High Glucose Research Articles

Elevated blood glucose levels are associated with the progression of brain hypometabolism, and HDL-C and APOE4 add to this association.

Brain glucose hypometabolism has consistently been found in neurodegenerative disorders, including Alzheimer's disease (AD). High blood glucose and HDL cholesterol (HDL-C) levels have also been linked to neurodegeneration and AD. However, there is limited understanding of the relationships between dementia-related risk factors in the brain and blood. A linear mixed model was used to examine the relationship between blood glucose and HDL-C levels and the progression of brain hypometabolism, adjusting for APOE4 and other clinical covariates. The hypometabolic convergence index (HCI) was measured by fluorodeoxyglucose-18 (FDG) positron emission tomography (PET) in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data visualizations were generated to understand the joint effects of plasma glucose, HDL-C, and APOE4 on HCI. There were 336 individuals (781 observations), of whom 22.62% had AD. The majority were male (63.98%) and of white race, and 48.51% were carriers of APOE4. Over time, high blood glucose level was associated with the progression of brain glucose hypometabolism (β=0.33, 95% CI: 0.02, 0.64, p<0.05). A high plasma HDL-C level (β=1.22, 95% CI: 0.09, 2.35, p<0.05), more study visits (β=1.67, 95% CI: 1.37, 1.98, p<0.001), and being an APOE4 allele carrier (β=1.29, 95% CI: 0.15, 2.42, p<0.05) were also significant predictors of brain hypometabolism progression. APOE4 carrier status and number of visits account for the largest proportion of the variance from the fixed effects model. Random effects due to participant characteristics and fixed effects together accounted for 95.2% of the model variance. Subgroup analysis revealed that these effects were observed only in those without AD. High plasma glucose levels facilitated the progression of brain hypometabolism. The effect was more prominent in the APOE4 double-carriers with elevated HDL-C. Elevated blood glucose may reflect systemic insulin resistance, which could impair brain glucose uptake, resulting in brain hypometabolism. Controlling blood glucose and HDL-C levels in APOE4 carriers may improve brain metabolism, potentially delaying the onset of dementia.

Analysis of Patients Admitted to the Emergency Department With High Blood Glucose Level in the COVID-19 Pandemic Era

Introduction: This study aims to analyze the relationship and effects of sociodemographic characteristic data and clinical, laboratory and other findings of cases who are admitted to the emergency department (ED) with high blood glucose levels during the COVID-19 pandemic period. Method: This is a cross-sectional study in which the demographic data, blood gases, blood count and biochemical variables of adult patients admitted to the ED between 01.01.2020 and 31.05.2021 in a 17-month period were retrospectively screened and analyzed. Results: Infection was detected in 67 (10.5%) of 638 patients with blood glucose level of 300 mg/dl and above. Pneumonia was detected in 56 (8.7%) patients and 203 (31.8%) were hospitalized and 34 (5.3%) died during follow-up. SpO2 was lower (p

Prognostic Characteristics of Metabolic Dysfunction-Associated Steatotic Liver in Patients with Obesity Who Undergo One Anastomosis Gastric Bypass Surgery: A Secondary Analysis of Randomized Controlled Trial Data.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with obesity and insulin resistance (IR). Identifying characteristics that predict a higher risk of fibrosis using noninvasive methods is particularly important. We performed a secondary analysis of data from an RCT of 48 patients after one anastomosis gastric bypass (OAGB) surgery, supplemented with specifically formulated probiotics and micronutrients or control treatment for 12 weeks. Patients were categorized using alanine aminotransferase (ALAT; >35 U/L for women, >50 U/L for men), higher NAFLD fibrosis score (NFS) > -1.455), and IR (HOMA-IR > 2.0). This trial was registered at Clinicaltrials.gov (ID: NCT03585413). Abnormal ALAT was associated with high triglycerides, blood pressure (BP), glucose, and fatty liver index (FLI). NFS > -1.455 was linked to higher age, body mass, waist circumference, and FLI, and lower albumin and platelet count. HOMA-IR > 2.0 was associated with higher BP and triglycerides, lower HDL-cholesterol, higher serum transaminases, and higher probabilities of steatosis and fibrosis. Twelve weeks postoperatively, patients with NFS > -1.455 showed greater reductions in body mass, systolic BP, serum insulin, and HbA1c, whereas those with NFS ≤ -1.455 showed improvements in FLI and lipid metabolism but had high glucose concentrations. Patients with HOMA-IR ≤ 2.0 also had high glucose concentrations. The evaluation of common biomarker scores for fibrosis and IR may help clinicians to recognize severe NAFLD and improve the outcomes of OAGB surgery.

Temporal trend and attributable risk factors of Alzheimer's disease and other dementias burden in China: Findings from the Global Burden of Disease Study 2021.

We examined the burden of Alzheimer's disease and other dementias (ADOD) and attributable factors at the national and provincial levels in China. Using the Global Burden of Diseases Study 2021, we estimated incidence, prevalence, mortality rate, disability-adjusted life years (DALYs), and the ratio of years lived with disability (YLD) to DALYs for ADOD in China. Estimated annual percentage changes (EAPCs) were used to quantify the temporal trends from 1990 to 2021. In 2021, China experienced the highest ADOD burden among Group of 20 member nations. The EAPCs for age-standardized rates for incidence, age-standardized rates for prevalence, and age-standardized mortality rate were 0.41 (uncertainty intervals [UIs] 0.34-0.49); 0.44 (UI: 0.36-0.52); and -0.19 (UI: -0.23 to -0.15), respectively. Between 1990 and 2021, the number of people with ADOD increased by 322.18% and DALYs associated with ADOD increased by 272.71%; most of these increases were explained by population aging. Considering the aging Chinese population, targeted strategies to prevent dementia are urgently needed. China experienced the highest dementia burden among Group of 20 member nations. High body mass index, high fasting plasma glucose, and smoking were major risk factors for Alzheimer's disease and other dementias (ADOD) burden. Since 1990, the incidence and prevalence of ADOD increased substantially in China. The mortality rate related to ADOD decreased consistently. Considering the aging Chinese population, targeted strategies are urgently needed.

Role of Circulating Biomarkers in Diabetic Cardiomyopathy.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has alarmingly increased in incidence in recent decades. One of the most serious complications of T2DM is diabetic cardiomyopathy (DCM), an often underrecognized yet severe condition that is a leading cause of mortality among diabetic patients. In the early stages of DCM, patients typically show no symptoms and maintain normal systolic and diastolic left ventricle function, making early detection challenging. Currently available clinical markers are often not specific enough to detect the early stage of DCM. Conventional biomarkers of cardiac mechanical stress and injury, such as natriuretic peptides (NPs) and cardiac troponin I (cTnI), have shown limited predictive value for patients with T2DM. NPs have proven efficacy in detecting diastolic dysfunction in diabetic patients when used alongside 2D echocardiography, but their utility as biomarkers is limited to symptomatic individuals. While cTnI is a reliable indicator of general cardiac damage, it is not specific to cardiac injury caused by high glucose levels or T2DM. This underscores the need for research into biomarkers that can enable early diagnosis and management of DCM to reduce mortality rates. Promising novel biomarkers that showed good performance in detecting diastolic dysfunction or heart failure in diabetic patients include galectin-3, ST2, FGF-21, IGFBP-7, GDF-15, and TGF-β. This review summarizes the current understanding of DCM biomarkers, aiming to generate new ideas for the early recognition and treatment of DCM by exploring related pathophysiological mechanisms.

Non-alcoholic fatty liver disease: Genetic susceptibility

The prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) is increasing, particularly in individuals who consume minimal to no alcohol. Currently, NAFLD affects at least 32% of the global population. Although not all but approximately 5-10% cases of NAFLD progress to non-alcoholic steatohepatitis (NASH), a condition arising from lipotoxicity. Patients with NASH may further develop liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, it is important to note that progression from NAFLD to NASH and HCC is not inevitable for all patients. The pathogenesis of HCC in the context of NAFLD and NASH remains poorly understood, however, fat accumulation, often due to obesity or metabolic syndrome, leads to lipotoxicity. In individuals with type 2 diabetes (T2D), elevated insulin levels promote lipolysis in adipose tissue and activate lipid-synthesizing enzymes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1), which contribute to lipid accumulation in the liver. Additionally, high glucose levels in T2D can alter gene regulation by activating carbohydrate response-element binding protein (ChREBP) and insulin can increase the activity of sterol regulatory element binding protein (SREBP-1c). These lipogenic transcription factors are known to directly or indirectly activate patatin-like phospholipase domain-containing protein 3 (PNPLA3). Recent research has found elevated levels of angiotensinogen (AGT) and des-angiotensin in both experimental animals and patients with NAFLD. Emerging evidence highlights the significance of genetic factors in the risk of developing NAFLD. Here we explore the association between specific genes and hepatosteatosis, detailing the roles of T2D and obesity in the progression from NAFLD to NASH, and involvement of hepatic stellate cells in liver fibrosis. Additionally, we examine the impact of genes such as PNPLA3, MBOAT7, TM6SF2, GKRP, CCN3, and AGT as well as role of single nucleotide polymorphisms in gene regulation and their contribution to the risk of NAFLD.

Melatonin alleviates high glucose-induced cardiomyocyte injury through suppressing mitochondrial FUNDC1-DRP1 axis.

To use H9c2 cardiomyocytes to establish a diabetic cardiomyopathic model by exposing these cells to high glucose (HG), followed by treating them with melatonin (MEL) or plasmid vectors overexpressing FUN14 Domain Containing 1 (FUNDC1). We employed quantitative real-time PCR, mitochondrial staining, and biochemical assays to measure the activity of various antioxidant and mitochondrial complex functions under various treatment conditions. Our results showed that HG induced the expression of FUNDC1 and increased mitochondrial oxidative stress and fragmentation, while MEL treatment reversed most of these pathological effects. Moreover, HG exposure activated dynamin-related protein 1 expression and its translocation to mitochondria. Modulation of AMP-activated protein kinase level was found to be another pathological hallmark. In silico molecular docking, analysis revealed that MEL could directly bind the catalytic groove of FUNDC1 through Van der Waal's force and hydrogen bonding. Finally, MEL ameliorated diabetic cardiomyopathy-induced mitochondrial injury through FUNDC1 in vivo. Hyperglycemia induced mitochondrial fragmentation and altered electron transport chain complex functions, which could be ameliorated by MEL treatment, suggesting its potential as a cardiovascular therapeutic.

Abstract C109: Identifying a novel metabolic reprogramming strategy to inhibit diabetes-associated TNBC in African American

Abstract Cancer cells have an increased glucose metabolism, primarily characterized by augmented glucose uptake and aerobic glycolysis, converting glucose into pyruvate, eventually producing lactate. Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of death among women in the United States. The triple-negative breast cancer (TNBC) subgroup is the most aggressive, metastatic, and refractory because of the absence of the three characteristic receptors: Estrogen (ER), progesterone (PR), and human epidermal growth factor (Her2/neu), representing approximately 10-15% of all BC cases. Racial disparities analysis demonstrates that African American (AA) has a higher incidence of TNBC subtype, with an earlier onset, more advanced stage, more aggressive histologic features, and poor survival, compared to other ethnic groups. Hyperglycemia affects the cancer progression through metabolic reprogramming and molecular alterations. AA women with Type 2 diabetes (T2D) are at increased risk of developing ER-negative BC. The reasonable combination therapy of metformin with NF-𝜅Bi and MCT4i, is promising because it can rapidly disable tumor cell growth but with a minor effect on normal cells, holding promise as an anti-BC treatment. Because of the potential side effects of MCT4 inhibitors and the potent inhibitory effect of microRNA on target genes, we consider using microRNA instead of inhibitors to suppress MCT4 expression. We will investigate the anti-diabetes-associated TNBC effect of the MRS, consisting of blocking lactate export via MCT4 degradation by miR-206, in combination with promoting lactate production via forcing glycolysis with metformin and NF-𝜅Bi treatment, in a preclinical study of AA women. Moreover, our previous study and other studies have also shown an elevated expression of Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) in BC tissues and cells, particularly in metastatic TNBC. We will also explore the molecular mechanisms by which high glucose (HG) leads to lactate accumulation in BC cells. Our overall strategy is that excessive glucose uptake upregulates the MCT4 through a MALAT1/miR-206/MCT4 axis, miR-206-directed MRS shifts glucose metabolism from Oxidative phosphorylation (OXPHOS) to glycolysis, increasing lactate production. Meanwhile, blocking the export of excessive lactate through MCT4 degradation causes high intracellular lactate accumulation and a decrease in intracellular pH (pHi), resulting in metabolic crisis and BC cell death. Due to a complex interplay between hyperglycemia and cancer, antihyperglycemic drugs have often been devised in combination with anticancer drugs for cancer treatment. Our proposed approach will broadly impact the field by providing a novel idea for therapies targeting cancer cell lactate metabolism. In the long term, these studies may reveal an effective therapeutic strategy for diabetes-associated BC, especially in AA women. Citation Format: Qiongyu Hao, Yong Wu, Yanyuan Wu, Jaydutt Vadgama. Identifying a novel metabolic reprogramming strategy to inhibit diabetes-associated TNBC in African American [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C109.

Poricoic acid a ameliorates high glucose-induced podocyte injury by regulating the AMPKα/FUNDC1 pathway.

Poricoic acid A (PAA), a major triterpenoid component of Poria cocos with anti-tumor, anti-fibrotic, anti-inflammatory, and immune-regulating activities, has been shown to induce podocyte autophagy in diabetic kidney disease (DKD) by downregulating FUN14 domain containing 1 (FUNDC1). This study aimed to identify the role of adenosine monophosphate-activated protein kinase alpha (AMPKα) in PAA-mediated phosphorylation of FUNDC1 in podocyte injury occurring in the pathogenesis of DKD. A cellular model of renal podocyte injury was established by culturing MPC5 cells under high-glucose (HG) conditions. MPC5 cells were subjected to transfection with small interfering RNA (siRNA) targeting AMPKα or siRNA targeting FUNDC1, an AMPKα activator, or PAA. PAA treatment induced the phosphorylation of AMPKα in HG-cultured podocytes. AMPKα activation was implicated in the inhibitory effect of PAA on FUNDC phosphorylation in HG-cultured podocytes. Treatment targeting the AMPKα activator also significantly augmented proliferation, migration, mitochondrial membrane potential, and autophagy levels, while reducing apoptosis levels, inhibiting oxidative stress, and suppressing the release of proinflammatory factors in HG-cultured MPC5 cells. In contrast, insufficient expression of AMPKα reversed the effects of PAA on the proliferation, migration, and apoptosis of podocytes and further exacerbated the reduction of phosphorylated FUNDC1 expression in podocytes under HG conditions. AMPKα is involved in the regulation of FUNDC1 phosphorylation by PAA in HG-induced podocyte injury. Furthermore, the AMPKα/FUNDC1 pathway plays a crucial regulatory role in HG-induced podocyte injury. These findings support AMPKα, FUNDC1, and the AMPKα/FUNDC1 pathway as targets for PAA intervention.

Abstract C029: Surface localization and targeting of enolase-1 (ENO1) as a novel theranostic approach for docetaxel-resistant neuroendocrine prostate cancer

Abstract Prostate cancer (PCa) is American men's second most common cancer. This cancer exhibits the most significant racial disparities among all cancer types, with elevated incidence and mortality in men of African ancestry. Although taxane-based chemotherapy with docetaxel (DTX) and cabazitaxel is the last line of defense for metastatic Castration Resistant Prostate Cancer (mCRPC), it invariably fails due to the development of chemoresistance. The protein-specific membrane antigen (PSMA) is currently an effective target for the imaging and therapy of mCRPC. However, although PSMA radioligand therapy (PSMA-RLT) is a theranostic option for men with advanced PCa, about 30% have a limited response to this treatment, particularly those that lack PSMA. In addition, some reports indicate that PSMA is suppressed in neuroendocrine PCa (NEPC), making it an unreliable theranostic target for this aggressive subtype. The glycolytic enzyme Enolase (ENO) is a promising theranostic alternative due to its cell surface localization in many human tumors. We hypothesized that ENO1 is abundant on the surface of NEPC-like cell lines and can be targeted with small molecule inhibitors (SMIs) that could potentially be used as theranostic agents. Western blotting (WB) analysis revealed that DTX-sensitive PCa cell lines expressing NEPC markers express both ENO1 and ENO2. By contrast, DTX-resistant NEPC-like cells only express ENO1 and therefore have a metabolic vulnerability due to the loss of ENO2. Additionally, we observed by WB and confocal microscopy changes in the expression and localization of ENO1 in NEPC-like cell lines under different glucose concentrations. Our results showed that under high glucose conditions, found on metabolically active metastatic tumors, ENO1 is highly abundant on the cell surface, making it a promising candidate target for theranostics. However, standard glucose conditions resulted in ENO1 downregulation, most likely due to inhibition of the activity of the c-MYC oncogene and upregulation of MBP1, the small splice variant of ENO1 that blocks the transcriptional activity of c-MYC. We also evaluated the cytotoxicity of SMIs designed to target ENO1 in chemoresistant NEPC-like cell lines using MTT viability assays, clonogenic assays, and Hoffman Modulation microscopy imaging. We observed that these inhibitors can significantly impair, with IC50 values at low micromolar concentrations, the proliferation and clonogenicity of NEPC cell lines. These results support our long-term goal to identify an alternative theranostic option for patients with NEPC by establishing ENO1 as a novel theranostic target. Citation Format: Krystal R. Santiago Torres, Kristen Whitley, Alfonso Duran, Bhaskar Das, Carlos Casiano, Frankis Almaguel. Surface localization and targeting of enolase-1 (ENO1) as a novel theranostic approach for docetaxel-resistant neuroendocrine prostate cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C029.

Computational Modeling of Sodium-Ion-Channel-Based Glucose Sensing Biophysics to Study Cardiac Pacemaker Action Potential

Elevated blood glucose levels, known as hyperglycemia, play a significant role in sudden cardiac arrest, often resulting in sudden cardiac death, particularly among those with diabetes. Understanding the internal mechanisms has been a challenge for healthcare professionals, leading many research groups to investigate the relationship between blood glucose levels and cardiac electrical activity. Our hypothesis suggests that glucose-sensing biophysics mechanisms in cardiac tissue could clarify this connection. To explore this, we adapted a single-compartment computational model of the human pacemaker action potential. We incorporated glucose-sensing mechanisms with voltage-gated sodium ion channels using ordinary differential equations. Parameters for the model were based on existing experimental studies to mimic the impact of glucose levels on pacemaker action potential firing. Simulations using voltage clamp and current clamp techniques showed that elevated glucose levels decreased sodium ion channel currents, leading to a reduction in the pacemaker action potential frequency. In summary, our mathematical model provides a cellular-level understanding of how high glucose levels can lead to bradycardia and sudden cardiac death.

Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling

Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9–39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9–39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.

Noncommunicable disease burden in Brazil and its states from 1990 to 2021, with projections for 2030

ObjectivesThe aim of this study was to analyse the burden of disease due to noncommunicable diseases (NCDs) between 1990 and 2021 in Brazil. In addition, this study compared mortality from NCDs with mortality from all causes and COVID-19, analysed NCD mortality trends and projections for 2030, and analysed NCD mortality rates and risk factors attributed to these deaths among the 27 states of Brazil. Study designEcological studies. MethodsThis study used the Global Burden of Disease study (GBD) database from 1990 to 2021. Premature deaths from four NCDs (neoplasms, cardiovascular disease, chronic respiratory diseases and diabetes mellitus) were analysed. The following metrics were used to analyse the burden of NCDs in Brazil: absolute number of deaths, proportional mortality, mortality rate, years of life lost due to premature death (YLL), years lived with disabilities (YLD) and disability-adjusted years of life lost due to premature death (DALY). For comparison between the years studied and states, age-standardised rates were used. ResultsFinding from this study showed that there was increase in the proportion of premature deaths due to NCDs between 1990 and 2019 (29.4 % in 1990, 30.8 % in 2019), and a reduction in 2021 (24.7 %). The mortality rates, DALY and YLL from NCDs declined between 1990 and 2019 (−37.7 %, −34.5 % and −38.3 %, respectively); however, a stability in mortality rates, DALY, YLD, YLL was observed between 2019 and 2021 (−0.1 %, 0.7 %, −0.1 % and 0.8 %, respectively). Between 1990 and 2021, there was a decline in mortality rates, DALY and YLL for most states and an increase in YLD rates. However, results suggest that the Sustainable Development Goal (SDG) for the reduction in mortality from NCDs by one-third by 2030 will not be achieved. The main risk factors associated with premature death from NCDs in 2021 were high blood pressure, tobacco use, dietary risks, high body mass index (BMI) and high blood glucose levels. The correlation between sociodemographic index and percentage change in mortality rates was significant for the following total NCDs, cardiovascular disease, chronic respiratory disease, diabetes and neoplasms. ConclusionsThe current study highlights the importance of deaths from NCDs in Brazil and the worsening of mortality rates since 2016, as a result of austerity measures and the COVID-19 pandemic, which compromises the achievement of the SDG reduced mortality targets for NCDs. There was a reduction in risk factors for NCDs, mainly behavioural, although metabolic risk factors are of great concern and require new strategies to promote health, prevention and comprehensive care.

High glucose induces DNA methyltransferase 1 dependent epigenetic reprogramming of the endothelial exosome proteome in type 2 diabetes

In response to hyperglycemia, endothelial cells (ECs) release exosomes with altered protein content and contribute to paracrine signalling, subsequently leading to vascular dysfunction in type 2 diabetes (T2D). High glucose reprograms DNA methylation patterns in various cell/tissue types, including ECs, resulting in pathologically relevant changes in cellular and extracellular proteome. However, DNA methylation-based proteome reprogramming in endothelial exosomes and associated pathological implications in T2D are not known. Hence, in the present study, we used Human umbilical vein endothelial cells (HUVECs), High Fat Diet (HFD) induced diabetic mice (C57BL/6) and clinical models to understand epigenetic basis of exosome proteome regulation in T2D pathogenesis . Exosomes were isolated by size exclusion chromatography and subjected to tandem mass tag (TMT) labelled quantitative proteomics and bioinformatics analysis. Immunoblotting was performed to validate exosome protein signature in clinically characterized individuals with T2D. We observed ECs cultured in high glucose and aortic ECs from HFD mouse expressed elevated DNA methyltransferase1 (DNMT1) levels. Quantitative proteomics of exosomes isolated from ECs treated with high glucose and overexpressing DNMT1 showed significant alterations in both protein levels and post translational modifications which were aligned to T2D associated vascular functions. Based on ontology and gene-function-disease interaction analysis, differentially expressed exosome proteins such as Thrombospondin1, Pentraxin3 and Cystatin C related to vascular complications were significantly increased in HUVECs treated with high glucose and HFD animals and T2D individuals with higher levels of glycated hemoglobin. These proteins were reduced upon treatment with 5-Aza-2’-deoxycytidine. Our study shows epigenetic regulation of exosome proteome in T2D associated vascular complications.

Effect of Different Glucose Levels and Glycation on Meningioma Cell Migration and Invasion.

Meningiomas are predominantly benign tumors, but there are also malignant forms that are associated with a poor prognosis. Like almost all tumors, meningiomas metabolize glucose as part of aerobic glycolysis (Warburg effect) for energy supply, so there are attempts to influence the prognosis of tumor diseases using a glucose-reduced diet. This altered metabolism leads to so called hallmarks of cancer, such as glycation and glycosylation. In this study, we investigated the influence of low (3 mM), normal (5.5 mM) and high glucose (15 mM) on a malignant meningioma cell line (IOMM-Lee, WHO grade 3). In addition, the influence of methylglyoxal, a by-product of glycolysis and a precursor for glycation, was investigated. Impedance-based methods (ECIS and RTCA) were used to study migration and invasion, and immunoblotting was used to analyze the expression of proteins relevant to these processes, such as focal adhesion kinase (FAK), merlin or integrin ß1. We were able to show that low glucose reduced the invasive potential of the cells, which was associated with a reduced amount of sialic acid. Under high glucose, barrier function was impaired and adhesion decreased, which correlated with a decreased expression of FAK.

Carbohydrate response element-binding protein (ChREBP) mediates decreased SNAP25 expression in islets from diabetic Goto-Kakizaki (GK) rats.

SNAP25 plays an essential role in the glucose-stimulated insulin secretion (GSIS) of pancreatic β-cells. Carbohydrate response element-binding protein (ChREBP) is an important transcription factor in β-cells and, in this study, we aimed to explore whether ChREBP regulates SNAP25 expression in β-cells. We show that diabetic Goto-Kakizaki (GK) rats exhibited impaired insulin secretion and hyperglycemia, along with decreased SNAP25 expression and ChREBP phosphorylation in islets. SNAP25 knockdown decreased GSIS in β-cells, while SNAP25 overexpression increased GSIS in β-cells. Activation or overexpression of ChREBP led to reduced SNAP25 expression and subsequent suppression of GSIS. Conversely, ChREBP knockdown mitigated the reduction in SNAP25 expression caused by high glucose. Mechanistically, the activation of ChREBP by high glucose increased its occupancy and decreased the level of H3K4me3 at the Snap25 promoter. Our findings reveal the novel regulatory mechanisms of SNAP25 expression in β-cells and suggest that SNAP25 may be involved in the regulation of β-cell secretory function controlled by ChREBP.

Diabetes and Cognitive Decline: An Innovative Approach to Analyzing the Biophysical and Vibrational Properties of the Hippocampus.

Diabetes Mellitus (DM) is a disease characterized by high blood glucose levels, known as hyperglycemia. Diabetes represents a risk factor for the development of neurodegenerative diseases, such as Alzheimer's Disease (AD), one of the most prevalent neurodegenerative diseases worldwide, which leads to progressive mental, behavioral, and functional decline, affecting many brain structures, especially the hippocampus. Here, we aim to characterize the ultrastructural, nanomechanical, and vibrational changes in hyperglycemic hippocampal tissue using atomic force microscopy (AFM) and Raman spectroscopy. DM was induced in rats by streptozotocin injection (type 1) or dietary intervention (type 2). Cryosections of the hippocampus were prepared and analyzed on an MM8 AFM (Bruker) in Peak Force Quantitative Nanomechanics mode, performing 25 μm2 scans in 9 regions of 3 samples from each group. Ultrastructural and nanomechanical data such as surface roughness, area, volume, Young's modulus, and adhesion were evaluated. The hippocampal samples were also analyzed on a T64000 Spectrometer (Horiba), using a laser λ = 632.8 nm, and for each sample, four spectra were obtained in different regions. AFM analyses show changes on the ultrastructural scale since diabetic animals had hippocampal tissue with greater roughness and volume. Meanwhile, diabetic tissues had decreased adhesion and Young's modulus compared to control tissues. These were corroboratedby Raman data that shows changes in the molecular composition of diabetic tissues. The individual spectra show that the most significant changes are in the amide, cholesterol, and lipid bands. Overall, the data presented here show that hyperglycemia induces biophysical alterations in the hippocampal tissue of diabetic rats, providing novel biophysical and vibrational cues on the relationship between hyperglycemia and dementia.

Application of self-assembled antibacterial nanofiber loaded oriented artificial skin in infected diabetic-related wound regeneration

Diabetic patients develop wounds that exhibit delayed healing, prolonged inflammatory responses, and slower epithelialization kinetics compared to non-diabetic patients. Diabetic foot ulcers(DFUs) affect approximately 18.6 million people worldwide. The presence of a high glucose microenvironment in DFUs results in the significant accumulation of bacterial infection and advanced glycation end products (AGEs). To solve this, a self-assemble antibacterial nanofiber(ANF) loaded oriential artificial skin (ANF@OAS) was introduced in this research, which is consisted of L/D-phenylalanine derivatives coupled the natural antimicrobial peptides. The ANF@OAS can effectively reduce AGEs production and suppress multiple resistant bacteria. Additionally, the ANF@OAS can suppress infection and stimulate wound healing in infected diabetic mice.

Hemocompatibility and hemorheological activity of aqueous extracts from Phyllanthus sellowianus: effects on in vitro glycated erythrocytes

IntroductionPhyllanthus sellowianus (Klotzsch) Müll Arg. is an Argentinian and Brazilian native plant used to treat diabetes. In vascular diseases like diabetes, erythrocytes form anomalous aggregates resistant to dissociation, associated with high glucose levels. This work aims to evaluate the hemocompatibility and hemorheological activity of aqueous extracts from P. sellowianus and its anti-diabetic activity using in vitro glycated erythrocytes as occur by hyperglycemia. MethodsFor this work, P. sellowianus specimens were collected on the Nogoyá River coast, Argentina, and morphoanatomical identified. Infusion, maceration, digestion, and cooking extracts were prepared with collected leaves and bark using saline as solvent. The osmolality and pH of the extracts were adjusted to an adequate interaction with human cells. Red blood cells (RBCs) from healthy donors (n=3) were used and incubated with glucose solution for in vitro simulation of the hyperglycemia effects. RBCs were incubated with the aqueous extracts to assess their hemocompatibility. Also, glycated RBCs were incubated with the extracts to analyze their anti-diabetic properties. Erythrocyte Rheometer and Optical Chip Aggregameter were used for the hemorheological evaluation. ResultsAssays with the different P. sellowianus extracts modified the viscoelasticity and aggregation of RBCs. Moreover, in some cases, P. sellowianus extracts reversed the in vitro glycation effect and hemorheological parameters got nearer control values. ConclusionThese results would be helpful for the development of pharmaceutical formulations using this species or its phytocomponents. They also give relevant information to understand the action mechanisms through which these extracts or their components can be used as anti-diabetics in Phytomedicine.

Astaxanthin attenuates glucose-induced liver injury in largemouth bass: role of p38MAPK and PI3K/Akt signaling pathways

BackgroundAstaxanthin (ASX) has been documented to exert beneficial influence on various processes in fish. Largemouth bass (Micropterus salmoides) serves as a common model for studying glucose-induced liver disease, making it imperative to investigate the regulatory mechanisms underlying its liver health.MethodsLargemouth bass were fed with a control diet (CON), a high carbohydrate diet (HC), or a HC diet supplemented astaxanthin (HCA) for 8-weeks, followed by the glucose tolerance test (GTT). Primary hepatocytes were treated with low glucose and high glucose combined with different concentrations of astaxanthin for 48 h. The histopathology, enzymology, transcriptomics, molecular biology and cell biology were combined to investigate the mechanism of liver injury.ResultsThis study provides evidence for the protective effects of ASX against growth performance reduction and hepatic liver injure in largemouth bass fed HC diet. In GTT, HCA diet exhibited an improvement in glucose tolerance following glucose loading. Although HCA diet did not restore the expression of insulin resistance-related genes in livers at different time during the GTT, the addition of ASX in the long-term HC diet did improve the insulin resistance pathway by regulating the PTP1B/PI3K/Akt signaling pathway. Hepatic transcriptome analyses showed that ASX plays an essential role in the modulation of glucose homeostasis in response to treated with HC diet. In in vitro study, ASX treatment resulted in an exaltation in cell viability and a reduction in the rate of cell apoptosis and reactive oxygen species (ROS). Additionally, astaxanthin was observed to improve apoptosis induced by high-glucose via p38MAPK/bcl-2/caspase-3 signaling pathway.ConclusionsAstaxanthin exhibited a protective effect against apoptosis by regulating p38MAPK/bcl-2/caspase-3 pathway, and ameliorated insulin resistance by activating the PTP1B/PI3K/Akt pathway. This study elucidated the mechanism of astaxanthin in the liver injury of largemouth bass from a new perspective and provided a new target for the treatment of insulin resistance.Graphical