ED-71 Ameliorates Bone Loss in Type 2 Diabetes Mellitus by Enhancing Osteogenesis Through Upregulation of the Circadian Rhythm Coregulator BMAL1.

Purpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms. Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3ß signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels. Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3ß activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3ß inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression. Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3ß signaling pathway is involved in the regulation of BMAL1.

Targeting S100A12 to Improve Angiogenesis and Accelerate Diabetic Wound Healing.

Long-term inflammation and impaired angiogenesis are thought to be the causes of delayed healing or nonhealing of diabetic wounds. S100A12 is an essential pro-inflammatory factor involved in inflammatory reactions and serves as a biomarker for various inflammatory diseases. However, whether high level of S100A12 exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that the serum concentration of S100A12 is significantly elevated in patients with type 2 diabetes. Exposure of stratified epidermal cells to high glucose environment led to increased expression and secretion of S100A12, resulting in impaired endothelial function by binding to the advanced glycation endproducts (RAGE) or Toll-like receptor 4 (TLR4) on endothelial cell. The transcription factor Krüpple-like Factor 5 (KLF5) is highly expressed in the epidermis under high glucose conditions, activating the transcriptional activity of the S100A12 and boost its expression. By establishing diabetic wounds model in alloxan-induced diabetic rabbit, we found that local inhibition of S100A12 significantly accelerated diabetic wound healing by promoting angiogenesis. Our results illustrated the novel endothelial-specific injury function of S100A12 in diabetic wounds and suggest that S100A12 is a potential target for the treatment of diabetic wounds.

Diabetic retinopathy incidence, predictors and its association with longitudinal fasting blood sugar level changes among diabetes mellitus patients in Ethiopia: joint model.

Background: Diabetes mellitus (DM) is a global public health problem characterized by an elevated blood glucose level. Monitoring blood sugar levels is vital for effective diabetes management and preventing complications. However, the association between longitudinal biomarkers and the incidence of diabetic complications is often overlooked. Therefore, this study aimed to assess the incidence of diabetic retinopathy, predictors, and association with longitudinal fasting blood sugar level changes among diabetes mellitus patients in Ethiopia. Methods: A multicenter retrospective follow-up study was carried out in referral hospitals in Amhara region, Ethiopia. A random sample of 462 newly diagnosed DM patients was selected. The proportional hazard assumption was checked for the survival sub-model, and for the longitudinal sub-model, the normality assumption was checked. Then the joint modeling with time-dependent lagged parameterizations was fitted. Model assumptions and comparisons were checked. Finally, the hazard ratio with a 95% confidence interval (CI) with a corresponding P-value<0.05 was used to identify predictors. Results: In this study, Overall, 54 patients developed DR, and the incidence rate was 2.33 per 1000 person-months over the follow-up period, with a 95% CI of [1.78, 3.05]. Rural residence (AHR = 2.21, 95% CI: [1.21, 4.05]), hypertension co-morbidity (AHR = 3.01, 95% CI: [1.85, 6.53]), and longer duration of DM (>5 years) (AHR = 2.28, 95% CI: [1.91, 5.15]) were important predictors for the incidence of DR. In addition, the incidence of DR was substantially correlated with the time-dependent lagged value of FBS change (AHR = 4.20, 95% CI [1.62, 10.85]). Conclusions: In this study, the incidence of diabetic retinopathy was somewhat high when compared to prior similar studies in Ethiopia. A joint model of longitudinal fasting blood sugar level changes was significantly associated with an increased risk of DR. Besides, being rural residence, hypertension co-morbidity, and a longer duration of DM were significant predictors for the incidence of DR. Therefore, public awareness, an integrated care approach, and prioritizing glycemic control are highly recommended.

Oxidative Stress in Prediabetic Young Adults.

Background Malondialdehyde (MDA) and nitric oxide (NO) are considered specific biomarkers for oxidative stress. Oxidative stress in prediabetics with an augmented potential for the onset of diabetes is at least partly responsible for the various complications of diabetes. Evidence shows that the early features of cell injury are due to transient acute elevations in blood glucose. This study aims to determine whether oxidative stress in prediabetic young adults increases the risk of developing diabetes. Aim and objectives We envisaged a study to determine whether the parameters representing oxidative stress are deranged in prediabetics. Materials and methods The study was conducted on prediabetic young individuals from 18 to 35 years, screened from the tertiary-level hospital, and a similar group of non-prediabetic young individuals identified from the same in a tertiary-level hospital in India. Results We observed significant elevations in prediabetics in the following oxidative stress parameters: MDA (P= <0.001), and NO (P= <0.001); indicating that these parameters were significantly higher among the prediabetics than the controls. We also observed significantly greater body weight, waist circumference, and BMI among the prediabetics than the controls. Conclusion Early identification and appropriate treatment of hyperglycemia in prediabetics is essential, as impairments in pancreatic beta-cell functioning and resistance to insulin are already present before the onset of type 2 diabetes mellitus (T2DM). Owing to the high potential for mortality and morbidity due to cardiovascular diseases (CVDs) as a complication of diabetes, treatment plans must be put in place early enough so that complications can be prevented. Inflammation and oxidative stress may be viewed as valuable targets to hinder the evolution of T2DM from prediabetes.

Exploring mechanisms of insulin action and strategies to treat diabetes.

Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired insulin action. My colleagues and I have elucidated multifaceted insulin action in various tissues mainly by means of model mice. In the liver, insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis comorbid with diabetes. Not only the liver but also the proximal tubules of the kidney are important in the regulation of gluconeogenesis, and we revealed that insulin suppresses gluconeogenesis in accordance with absorbed glucose in the latter tissue. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease of skeletal muscle, but also to osteopenia and shorter longevity. Aging is regulated by adipokines as well, and it should be considered that aging could be accelerated by 'imbalanced adipokines' in patients with a genetic background of progeria. Moreover, we reported the effects of intensive multifactorial intervention on diabetic vascular complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, and the results of subsequent sub-analyses of renal events and fracture events. Various approaches of research enable us of endocrinologists to elucidate the physiology of hormone signaling, the mechanisms underlying the development of endocrine diseases, and the appropriate treatment measures. These approaches also raise fundamental questions, but addressing them in an appropriate manner will surely contribute to the further development of endocrinology.

Effectiveness of Oral Health Education and Interventions in Improving Oral Health Outcomes in Type II Diabetes Mellitus Patients: A Prospective Study.

Introduction Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The study aimed to evaluate the effectiveness of oral health education and intervention in improving oral health outcomes in type 2 DM (T2DM) patients. Methods The present study was conducted in the Department of Oral Medicine and Radiology between February 2023 and August 2023 at Saveetha Dental College and Hospitals in Chennai, India. All of the patients in the study had T2DM with oral manifestations. This study enrolled 105 participants, of whom 63 were female and 42 were male. A standard pro forma was given to all the participants, and the findings were recorded. The pro forma comprises different oral manifestations, blood glucose levels, the Decayed, Missing, and Filled Teeth (DMFT) index, and Russell's periodontal index. The results were then statistically analyzed. Results This study of 105 individuals with T2DM (60% females and 40% males) revealed significant oral health challenges: 33% had periodontitis, 20% had gingivitis, 5% had lichenoid reactions, 23% had xerostomia, 11% had halitosis, and 8% had candidiasis, illustrating diabetes' impact on dental health. Following appropriate, tailor-made treatment for individual patients, such as scaling, root planning, oral hygiene education, pharmacotherapy, and post-intervention, the prevalence of complications notably decreased by 61%. A total of 7% of patients had gingivitis, 11% had periodontitis, 12% had xerostomia, 4% had halitosis, 2% had candidiasis, and 1% had lichenoid reactions, respectively. This highlights the importance of regular oral care positively impacting diabetes patients, with 61% experiencing improved oral health and 39% experiencing no improvement. Conclusion This study provides compelling evidence for the effectiveness of oral health education and interventions in improving oral health outcomes in T2DM patients. This approach offers a promising strategy for managing the oral health complications associated with diabetes and improving this population's overall health and well-being.

Role of angiotensin receptor-neprilysin inhibitor in diabetic complications.

Diabetes mellitus is a prevalent disorder with multi-system manifestations, causing a significant burden in terms of disability and deaths globally. Angio-tensin receptor-neprilysin inhibitor (ARNI) belongs to a class of medications for treating heart failure, with the benefits of reducing hospitalization rates and mortality. This review mainly focuses on the clinical and basic investigations related to ARNI and diabetic complications, discussing possible physiological and molecular mechanisms, with insights for future applications.

Myopia and Rate of Peripapillary Retinal Nerve Fiber Layer Thickness in Diabetic Patients Without Retinopathy: A 2-Year Longitudinal Study.

PURPOSE: The aim of this study was to investigate the association between myopia and longitudinal changes in peripapillary retinal nerve fiber layer (pRNFL) thickness in type 2 diabetic patients without diabetic retinopathy (DR). METHODS: A total of 1069 participants with a median follow-up time of 1.9 years were included in this study. The participants were categorized into four groups based on the presence of myopia (≤ -0.5 diopter [D]) and diabetes without DR, including a control group (n = 412), diabetes group (n = 416), myopia group (n = 115), and diabetes + myopia group (n = 126). Peripapillary average and sectoral RNFL measurements were obtained using 6 × 6 mm swept-source optical coherence tomography (SS-OCT) scans centered at the optic disc. The change rate of pRNFL, adjusted for age and sex, was calculated and compared among the four groups to investigate the impact of myopia and diabetes. RESULTS: The baseline estimated pRNFL thickness after adjustment for covariates was 113.7 µm, 116.2 µm, 108.0 µm, and 105.6 µm in the control, diabetes, myopia, and diabetes + myopia group, respectively (diabetes > control > myopia = diabetes + myopia, p < 0.001). The respective average pRNFL loss in the four groups was -0.48 µm/year, -1.11 µm/year, -1.23 µm/year, and -2.62 µm/year (all p < 0.01). The diabetes + myopia group exhibited a greater rate of average pRNFL reduction compared to the other groups (all p < 0.001). Multivariate analysis using a linear mixed-effects model showed that age, diabetes, axial length (AL), and baseline pRNFL thickness were significantly associated with the rate of average pRNFL reduction. CONCLUSIONS: The diabetes group showed a faster rate of average pRNFL thickness reduction compared to healthy controls, regardless of the presence of myopia. The average pRNFL thickness decreased more rapidly when diabetes and myopia were present simultaneously than in the individual diabetes or myopia group. Both diabetes and myopia were associated with accelerated pRNFL loss.

Feasibility of Point Shear Wave Elastography for Evaluating Renal Cortical Thickness: A Prospective Study.

BACKGROUND: Chronic Kidney Disease [CKD] affects individuals of different age groups worldwide. Moreover, CKD is associated with several risk factors, including obesity, lifestyle, and hypertension, which are common in the Middle East. Ultrasonography is the examination of choice for CKD. In recent years, Shear Wave Elastography [SWE] has developed through the continued development of ultrasound and received substantial attention ;therefore, it can be used to measure tissue stiffness. The study aimed to use point Shear Wave Elastography [p-SWE] to determine the correlation between diabetes and cortical renal thickness in detecting pathologies. METHODS: This study was performed at the King Abdul-Aziz University Hospital. We examined 61 patients who underwent SWE. The patients were classified into two groups based on the presence or absence of type 2 Diabetes Mellitus [DM]. RESULTS: The results showed that there was a significant correlation between cortical stiffness and DM duration [p<0.005]. In addition, there was a negative correlation between cortical stiffness and cortical thickness [p=0.147] in patients with DM. Moreover, the eGFR decreased with an increase in cortical stiffness [p=0.499]. The cortical thickness in patients with and without DM was 0.750 ± 0.2 kPa and 0.788 ± 0.4 kPa, respectively. The kidney stiffness in patients with DM and control patients was 8.5 ± 8.6 cm and 14.0 ± 25.16 cm, respectively. CONCLUSION: This study showed that kidney p-SWE measurements were reliable. Therefore, further studies assessing kidney stiffness in patients with and without people with diabetes are recommended.

Novel lipid mediator 7S,14R-docosahexaenoic acid: biogenesis and harnessing mesenchymal stem cells to ameliorate diabetic mellitus and retinal pericyte loss.

Introduction: Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7S,14R-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid (7S,14R-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7S,14R-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic db/db mice. Methods: MSCs treated with 7S,14R-diHDHA were delivered into db/db mice i.v. every 5 days for 35 days. Results: Blood glucose levels in diabetic mice were lowered by 7S,14R-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7S,14R-diHDHA-treated MSCs increased insulin+ ß-cell ratio and decreased glucogan+ α-cell ratio in islets, as well as reduced macrophages in pancreas. 7S,14R-diHDHA induced MSC functions in promoting MIN6 ß-cell viability and insulin secretion. 7S,14R-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7S,14R-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in db/db mice. Discussion: Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7S,14R-diHDHA-primed MSCs.

Causal relationship between gut microbiota and diabetic nephropathy: a two-sample Mendelian randomization study.

Objective: Emerging evidence has provided compelling evidence linking gut microbiota (GM) and diabetic nephropathy (DN) via the "gut-kidney" axis. But the causal relationship between them hasn't been clarified yet. We perform a Two-Sample Mendelian randomization (MR) analysis to reveal the causal connection with GM and the development of DN, type 1 diabetes nephropathy (T1DN), type 2 diabetes nephropathy (T2DN), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM). Methods: We used summary data from MiBioGen on 211 GM taxa in 18340 participants. Generalized MR analysis methods were conducted to estimate their causality on risk of DN, T1DN, T2DN, T1DM and T2DM from FinnGen. To ensure the reliability of the findings, a comprehensive set of sensitivity analyses were conducted to confirm the resilience and consistency of the results. Results: It was showed that Class Verrucomicrobiae [odds ratio (OR) =1.5651, 95%CI:1.1810-2.0742,PFDR=0.0018], Order Verrucomicrobiales (OR=1.5651, 95%CI: 1.1810-2.0742, PFDR=0.0018) and Family Verrucomicrobiaceae (OR=1.3956, 95%CI:1.0336-1.8844, PFDR=0.0296) had significant risk of DN. Our analysis found significant associations between GM and T2DN, including Class Verrucomimicrobiae (OR=1.8227, 95% CI: 1.2414-2.6763, PFDR=0.0139), Order Verrucomimicrobiae (OR=1.5651, 95% CI: 1.8227-2.6764, PFDR=0.0024), Rhodospirillales (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0026), and Family Verrucomicroniaceae (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0083). The Eubacteriumprotogenes (OR=0.4076, 95% CI: 0.2415-0.6882, PFDR=0.0021) exhibited a protection against T1DN. Sensitivity analyses confirmed that there was no significant heterogeneity and pleiotropy. Conclusions: At the gene prediction level, we identified the specific GM that is causally linked to DN in both T1DM and T2DM patients. Moreover, we identified distinct microbial changes in T1DN that differed from those seen in T2DN, offering valuable insights into GM signatures associated with subtype of nephropathy.

Xanthones with multiple roles against diabetes: their synthesis, structure-activity relationship, and mechanism studies.

A four-step synthetic process has been developed to prepare 1,3,5,8-tetrahydroxyxanthone (2a) and its isomer 1,3,7,8-tetrahydroxyxanthone (2b). 25 more xanthones were also synthesized by a modified scheme. Xanthone 2a was identified as the most active inhibitor against both α-glucosidase and aldose reductase (ALR2), with IC50 values of 7.8 ± 0.5 µM and 63.2 ± 0.6 nM, respectively, which was far active than acarbose (35.0 ± 0.1 µM), and a little more active than epalrestat (67.0 ± 3.0 nM). 2a was also confirmed as the most active antioxidant in vitro with EC50 value of 8.9 ± 0.1 µM. Any structural modification including methylation, deletion, and position change of hydroxyl group in 2a will cause an activity loss in inhibitory and antioxidation. By applying a H2 O2 -induced oxidative stress nematode model, it was confirmed that xanthone 2a can be absorbed by Caenorhabditis elegans and is bioavailable to attenuate in vivo oxidative stress, including the effects on lifespan, superoxide dismutase, Catalase, and malondialdehyde. 2a was verified with in vivo hypoglycemic effect and mitigation of embryo malformations in high glucose. All our data support that xanthone 2a behaves triple roles and is a potential agent to treat diabetic mellitus, gestational diabetes mellitus, and diabetic complications.

Impact of coexisting type 2 diabetes mellitus on the urinary microbiota of kidney stone patients.

Objectives: Type 2 diabetes mellitus (T2DM) commonly complicates kidney stone disease (KSD). Our objective is to investigate the variations in the urinary microbiota between individuals with KSD alone and those with KSD plus T2DM. This exploration could have implications for disease diagnosis and treatment strategies. Methods: During lithotripsy, a ureterscope was employed, and 1 mL of urine was collected from the renal pelvis after bladder disinfection. Sequencing targeting the V3-V4 hypervariable region was performed using the 16S rRNA and Illumina Novaseq platform. Results: The Shannon index showed a significant decrease in the KSD plus T2DM group compared to the KSD-only group (false discovery rate = 0.041). Principal Coordinate Analysis (PCoA) demonstrated a distinct bacterial community in the KSD plus T2DM group compared to the KSD-only group (false discovery rate = 0.027). The abundance of Sphingomonas, Corynebacterium, and Lactobacillus was significantly higher in the KSD plus T2DM group than in the KSD-only group (false discovery rate < 0.05). Furthermore, Enhydrobacter, Chryseobacterium, and Allobaculum were positively correlated with fasting blood glucose and HbA1c values (P < 0.05). Conclusions: The urinary microbiota in the renal pelvis exhibits differences between patients with KSD plus T2DM and those with KSD alone. Further studies employing animal models are necessary to validate these distinctions, potentially paving the way for therapeutic developments based on the urinary microbiota.

Evaluation of Effect of Montelukast in the Model of Streptozotocin Induced Diabetic Nephropathy in Rats.

Background: Diabetic nephropathy is a progressive condition and a leading cause of end-stage renal disease. Oxidative stress and inflammation play an important role in its pathogenesis. In pre-clinical studies, Montelukast had shown renoprotective and anti-oxidant properties, hence the study was planned to evaluate the effect of Montelukast in a Streptozotocin (STZ) induced model of diabetic nephropathy. Methods: 40 Wistar rats of either sex were randomly divided into four groups viz. 1. Vehicle control group, 2. Enalapril (5 mg/kg), 3. Montelukast low-dose (10 mg/kg) and 4. High-dose (20 mg/kg) group. On day 1, diabetes was induced using a single dose of STZ (60 mg/kg) intraperitoneally. Diabetes induction was verified based on fasting blood glucose (FBG) levels on day 7 and from day 8 to day 42, rats were given study drugs. FBG, serum creatinine, blood urea nitrogen (BUN) and urine microalbumin levels were assessed pre-study and post-study. Assessments of kidney malondialdehyde (MDA), reduced glutathione (GSH) and renal histopathology were carried out at the end of the study. Results: Montelukast 10 mg/kg group showed significantly lower urine microalbumin levels compared to the vehicle control group (p < 0.05). Montelukast 20 mg/kg group showed significantly lower levels of FBG, serum creatinine, BUN and urine microalbumin compared to the vehicle control group (p < 0.05). In addition, Montelukast 20 mg/kg group also showed better effects on kidney MDA and GSH levels (p < 0.05) and histopathological scores compared to the vehicle control group. Conclusion: Montelukast showed a protective effect in the model of diabetic nephropathy because of its antioxidant effect.

Increased skeletal muscle mass index was involved in glycemic efficacy following diabetes treatment, and changes in fat mass index correlated with the changes in the lipid ratio in type 2 diabetes.

AIM: This study aimed to investigate the association between changes in body composition, glycated hemoglobin, and lipid ratio during the treatment of patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective analysis used data from outpatients with T2DM who had confirmed body composition and measured laboratories at administration and after treatment. The baseline characteristics and prescribed treatment were collected. The total cholesterol/high-density lipoprotein cholesterol (HDL) ratio, low-density lipoprotein cholesterol (LDL)/HDL ratio, and triglyceride-glucose (TyG) index were also calculated. RESULTS: A total of 207 patients (mean patient age, 62.0 ± 13.7 years; 68.1 % males) were enrolled. Fat mass index (FMI) changes correlated with the changes in the lipid ratio, whereas skeletal muscle mass index (SMI) changes inversely correlated with glycated hemoglobin (HbA1c) changes. Multiple regression analysis showed that changes in LDL/HDL and TyG correlated with FMI changes (t = 2.388, p = 0.017, t = 2.022, p = 0.044). Conversely, HbA1c changes correlated with SMI changes (t = -2.552, p = 0.011). CONCLUSION: In patients with T2DM, increased SMI was involved in glycemic efficacy, and FMI changes were associated with LDL/HDL and TyG.

Expression of miRNA-29c in the carotid plaque and its association with diabetic mellitus.

Background: Carotid artery atherosclerosis is a major cause of ischemic stroke, and ischemic stroke is the leading cause of morbidity and mortality worldwide. Unfortunately, the reason for the build-up of atherosclerosis plaque is unknown. The miRNA-29c was reported to promote the phenotype transformation of vascular smooth muscle cells (VSMCs) in diabetes mice, eventually leading to plaque formation and bleeding. However, such studies are rare and limited to animal experiments. Methods: In our study, 40 patients were divided into a diabetic mellitus (DM) group and a non-DM group according to whether they were diagnosed with DM. Then, the real-time quantitative PCR was applied to examine the miRNA-29c level in human carotid plaque tissue derived from 40 subjects receiving carotid endarterectomy. Results: Briefly, diabetes patients had a decreased miRNA-29c level as compared with non-DM subjects, and this comparison was statistically significant (P = 0.02). Notably, variable miRNA-29c level was negatively associated with HbA1c level, although no statistical significance was observed. Moreover, there was an increased miRNA-29c level in patients with cerebral stroke. Conclusion: Collectively, the miRNA-29c level in the carotid plaque is closely associated with DM and cerebral stroke, which may contribute to atherosclerosis formation.

3-Hydroxy-3-methylglutaryl-CoA synthase 2 facilitates erectile dysfunction via inhibiting autophagy by enhancing the mammalian target of rapamycin pathway in type 1 diabetic mellitus rats.

BACKGROUND: The relationship between erectile dysfunction (ED) and type 1 diabetes mellitus (T1DM) is currently a hot topic of medical research. It has been reported that autophagy plays a crucial role in causing erectile dysfunction in T1DM. Recent research has shown that mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) is strongly linked to the development of T1DM. However, the specific mechanism by which it regulates the erectile function is not yet fully understood. OBJECTIVES: To investigate whether HMGCS2 affects erectile function in type 1 diabetic rats by regulating autophagy in corpus cavernosum endothelial cells (CCECs). MATERIALS AND METHODS: First, the rat model of T1DM was established. Then, the ratio of maximum penile intracavernous pressure (ICPmax) and mean arterial pressure (MAP) was detected to assess the erectile function in various groups, and the protein expression of HMGCS2, mTOR and p-mTOR was evaluated by western blot (WB) and immunohistochemistry (IHC). To explore the relationship between HMGCS2 and the mTOR signaling pathway in T1DM ED rats, we silenced the expression of HMGCS2 and activated the mTOR signaling pathway with MHY1485 in CCECs and then assessed the expression of beclin1, P62, LC3, autophagosome, endothelial nitric oxide synthase (eNOS), phosphorylation of eNOS (p-eNOS), and nitric oxide (NO) to evaluate autophagy and the erectile function by reverse transcription quantitative polymerase chain reaction and western blot. RESULTS: The study conducted on T1DM ED rats showed that the expression of HMGCS2 was significantly increased, while the autophagy was suppressed. Additionally, the mTOR signaling pathway was highly activated. In contrast, when HMGCS2 was silenced in vitro, p-mTOR/mTOR was reduced, and autophagy was improved. These effects were accompanied by the enhanced activity of eNOS. Furthermore, when HMGCS2 was silenced and the mTOR signaling pathway was simultaneously activated, the results revealed a decrease in autophagy as well as a reduction in activity of eNOS in comparison to just silencing HMGCS2 alone. DISCUSSION AND CONCLUSION: HMGCS2 upregulation in T1DM rats inhibited autophagy and eNOS activity by activating the mTOR pathway and led to a decrease in the erectile function.

The upregulation of miR-3945 in CD14+ monocytes is the risk factor for cardiovascular disease.

Patients with type 1 diabetes (T1DM) show an increased risk of cardiovascular disease. Bioinformatics analysis revealed that it is characterized by changes in the function of CD14+ mononuclear macrophages. The current study was to explore the potential relationship between the miR-3845/TRIM35/PKM2 and abnormal polarization of mononuclear macrophages. Using bioinformatics to analyze the gene expression of mononuclear macrophages. The polarization of macrophages was analyzed using flow cytometry, and the expression changes of TRIM35/PKM2 were analyzed using Western blot, luciferase activity assay, and co-immunoprecipitation. Database analysis showed that T1DM patients showed an abnormal increase of miR-3945 in CD14+ monocyte macrophages. miR-3945 targets TRIM35 to release PKM2 to cytometry, and PKM2 causes M1-like polarization of mononuclear macrophages. Database analysis showed that miR-3945 was abnormally upregulated in CD14+ monocytes in T1DM patients. miR-3945 upregulates the expression of PKM2 in the cytoplasm by targeting TRIM35, which leads to M1 polarization of macrophages.

Scutellarin alleviates liver injury in type 2 diabetic mellitus by suppressing hepatocyte apoptosis in vitro and in vivo.

Objective: Scutellarin is a primary active composition come from Erigeron breviscapus. It is well known that scutellarin has anti-inflammatory and antioxidant physiological functions. In this study, we detected the effects of scutellarin on hepatocyte cell apoptosis in type 2 diabetes mellitus (T2DM) rats. Methods: Sprague Dawley (SD) (6-8 weeks, 160-180 g) rats were randomly divided into six groups: control, model, scutellarin low-dose, medium-dose, high-dose treatment, and rosiglitazone positive groups; with 10 SD rats in each group (n = 10). The changes of biochemical factors in serum were detected by automatic biochemical instrument, the pathological changes of liver tissue were detected by hematoxylin and eosin (HE) staining, the apoptosis of liver tissue and cells was detected by tissue staining and flow analyzer, and the expression of apoptosis-related factors were determined by qPCR, Western blot and immunohistochemistry in liver tissues or cells. Results: The results showed that scutellarin decreased the levels of fasting blood glucose, total cholesterol, triglyceride, and low-density lipoprotein and increased the levels of high-density lipoprotein. Meanwhile, scutellarin decreased the levels of alanine transaminase (ALT) and aspartate transaminase (AST) and improved liver function. In addition, scutellarin suppressed the secretion of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and reduced hepatocyte apoptosis. Furthermore, scutellarin inhibited the expression of cleaved Caspase-3, Bax, and cytochrome C (Cyt-C) and promoted the expression of Bcl-2. Conclusion: Scutellarin can inhibit the apoptotic pathway, thereby relieving T2DM.

Cardiometabolic Risk Factors Associated With Type 2 Diabetes Mellitus: A Mechanistic Insight.

A complex metabolic condition referred to as Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and decreased insulin production. Obesity, dyslipidemia, hypertension, and chronic inflammation are just a few of the cardiometabolic illnesses that people with T2DM are more likely to acquire and results in cardiovascular issues. It is essential to comprehend the mechanistic insights into these risk variables in order to prevent and manage cardiovascular problems in T2DM effectively. Impaired glycemic control leads to upregulation of De novo lipogenesis (DNL), promote hepatic triglyceride (TG) synthesis, worsening dyslipidemia that is accompanied by low levels of high density lipoprotein cholesterol (HDL-C) and high amounts of small, dense low-density lipoprotein cholesterol (LDL-C) further developing atherosclerosis. By causing endothelial dysfunction, oxidative stress, and chronic inflammation, chronic hyperglycemia worsens already existing cardiometabolic risk factors. Vasoconstriction, inflammation, and platelet aggregation are caused by endothelial dysfunction, which is characterized by decreased nitric oxide production, increased release of vasoconstrictors, proinflammatory cytokines, and adhesion molecules. The loop of IR and endothelial dysfunction is sustained by chronic inflammation fueled by inflammatory mediators produced in adipose tissue. Infiltrating inflammatory cells exacerbate inflammation and the development of plaque in the artery wall. In addition, the combination of chronic inflammation, dyslipidemia, and IR contributes to the emergence of hypertension, a prevalent comorbidity in T2DM. The ability to target therapies and management techniques is made possible by improvements in our knowledge of these mechanistic insights. Aim of present review is to enhance our current understanding of the mechanistic insights into the cardiometabolic risk factors related to T2DM provides important details into the interaction of pathophysiological processes resulting in cardiovascular problems. Understanding these pathways will enable us to create efficient plans for the prevention, detection, and treatment of cardiovascular problems in T2DM patients, ultimately leading to better overall health outcomes.

Understanding the factors that increase the risk of type 2 diabetes: Exploring how the body works Type 2 diabetes mellitus (T2DM) is a complex condition where the body struggles to use insulin properly and doesn't produce enough of it. This often leads to other health issues like obesity, high cholesterol, high blood pressure, and chronic inflammation. These problems increase the risk of heart and blood vessel diseases in people with T2DM. To tackle these issues effectively, it's crucial to understand the underlying mechanisms. When blood sugar levels are not controlled, the body starts making more fat and storing it in the liver, leading to high triglycerides and low levels of good cholesterol. This process can block arteries, causing heart problems. High blood sugar also damages blood vessel linings, making them inflamed and less functional. This inflammation, combined with other factors like high cholesterol and insulin resistance, can lead to high blood pressure. Chronic inflammation, where the body's defense system stays active for too long, worsens these problems. In T2DM, inflammation occurs in fat tissues, making the situation even worse. Inflammatory cells infiltrate blood vessel walls, promoting plaque buildup and further worsening heart issues. Understanding these processes helps us develop better strategies to prevent, detect, and treat heart problems in people with T2DM. By targeting these mechanisms, doctors can create more effective plans to improve the overall health of individuals with diabetes and reduce the risk of cardiovascular diseases.