DRP1-mitochondrial fission-VDAC1 axis.

Vascular endothelial senescence is a major risk factor for diabetic vascular complications. Abnormal mitochondrial fission by dynamically related protein 1 (DRP1) accelerates vascular endothelial cell senescence. Homoplantaginin (Hom) is a flavonoid in Salvia plebeia R. Br. with protecting mitochondrial and repairing vascular properties. However, the relevant mechanism of Hom against diabetic vascular endothelial cell senescence remains unclear. Here, we used db/db mice and high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs) to assess the anti-vascular endothelial cell senescence of Hom. We found that Hom inhibited senescence-associated β-galactosidase activity, decreased the levels of senescence markers, and senescence-associated secretory phenotype factors. Additionally, Hom inhibited the expression of cGAS-STING pathway and downstream inflammatory factors. STING inhibitor H-151 delayed endothelial senescence, whereas STING overexpression attenuated the anti-endothelial senescence effect of Hom. Furthermore, we observed that Hom reduced mitochondrial fragmentation and inhibited abnormal mitochondrial fission using transmission electron microscopy. Importantly, Hom has a stronger effect on mitochondrial fission protein than mitochondrial fusion protein, especially downregulated the expression of DRP1. DRP1 inhibitor Mdivi-1 suppressed cGAS-STING pathway and vascular endothelial senescence, yet DRP1 agonist FCCP attenuated the effect of Hom. Surprisingly, Hom blunted abnormal mitochondrial fission mediated by DRP1 mitochondrial localization, suppressed interaction of DRP1 with VDAC1 and prevented VDAC1 oligomerization, which was necessary for mtDNA escape and subsequent cGAS-STING pathway activation. These results revealed a previously unrecognized mechanism that Hom alleviated vascular endothelial senescence by inhibited mtDNA-cGAS-STING signaling pathway via blunting DRP1-mitochondrial fission-VDAC1 axis.

Nr-CWS regulates METTL3-mediated m6A modification of CDS2 mRNA in vascular endothelial cells and has prognostic significance

Metabolic memory (MM) is a major factor in the delayed wound healing observed in diabetic patients. While “Nocardia rubrum cell wall skeleton” (Nr-CWS) is utilized to enhance macrophage proliferation in immune diseases, its impact on MM wounds in diabetes is unclear. This study demonstrates that transient hyperglycemia leads to prolonged damage in vascular endothelial cells by decreasing METTL3 expression, leading to decreased RNA methylation and impaired cellular metabolism. Remarkably, Nr-CWS application increases METTL3 levels in these cells, facilitating the recovery of cell function. Further in vivo and in vitro analyses demonstrate that transient hyperglycemia-induced reduction in METTL3 hinders RNA methylation of the downstream gene Cds2, impacting mitochondrial function and energy metabolism and consequently reducing angiogenic capacity in endothelial cells. This impairment significantly influences diabetic wound healing. Our findings highlight the profound impact of transient hyperglycemia on wound healing, establishing METTL3 as a significant role in vascular complications of diabetes. This study not only elucidates the pathophysiological mechanisms behind MM in diabetic wounds but also suggests Nr-CWS as a potential therapeutic agent, offering a novel approach for treating diabetic wounds.

Altered RBC deformability in diabetes: clinical characteristics and RBC pathophysiology

BackgroundReduced red blood cell deformability (RBCD) is associated with diabetic vascular complications, but early pathophysiological RBC changes and predictive demographic and clinical factors in populations with diabetes are unclear. An understanding of early diabetes-specific RBC changes associated with impaired RBCD is essential in investigating mechanisms that predispose to diabetic vascular complications.MethodsWe conducted an outpatient cross-sectional study of participants in a well-controlled diabetes cohort (N81) and nondiabetic controls (N78) at the National Institutes of Health. First, between-group differences in RBCD measures were assessed with shear stress-gradient ektacytometry. Differences in structural RBC parameters were assessed using osmotic gradient ektacytometry and NaCl osmotic fragility. Functional RBC changes were assessed using hemoglobin-oxygen dissociation: p50.ResultsAll shear-stress gradient RBCD measures were significantly altered in the diabetes cohort vs. nondiabetic controls, even after adjustment for confounding covariates (p < 0.001). Adjusted for diabetes-status and demographic factors, significant predictors of reduced RBCD included older age, Black race, male gender, hyperglycemia, and vascular complications (all p < 0.05). Reduced RBCD was also associated with aberrant osmotic-gradient parameters, with a left-shift on osmotic gradient profile indicative of dehydrated RBCs in diabetes. A structure-function relationship was observed with reduced RBCD associated with reduced osmotic fragility (P < 0.001) and increased hemoglobin-oxygen dissociation (P < 0.01).ConclusionsFindings suggest impaired RBCD incurs similar demographic and clinical risk factors as diabetic vascular disease, with early pathophysiological RBC changes indicative of disordered RBC hydration in diabetes. Findings provide strong evidence for disordered oxygen release as a functional consequence of reduced RBCD.Clinical trial number: NCT00071526.

A-9-Years-Old Female with Diabetes Mellitus Type 1 with Hyperthyroidism

Diabetes Mellitus Type 1 (DMT1) and thyroid disease can occur together, which is defined as a variant of autoimmune polyglandular syndrome type 3. It is known that the action of insulin and thyroid hormones affect cellular metabolism, thyroid hormones contribute to carbohydrate metabolism and pancreatic function. Since the thyroid gland plays a central role in the regulation of metabolism, abnormal thyroid function can have a major impact on the control of diabetes and poor glycemic control can cause alterations in thyroid hormone. A female, 9 years old, with decreased consciousness. Previous medical history, polyuria, increased appetite, and drastic weight loss. She also complained of sweating even in a cold room and was often emotional. On physical examination, there was fever, shortness of breath, tachycardia, and a soft and diffused slightly enlarged thyroid gland, with no bruit on auscultation. Laboratory tests showed blood glucose levels at 739 mg/dL, HbA1c 9.2%, C-peptide 0.2 ng/mL, TSH levels 0.01 µIU/mL, FT4 levels 2.77 ng/dL, the presence of metabolic acidosis, proteinuria, glucosuria, and ketonuria. Thyroid dysfunction will have a negative effect on DM control while poor glucose control will harm the work of thyroid hormones. Improvement in glycemic control and routine insulin injection with the right dose will reduce the risk of diabetic vascular and metabolic complications onset and progression.

New insights on genetic background of major diabetic vascular complications

BackgroundBy 2045, it is expected that 693 million individuals worldwide will have diabetes and with greater risk of morbidity, mortality, loss of vision, renal failure, and a decreased quality of life due to the devastating effects of macro- and microvascular complications. As such, clinical variables and glycemic control alone cannot predict the onset of vascular problems. An increasing body of research points to the importance of genetic predisposition in the onset of both diabetes and diabetic vascular complications.ObjectivesPurpose of this article is to review these approaches and narrow down genetic findings for Diabetic Mellitus and its consequences, highlighting the gaps in the literature necessary to further genomic discovery.Material and methodsIn the past, studies looking for genetic risk factors for diabetes complications relied on methods such as candidate gene studies, which were rife with false positives, and underpowered genome-wide association studies, which were constrained by small sample sizes.ResultsThe number of genetic findings for diabetes and diabetic complications has over doubled due to the discovery of novel genomics data, including bioinformatics and the aggregation of global cohort studies. Using genetic analysis to determine whether diabetes individuals are at the most risk for developing diabetic vascular complications (DVC) might lead to the development of more accurate early diagnostic biomarkers and the customization of care plans.ConclusionsA newer method that uses extensive evaluation of single nucleotide polymorphisms (SNP) in big datasets is Genome-Wide Association Studies (GWAS).