High Glucose Research Articles

HDAC/H3K27ac-mediated transcription of NDUFA3 exerts protective effects on high glucose-treated human nucleus pulposus cells through improving mitochondrial function

Diabetes mellitus (DM) is a well-documented risk factor of intervertebral disc degeneration (IVDD). The current study was aimed to clarify the effects and mechanisms of NADH: ubiquinone oxidoreductase subunit A3 (NDUFA3) in human nucleus pulposus cells (HNPCs) exposed to high glucose. NDUFA3 was overexpressed in HNPCs via lenti-virus transduction, which were co-treated with high glucose and rotenone (a mitochondrial complex I inhibitor) for 48 h. Cell activities were assessed for cell viability, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) ratio, oxygen consumption rate (OCR) and mitochondrial complexes I activities. High glucose decreased cell viability, increased apoptotic cells, increased ROS production, decreased MMP levels and OCR values in HNPCs in a dose-dependent manner. Rotenone co-treatment augmented the high glucose-induced injuries on cell viability, apoptosis, ROS production and mitochondrial function. NDUFA3 overexpression counteracted the high glucose-induced injuries in HNPCs. HDAC/H3K27ac mechanism was involved in regulating NDUFA3 transcription. NDUFA3 knockdown decreased cell viability and increased apoptotic cells, which were reversed by ROS scavenger N-acetylcysteine. HDAC/H3K27ac-mediated transcription of NDUFA3 protects HNPCs against high glucose-induced injuries through suppressing cell apoptosis, eliminating ROS, improving mitochondrial function and oxidative phosphorylation. This study sheds light on candidate therapeutic targets and deepens the understanding of molecular mechanisms behind DM-induced IVDD.

Identification of the Shared Gene Signatures Between Alzheimer's Disease and Diabetes-Associated Cognitive Dysfunction by Bioinformatics Analysis Combined with Biological Experiment.

The connection between diabetes-associated cognitive dysfunction (DACD) and Alzheimer's disease (AD) has been shown in several observational studies. However, it remains controversial as to how the two related. To explore shared genes and pathways between DACD and AD using bioinformatics analysis combined with biological experiment. We analyzed GEO microarray data to identify DEGs in AD and type 2 diabetes mellitus (T2DM) induced-DACD datasets. Weighted gene co-expression network analysis was used to find modules, while R packages identified overlapping genes. A robust protein-protein interaction network was constructed, and hub genes were identified with Gene ontology enrichment and Kyoto Encyclopedia of Genome and Genome pathway analyses. HT22 cells were cultured under high glucose and amyloid-β 25-35 (Aβ25-35) conditions to establish DACD and AD models. Quantitative polymerase chain reaction with reverse transcription verification analysis was then performed on intersection genes. Three modules each in AD and T2DM induced-DACD were identified as the most relevant and 10 hub genes were screened, with analysis revealing enrichment in pathways such as synaptic vesicle cycle and GABAergic synapse. Through biological experimentation verification, 6 key genes were identified. This study is the first to use bioinformatics tools to uncover the genetic link between AD and DACD. GAD1, UCHL1, GAP43, CARNS1, TAGLN3, and SH3GL2 were identified as key genes connecting AD and DACD. These findings offer new insights into the diseases' pathogenesis and potential diagnostic and therapeutic targets.

Discovering the anti-diabetic potential of pomegranate peel metabolites by examining molecular interplay with the thioredoxin-interacting protein.

Medicinal plants like Punica granatum (pomegranate) have traditional uses against diabetes, inflammation and other diseases. The study was initiated to get an insight into the interaction tendency of P. granatum derived compounds with diabetes associated human thioredoxin-interacting protein (TXNIP). High glucose in diabetes induces production of TXNIP resulting in β-cells apoptosis. Its inhibition might reduce the diabetes incidence. To elucidate the therapeutic potential of P. granatum peel against diabetes through GC-MS based identification of extracted compounds followed by application of computational algorithms. P. granatum peel extracts were screened for antioxidant, anti-inflammatory, anti-diabetic, antimicrobial and wound healing properties. Phytochemical and GC-MS based analysis were performed to identify the bioactive compounds. Molecular docking analysis was performed by Auto Dock Vina to predict the binding tendency of P. granatum derived compounds with TXNIP. The peel exhibited antioxidant, anti-inflammatory and anti-diabetic activities, which were attributed to phytochemicals like phenols, tannins and steroids. GC-MS analysis identified 3,5-octadien-2-one, 1H-pyrrole -2,5-dione, Beta-D-lyxofuranoside, 5-O-(beta-D-lyxofuranosyl)-decyl, diethyl phthalate, 9-octadecenoic acid (Z)-, methyl ester, hexadecanoic acid, methyl ester, n-hexadecanoic acid, tetradecane, 2,6,10-trimethyl, bis (2-ethylhexyl) phthalate, decane, 3,8-dimethyl, 9-octadecenoic acid (Z)-, methyl ester and bis (2-ethylhexyl) phthalate in P. granatum peel extracts. Docking analysis revealed high binding affinities of bis (2-ethylhexyl) phthalate and 9-octadecenoic acid with TXNIP i.e., -4.5 and -5.0 kcal/mol, respectively, reflecting these compounds as potent antidiabetic agents. This study validates the traditional uses of P. granatum peel and demonstrates how computational approaches can uncover pharmacologically active phytochemicals. The results suggest P. granatum peel is a promising source of novel therapeutics against diabetes, inflammation, and oxidation. Further studies on the optimization of identified ligands are warranted.

Revolutionizing Diabetes Care: The Role of Marine Bioactive Compounds and Microorganisms.

Diabetes is a metabolic condition characterized by high blood glucose levels. Aquatic products like microalgae, bacteria, seagrasses, macroalgae, corals, and sponges have been investigated for potential anti-diabetic properties. We looked at polyphenols, peptides, pigments, and sterols, as well as other bioactive substances found in marine resources, to see if they could help treat or manage diabetes, in addition to describing the several treatment strategies that alter diabetes and its implications, such as inhibition of protein tyrosine phosphatases 1B (PTP1B), α-glucosidase, α-amylase, dipeptidyl peptidase IV (DPP-IV), aldose reductase, lipase, glycogen synthase kinase 3β (GSK-3β), and insulin resistance prevention, promotion of liver antioxidant capacity, natural killer cell stimulant, anti-inflammatory actions, increased AMP-activated protein kinase (AMPK) phosphorylation and sugar and metabolism of the lipid, reducing oxidative stress, and β-pancreatic cell prevention. This study highlights the revolutionary potential of marine bioactive compounds and microorganisms in transforming diabetes care. We believe in a future in which innovative, sustainable, and efficient therapeutic approaches will result in improved quality of life and better outcomes for people with diabetes mellitus by forging a new path for treatment, utilizing the power of the world's oceans, and capitalizing on the symbiotic relationship between humans and the marine ecosystem. This study area offers optimism and promising opportunities for transforming diabetes care.

Tracking multidrug resistant tuberculosis: a 30-year analysis of global, regional, and national trends.

To provide valuable insights for targeted interventions and resource allocation, our analysis delved into the multifaceted burden, trends, risks, and projections of multi drug resistant tuberculosis (MDR-TB). This research employed data from the Global Burden of Disease (GBD) 2019 dataset, which used a comparative risk assessment to quantify the disease burden resulting from risk factors. Initially, this database was utilized to extract details concerning the disability-adjusted life years (DALYs), mortality, incidence, and the number of individuals afflicted by MDR-TB. Subsequently, regression analyses were conducted using the Joinpoint program to figure average annual percent change (AAPC) to ascertain the trend. Thirdly, the age-period-cohort model (APCM) was adopted to analyze evolutions in incidence and mortality. Finally, utilizing the Nordpred model within R software, we projected the incidence and mortality of MDR-TB from 2020 to 2030. MDR-TB remained a pressing global health concern in regions with lower socio-demographic indexes (SDI), where the AAPC in DALYs topped 7% from 1990 to 2019. In 2019, the cumulative DALYs attributed to MDR-TB tallied up to 4.2 million, with India, the Russian Federation, and China bearing the brunt. Notably, the incidence rates have shown a steadfast presence over the past decade, and a troubling forecast predicts an uptick in these areas from 2020 to 2030. Additionally, the risk of contracting MDR-TB grew with advancing age, manifesting most acutely among men aged 40+ in lower SDI regions. Strikingly, alcohol consumption had been identified as a significant contributor, surpassing the impacts of smoking and high fasting plasma glucose, leading to 0.7 million DALYs in 2019. A robust strategy is needed to end tuberculosis (TB) by 2030, especially in lower SDI areas.

P4HB regulates the TGFβ/SMAD3 signaling pathway through PRMT1 to participate in high glucose-induced epithelial-mesenchymal transition and fibrosis of renal tubular epithelial cells

BackgroundDiabetic nephropathy (DN) is a common complication of diabetes mellitus, and Prolyl 4-Hydroxylase Subunit Beta (P4HB) expression is increased in high glucose (HG)-induced renal tubular epithelial cells (TECs). But it’s role in HG-induced TECs remains to be elucidated.MethodsThe HK-2 cells were induced using HG and transfected with SiRNA-P4HB. DCFH-DA staining was utilized for the detection of cellular levels of ROS. WB and immunofluorescence were utilized to detect the expression of P4HB, epithelial-mesenchymal transition (EMT), fibrosis, and TGFβ/SMAD3-related proteins in HK-2 cells. Online databases were utilized for predicting the interaction target of P4HB, and immunoprecipitation (IP) experiments were employed to validate the binding of P4HB with the target. SiRNA and overexpression vectors of target gene were used to verify the mechanism of action of P4HB.ResultsHG induced an increase in the expression of P4HB and TGFβ, p-SMAD3, and ROS in HK-2 cells. Furthermore, HG downregulated the expression of E-cadherin and upregulated the expression of N-cadherin, Vimentin, α-SMA, Fibronectin, Collagen IV, SNAIL, and SLUG in HK-2 cells. Interfering with P4HB significantly reversed the expression of these proteins. Database predictions and IP experiments showed that P4HB interacts with PRMT1, and the expression of PRMT1 was increased in HG-induced HK-2 cells. Interfering with PRMT1 inhibited the changes in expression of EMT and fibrosis related proteins induced by HG. However, overexpression of PRMT1 weakened the regulatory effect of P4HB interference on the EMT, fibrosis, and TGFβ/SMAD3-related proteins in HK-2 cells.ConclusionP4HB regulated the TGFβ/SMAD3 signaling pathway through PRMT1 and thus participates in HG-induced EMT and fibrosis in HK-2 cells.

Mealtime prediction using wearable insulin pump data to support diabetes management

Many patients with diabetes struggle with post-meal high blood glucose due to missed or untimely meal-related insulin doses. To address this challenge, our research aims to: (1) study mealtime patterns in patients with type 1 diabetes using wearable insulin pump data, and (2) develop personalized models for predicting future mealtimes to support timely insulin dose administration. Using two independent datasets with over 45,000 meal logs from 82 patients with diabetes, we find that the majority of people (∼\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sim$$\\end{document} 60%) have irregular and inconsistent mealtime patterns that change notably through the course of each day and across months in their own historical data. We also show the feasibility of predicting future mealtimes with personalized LSTM-based models that achieve an average F1 score of > 95% with less than 0.25 false positives per day. Our research lays the groundwork for developing a meal prediction system that can nudge patients with diabetes to administer bolus insulin doses before meal consumption to reduce the occurrence of post-meal high blood glucose.

Antagonistic insulin-like signaling influencing glucose regulation in C. elegans

The insulin/ IGF-signaling (IIS) is an evolutionary conserved signaling pathway within eukaryotic organisms that regulates glucose metabolism and cell division. The nematode, C. elegans is an excellent model for exploring IIS as they have 40 insulin-like peptides that act on a single receptor, DAF-2. We aim to explore the relationships between IIS and glucose metabolism, focusing on the antagonistic insulin-like peptide, INS-17 and its influence over FDGT-1 (facilitated glucose transporter 1). FDGT-1 is expressed throughout the nematode, including the basolateral membrane of intestinal cells and where it is theorized to export glucose to the surrounding somatic cells rather than absorb it from the intestinal tract. We hypothesize that IIS controls transcription of FDGT-1 and antagonistic peptides should lead to a decrease in FDGT-1 transcription, resulting in the increased lifespan and increased fat accumulation observed in daf-2(lf) loss of function and ins-17(oe) over expressing strains. In this study, survival assays are used to assess the impact which high-glucose content has on lifespan, along with Oil Red O (ORO) lipid staining to visualize lipid accumulation amongst conditions and protein quantification of FDGT-1:GFP to evaluate FDGT-1 protein levels. Our findings are consistent with the idea of low insulin signaling leading to extended lifespan as daf-2(lf) lived significantly longer than WT in both 0% and 2% glucose conditions and ins-17(oe) living significantly longer than wildtype in 2% glucose conditions. The ORO lipid staining revealed that high glucose conditions and low insulin signaling result in lipid accumulation within the nematode. Using the fdgt-1:gfp strain, we were able to determine an increase in the FDGT-1 in the presence of glucose, suggesting FDGT-1 expression is influenced by glucose. These findings aim to further our understanding of IIS regulating glucose uptake and metabolism, along with the significance of the FDGT-1 glucose transporter.

Gender Differential Prevalence of Overweight and Obesity, Hypertension and Diabetes in South India: A Population-Based Cross-Sectional Study.

India is facing triple epidemic of Non communicable diseases (NCDs) including high body mass index (BMI), high blood pressure and high blood glucose, contributing to more than half of deaths of all mortality, however, information in different demographics is limited, especially, in India. The aim of the study is to compare the prevalence of overweight, obesity, hypertension, and diabetes, along with the occurrence of multi-morbidity, across gender-specific populations in rural, suburban, and urban regions of India. This was a cross-sectional, population-based study including adults aged 20 and above in rural, suburban, and urban areas near Coimbatore, India. All participants were interviewed using a detailed questionnaire and had their anthropometric measurements, including height, weight, blood pressure, and blood samples collected. Gender specific and location specific prevalence of overweight, obesity, hypertension, diabetes, and multimorbidity were assessed. This study included 2976 individuals, of which 865 were from rural areas, 1030 from sub-urban areas, and 1081 from metropolitan areas. The mean systolic and diastolic blood pressure were higher in rural participants than in sub-urban and urban participants, despite the fact that the prevalence of hypertension was higher in sub-urban (47.1%) than in rural (36.4%) and urban (39.7%, p < 0.001). In sub-group analysis, sub-urban areas had a greater prevalence of hypertension in both men and women (53.5% and 41.7%, p < 0.001) than rural areas (41.9% and 31.3%, p = 0.001) or urban areas (45.9% and 35.5%, p < 0.001). Compared to rural (16.1%) and urban (23%), sub-urban areas had a greater prevalence of diabetes (25.8%, p < 0.001). Urban residents (47.5%) had higher rates of overweight and obesity than rural (31.4%) and sub-urban (34.1%, p < 0.001) residents. The association between diabetes and hypertension was present in the unadjusted model and persisted even after age and BMI adjustments. Though not in men, higher levels of education were associated to a higher prevalence of diabetes in women. Diabetes was associated to being overweight or obese in women, however this association was significantly reduced once BMI was taken into account. The overall multimorbidity was 3.8%, however, women had a higher overlapping prevalence (2.8%) compared to men (1%, p < 0.001). Diabetes and hypertension were prevalent comorbidities across all demographics, with higher rates in suburban and urban areas. Women exhibited higher rates of multimorbidity than men, regardless of the demographic area.

Yiqi Huoxue Tongluo formula-containing serum attenuates high glucose-induced injury in microglia via MAPK pathways: Network pharmacology-based analysis and biological validation

IntroductionThe Yiqi Huoxue Tongluo formula (YQHX), containing Astragalus mongholicus Bunge, Angelica sinensis (Oliv.) Diels, Rehmannia glutinosa Libosch., Pueraria lobata (Willd.) Ohwi, Corydalis yanhusuo W.T.Wang, Spatholobus suberectus Dunn, Clematis chinensis Osbeck, is a proprietary formula of the First Affiliated Hospital of Anhui University of Chinese Medicine, and can attenuate diabetic neuropathy pain (DNP). This study aimed to explore the mechanisms underlying YQHX-mediated DNP alleviation. Additionally, the effects of YQHX on BV2 microglia injured by high glucose via the mitogen-activated protein kinase (MAPK) signaling pathways were investigated. MethodsLiquid chromatography tandem mass spectroscopy (LC-MS/MS) was performed to identify the chemical compounds in YQHX. The potential mechanism of YQHX for treating DNP was explored through network pharmacology analysis. The established glucose-induced BV2 cell injury model was treated with varying concentrations of YQHX-containing serum. The effects of YQHX-containing serum and MAPK pathway inhibitors on microglial cells were assessed by Cell Counting Kit-8 and enzyme-linked immunosorbent assays. The messenger RNA (mRNA) and protein levels of microglial marker OX42 were measured. Additionally, phosphorylated-p38, -c-Jun-terminal kinase, and -extracellular signal-regulated kinase and downstream nuclear factor-κB/p65 and phosphorylated-activating transcription factor 2 (ATF2) proteins were detected by western blotting. ResultsIn total, 503 chemical components were identified in YQHX by LC-MS/MS analysis. Network pharmacology results showed 203 active ingredients and 363 overlapping targets, respectively, as potential therapeutic candidates for YQHX-mediated DNP treatment. Additionally, the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis yielded a total of 105 signal pathways. Notably, YQHX considerably improved the cell viability of BV2 cells (P < 0.01), remarkably reduced the production of proinflammatory factors (P < 0.01), significantly increased the production of anti-inflammatory factors (P < 0.01), and markedly inhibited the mRNA and protein levels of OX42 (P < 0.01). Furthermore, YQHX treatment inhibited MAPK activation and ATF2 expression. ConclusionsYQHX may protect against high-glucose-induced BV2 microglial cell injury by inhibiting the activation of MAPKs and downstream ATF2, thus, reducing microglial activation and proinflammatory cytokine release. These results provide a foundational theoretical basis for exploring the further mechanism of YQHX in treating DNP, and they provide a novel target for the application of traditional Chinese medicine.

Tangzu granule alleviate neuroinflammation in diabetic peripheral neuropathy by suppressing pyroptosis through P2X7R /NLRP3 signaling pathway

Ethnopharmacological relevanceDiabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, mainly manifested as paresthesia. Tangzu granule (TZG) is derived from famous traditional Chinese medicine decoctions and optimized by long-term temporary practice. TZG has good efficacy in improving numbness, pain and pruritus of the lower extremities of DPN patients. However, the overall regulatory mechanisms underlying its effects on DPN remain unclear. Aim of the studyThis study aims to explore the potential mechanism of TZG for treating DPN. Materials and methodsSprague-Dawley (SD) rats were used to establish an in vivo model of DPN with streptozotocin (STZ) injection and high-fat diet (HFD) feeding. Additionally, sciatic glial RSC96 cells were induced with high glucose in vitro. SD rats in intervention group received TZG treatment for 12 weeks. After 12 weeks of treatment, sciatic nerve function was evaluated by intelligent hot plate meter and neuro electrophysiology detector. The morphological changes of sciatic nerve cells were observed by hematoxylin-eosin staining and transmission electron microscope. IL-1β, IL-18 inflammatory cytokines, pyroptosis and P2X7R/NLRP3 signaling pathway were observed by Western blotting, immunofluorescence staining and ELISA. ResultsTZG improved nerve conduction velocity and sciatic neuropathy rational structural changes in DPN rats. It also inhibited RSC96 inflammatory response and cell death that induced by high glucose. This may be related to TZG inhibiting P2X7R, decreasing the activation of NLRP3 inflammasomes, down-regulating the levels of pyroptosis proteins such as caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N, and inhibiting the release of interleuki (IL)-18 and IL-1β inflammatory cytokines. ConclusionsTZG inhibited pyroptosis through P2X7R/NLRP3 signaling pathway, alleviated neuroinflammation, and showed protective effect in the treatment of DPN.

MiR-34a-5p Predicts the Risk of Diabetic Neuropathic Pain and Mediates Neuroinflammation in Microglia via Targeting ENPP3

ABSTRACT Introduction The pathogenesis of diabetic neuropathic pain (DNP) is complex involving various processes, which need exploring reliable biomarkers for its early detection and severity prediction. Methods Study enrolled 181 patients diagnosed with diabetes, among which 74 patients developed DNP. Serum miR-34a-5p levels were compared between DNP patients and non-DNP patients by polymerase chain reaction (PCR), and the potential of miR-34a-5p in predicting the risk and discriminating patients with DNP was evaluated. The regulatory effect of miR-34a-5p on the inflammation, proliferation, and polarization of microglia was evaluated in HMC3 cells treated with high glucose. Results Upregulated miR-34a-5p was identified as a risk factor and discriminated DNP patients miR-34a-5p was positively correlated with the levels of triglyceride (r = 0.797), fasting blood glucose (r = 0.840), and glycated hemoglobin (r = 0.894) of DNP patients. In HMC3 cells, the high-glucose-induced inflammation, promoted cell growth and caused polarization. The knockdown of miR-34a-5p showed the significant protective effect of microglia activation by high glucose, which was reversed by silencing ENPP3. Discussion miR-34a-5p served as a biomarker for the prediction and early detection of DNP and mediated microglia inflammation caused by DNP via modulating ENPP3.

The effect of diabetes on the alevel of thyroid gland hormones in patients with uncontrolled type 2 diabetes in Thi-Qar Province,Iraq.

Background: Diabetes mellitus and thyroid dysfunction represent two prominent endocrine disorders frequently encountered in clinical practice. The objective of this research was to examine the prevalence of hypothyroidism among hospitalized individuals diagnosed with type 2 diabetes mellitus, along with its associated factors. Methods: A total of 120 in patients suffering from type 2 diabetes mellitus were admitted to the metabolic diseases unit. The findings of this investigation indicated a notable elevation of T3 and T4 levels in patients with uncontrolled diabetes (GI) when compared to those with controlled diabetes (GII) and the control group. Conversely, the levels of TSH exhibited a significant reduction in patients with uncontrolled diabetes (GI) relative to both the controlled diabetic patients (GII) and the control group. Utilizing a significance threshold of (P ≤ 0.05), this study revealed a substantial decrease in the concentrations of thyroid hormones, alongside a reduction in thyroid stimulating hormone levels in patients with uncontrolled diabetes when contrasted with the controlled diabetic patients and the control group.. Aims of Study: Evaluation the risk degree of developing of metabolic disorders complications in patients with DM and their prevalence in Thi-Qar province. Conclusion: It was concluded from this study that there is a clear relationship between high blood glucose levels and low T3 and T4 levels.

UTRs and Ago-2/miR-335 Complex Restricts Amylin Translation in Insulinoma and Human Pancreatic β-Cells.

Amylin promoter and transcriptional factors are well-established, inducible factors in the production of the main amyloidogenic pancreatic hormone, human islet amyloid peptide (hIAPP) or amylin. However, posttranscriptional mechanisms driving hIAPP expression in pancreas remain enigmatic, and hence were explored here. The translational assay revealed that both 5' and 3' untranslated regions (UTRs) of hIAPP restricted expression of the luciferase constructs only in constructs driven by the hIAPP promoter. Bioinformatics analysis revealed several putative seed sequences for a dozen micro RNAs (miRNAs) in hIAPP's 3' UTR. miR-182, miR-335, and miR-495 were the most downregulated miRNAs in stressed human islets exposed to endoplasmic reticulum (ER) or metabolic stressors, thapsigargin (TG) or high glucose (HG). Correspondingly, miR-335 mimics alone or in combination with miR-495 and miR-182 mimics significantly and potently (>3-fold) reduced hIAPP protein expression in HG-treated cultured human islets. siRNA-mediated silencing of Ago2 but not Ago1 significantly stimulated hIAPP expression and secretion from transfected, HG-treated human islets. Conversely, ectopic expression of Ago2 in hIAPP-expressing RIN-m5F cell line driven by CMV promoter reduced hIAPP intracellular protein levels. Collectively, the results point to a novel and synergistic role for hIAPP promoter, 5/3' UTRs and Ago-2/miR-335 complex in post-transcriptional regulation of hIAPP gene expression in normal and metabolically active β-cells.

Investigation of Glucose Metabolism by Continuous Glucose Monitoring and Validation of Dipeptidyl Peptidase 4 Inhibitor Use in Patients with Myotonic Dystrophy Type 1.

Objectives: We characterized blood glucose fluctuations in patients with myotonic dystrophy type 1 (DM1). After confirming the incretin secretion capacity of patients with DM1, we intended to clarify whether dipeptidyl peptidase 4 (DPP-4) inhibitor administration was appropriate in cases of DM1 with diabetes mellitus. Methods: A 48 h continuous glucose monitoring (CGM) was performed in 29 Japanese patients with DM1. An oral glucose tolerance test (OGTT) was performed in patients with DM1 and five disease controls, and levels of blood glucose, insulin, and incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) were measured. DPP-4 inhibitors were administered to patients with diabetes mellitus complicated by DM1, and the CGM results were compared. Results: The CGM showed distinct patterns of blood glucose variability among patients classified by an OGTT pattern with significant differences in glucose parameters such as time above 140 mg/dL and mean amplitude of glycemic excursions between the groups. High sensor glucose values were observed in a certain number of patients who were classified as having normal or impaired glucose tolerance by the OGTT. The CGM confirmed the presence of low glucose levels in several patients. Incretin secretion, the target of DPP-4 inhibitors, was preserved in patients with DM1. DPP-4 inhibitor treatment resulted in lower glucose levels and improved insulin secretion in some patients. Conclusions: This is the first CGM study for DM1 patients. The CGM identified potential early abnormalities in glucose metabolism in DM1. In the future, it will be crucial to explore effective methods for harnessing CGM and assessing it quantitatively in DM1.

AIM2 Deficiency Alleviates Cardiac Inflammation and Hypertrophy in HFD/STZ-Induced Diabetic Mice by Inhibiting the NLRC4/IRF1 Signaling Pathway.

Absent in melanoma 2(AIM2) exacerbates atherosclerosis by inflammasome assembly. However, AIM2-mediated inflammation in diabetic cardiomyopathy remains incompletely understood. Here we investigate the role of AIM2 in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. By RNA-seq, we found that AIM2 were significantly upregulated in HG-induced macrophages, upregulation of AIM2 in cardiac infiltrating macrophages was confirmed in a high-fat diet (HFD)/streptozotocin (STZ)-induceddiabetic mouse model . Therefore, AIM2 knockout mice were constructed. Compared to WT mice, HFD/STZ-induced cardiac hypertrophy and dysfunction were significantly improved in AIM2-/- mice, despite no changes in blood glucose and body weight. Further, AIM2 deficiency inhibited cardiac recruitment of M1-macrophages and cytokine production. Mechanistically, AIM2-deficient macrophgaes reduced IL-1β and TNF-α secretion, which impaired the NLRC4/IRF1 signaling in cardiomyocytes, and reduced further recruitment of macrophages, attenuated cardiac inflammation and hypertrophy, these effects were confirmed by silencing IRF1 in WT mice, and significantly reversed by overexpression of IRF1 in AIM2-/- mice. Taken together, our findings suggest that AIM2 serves as a novel target for the treatment of diabetic cardiomyopathy.

PPAR gamma and PGC-1alpha activators protect against diabetic nephropathy by suppressing the inflammation and NF-kappaB activation.

Inflammation plays a critical role in the progression of diabetic nephropathy. Peroxisome proliferator-activated receptor gamma (PPARγ) and its coactivator PPARγ coactivator-1 alpha (PGC-1α) enhance mitochondrial biogenesis and cellular energy metabolism but inhibit inflammation. However, the molecular mechanism through which these two proteins cooperate in the kidney remains unclear. The aim of the present study was to investigate this mechanism. HK-2 human proximal tubular cells were stimulated by inflammatory factors, the expression of PPARγ and PGC-1α were determined via reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting (WB), and DNA binding capacity was measured by an EMSA. Furthermore, db/db mice were used to establish a diabetic nephropathy model and were administered PPARγ and PGC-1α activators. Kidney injury was evaluated microscopically, and the inflammatory response was assessed via WB, immunohistochemistry and immunofluorescence staining. Besides, HK-2 cells were stimulated by high glucose and inflammatory factors with and without ZLN005 treatment, the expression of PPARγ, PGC-1α, p-p65 and p65 were determined via qPCR and WB. Our results revealed that both TNF-α and IL-1β significantly decreased PPARγ and PGC-1 expression in vitro. Cytokines obviously decreased PPARγ DNA binding capacity. Moreover, we detected rapid activation of the NF-κB pathway in the presence of TNF-α or IL-1β. PPARγ and PGC-1α activators effectively protected against diabetic nephropathy and suppressed NF-κB expression both in db/db mice and HK-2 cells. PPARγ and its coactivator PGC-1α actively participate in protecting against renal inflammation by regulating the NF-κB pathway, which highlights their potential as therapeutic targets for renal diseases.

Self-Care Activities Among Diabetic Patients in an Urban Health Centre in Thirumazhisai, Tamil Nadu: A Cross-Sectional Study.

Background Diabetes is a long-term medical condition characterized by consistently high blood glucose levels, which can be attributed to both genetic and environmental factors. Global diabetes prevalence is predicted to reach 10.4% by 2040, impacting over 642 million people. Diabetes is becoming more common in India; by 2030, an estimated 87 million individuals are predicted to have the disease. Self-care activities are essential for managing diabetes, yet adherence to these practices is often low in developing countries like India due to socioeconomic, cultural, and healthcare barriers. Objective In this study, the self-care practices of diabetic patients who visited an Urban Health Center in Thirumazhisai, Tamil Nadu, were assessed, along with the factors influencing these practices. Methods A three-month cross-sectional study was conducted in a facility with 200 type 2 diabetic patients who had been unwell, for a minimum of a year. The participants were selected via purposeful sampling, and interviews were conducted using the most recent version of the Summary Diabetes Self-Care Activities (SDSCA) questionnaire. The data was analyzed using SPSS version 26 (IBM Corp., Armonk, NY, USA) to discover connections between the duration of diabetes and self-care practices using descriptive statistics and chi-square tests. Results The study found that 136 (68%) of participants tested their blood sugar levels at least once in the preceding three months, 104 (52%) exercised for at least 30 minutes each day, and 96 (48%) of individuals maintained a balanced diet. On the other hand, adherence to insulin injections and oral hypoglycemic medications was lower, at 98 (49%) and 79 (39.5%), respectively. Foot hygiene was also not at its best; only 85 (42.5%) people washed their feet daily. Considerable correlations have been shown between the length of diabetes and particular self-care behaviors, including eating patterns, exercise routines, and foot hygiene. Conclusion The results emphasize the necessity of focused interventions, especially in developing nations, to enhance diabetic patients' self-care behaviors.Tailored, patient-centered strategies are essential to address the complex factors influencing diabetes management, ultimately improving glycemic control and patient outcomes.

Nesfatin-1 regulates the phenotype transition of cavernous smooth muscle cells by activating PI3K/AKT/mTOR signaling pathway to improve diabetic erectile dysfunction.

This study aims to explore the impact of Nesfatin-1 on type 2 diabetic erectile dysfunction (T2DMED) and its underlying mechanism in regulating the phenotypic switching of corpus cavernosum smooth muscle cells (CCSMCs). Twenty-four 4-week-old male C57 wild-type mice were randomly assigned to the control group, model group, and Nesfatin-1 treatment group. Monitoring included body weight, blood glucose levels, and penile cavernous pressure (ICP). Histochemistry and Western blot analyses were conducted to assess the expressions of α-SMA, OPN, and factors related to the PI3K/AKT/mTOR signaling pathway. CCSMCs were categorized into the control group, high glucose and high oleic acid group (GO group), Nesfatin-1 treatment group (GO+N group), sildenafil positive control group (GO+S group), and PI3K inhibitor group (GO+N+E group). Changes in phenotypic markers, cell morphology, and the PI3K/AKT/mTOR signaling pathway were observed in each group. (1) Nesfatin-1 significantly ameliorated the body size, body weight, blood glucose, glucose tolerance, and insulin resistance in T2DMED mice. (2) Following Nesfatin-1 treatment, the ICP/MSBP ratio and the peak of the ICP curve demonstrated a significant increase. (3) Nesfatin-1 significantly enhanced smooth muscle and reduced collagen fibers in the corpus cavernosum. (4) Nesfatin-1 notably increased α-SMA expression and decreased OPN expression in CCSMCs. (5) Nesfatin-1 elevated PI3K, p-AKT/AKT, and p-mTOR/mTOR levels in penile cavernous tissue. Nesfatin-1 not only effectively improves body weight and blood glucose levels in diabetic mice but also enhances erectile function and regulates the phenotypic switching of corpus cavernosum smooth muscle. The potential mechanism involves Nesfatin-1 activating the PI3K/AKT/mTOR signaling pathway to induce the conversion of CCSMCs to a contractile phenotype.

Knockdown of HCK promotes HREC cell viability and inner blood-retinal barrier integrity by regulating the AMPK signaling pathway.

Diabetic retinopathy (DR), a major complication of diabetes causing blindness, is characterized by retinal damage due to capillary degeneration and vascular leakage. Current treatments are not fully effective, highlighting the need for searching new therapeutic targets. Hematopoietic cell kinase (HCK), a protein involved in various diseases, has been identified as a potential biomarker in DR, but its role in disease progression requires further investigation. Here we investigated the role of HCK in DR and its potential mechanism. We found the expression of HCK increased under the stimulation of high glucose (HG) in human retinal capillary endothelial cells (HRECs). Knockdown of HCK can improve HREC cell viability and the integrity of the internal blood-retinal barrier. HCK depletion suppressed the AMPK pathway in HG-induced HRECs. In summary, HCK may be a potential target for the treatment of DR, which provides a theoretical basis for the development of new treatment strategies.