Evolving Global Etiology of Hepatocellular Carcinoma (HCC): Insights and Trends for 2024.

The epidemiology of HCC is changing all over the world and the incidence of HCC is expected to continue increasing over the next 30 years. The changes are in the predisposing factors. Hepatitis B and hepatitis C as predisposing etiologies are decreasing while NAFLD/MAFLD is increasing. The increase in MAFLD is so great that despite the decrease in hepatitis B and C, the overall incidence of HCC is increasing. HCC in persons below the age of 20 years has distinct characteristics different from that of HCC in adults. The changing etiology of hepatocellular carcinoma has implications for the early detection, prevention, the stage of HCC at time of detection and in the treatment of HCC. The extent of these changes and their significance are discussed.

The relationship between microRNAs and COVID-19 complications.

Over the past three years, since the onset of COVID-19, several scientific studies have concentrated on understanding susceptibility to the virus, the progression of the illness, and possible long-term complexity. COVID-19 is broadly recognized with effects on multiple systems in the body, and various factors related to society, medicine, and genetics/epigenetics may contribute to the intensity and results of the disease. Additionally, a SARS-CoV-2 infection can activate pathological activities and expedite the emergence of existing health issues into clinical problems. Forming easily accessible, distinctive, and permeable biomarkers is essential for categorizing patients, preventing the disease, predicting its course, and tailoring treatments for COVID-19 individually. One promising candidate for such biomarkers is microRNAs, which could serve various purposes in understanding diverse forms of COVID-19, including susceptibility, intensity, disease progression, outcomes, and potential therapeutic options. This review provides an overview of the most significant findings related to the involvement of microRNAs in COVID-19 pathogenesis. Furthermore, it explores the function of microRNAs in a broad span of effects that may arise from accompanying or underlying health status. It underscores the value of comprehending how diverse conditions, such as neurological disorders, diabetes, cardiovascular diseases, and obesity, interact with COVID-19.

Visceral Fat and Diabetes: Associations With Liver Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Background: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is increasing globally. Noninvasive methods, such as bioelectrical impedance analysis (BIA), which measures body composition, including visceral fat, are gaining interest in evaluating MASLD patients. Our study aimed to identify factors associated with significant liver fibrosis, compare noninvasive scores, and highlight the importance of visceral fat measurement using BIA. Methods: MASLD patients seen in our out-patient department underwent comprehensive evaluations, including liver stiffness using transient elastography, body composition analysis using BIA, and metabolic measurements. Significant fibrosis was defined as a liver stiffness measurement of ≥8.2 kPa. Using multivariate analysis, we identified factors associated with significant liver fibrosis and compared four noninvasive scores with a novel diabetes-visceral fat 15 (DVF15) score. Results: We analyzed data from 609 MASLD patients seen between February 2022 and March 2023. The median age was 43 years (81% male). Among these, 78 (13%) had significant fibrosis. Patients with significant fibrosis had higher rates of type 2 diabetes (41% vs 21%, P < 0.001) and elevated levels of aspartate aminotransferase, alanine aminotransferase, hemoglobin A1c, Fibosis-4, aspartate-aminotransferase-to platelet-ratio index, and NAFLD fibrosis scores. They also exhibited higher visceral and subcutaneous fat. Binary logistic regression revealed type 2 diabetes and a visceral fat level of >15% as associated with significant liver fibrosis. Additionally, the DVF15 score, combining these factors, showed a modest area under the receiver operating characteristic curve of 0.664 (P < 0.001). Conclusion: Our study identified diabetes and high visceral fat as factors associated with significant liver fibrosis in MASLD patients. We recommend that visceral fat measurement using BIA be an essential part of MASLD evaluation. The presence of either diabetes or a visceral fat level of >15% should prompt clinicians to check for significant fibrosis in MASLD patients. Further research is warranted to validate our findings and evaluate the utility of the DVF15 score in larger cohorts and diverse populations.

The association of isocarbophos and isofenphos with different types of glucose metabolism: The role of inflammatory cells.

To investigate the associations between isocarbophos and isofenphos with impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), and to assess the mediation roles of inflammation cells. There were 2701 participants in the case-control study, including 896 patients with T2DM, 900 patients with IFG, 905 subjects with NGT. Plasma isocarbophos and isofenphos concentrations were measured using gas chromatography and triple quadrupole tandem mass spectrometry. Generalized linear models were used to calculate the relationships between plasma isofenphos and isocarbophos levels with inflammatory factor levels and T2DM. Inflammatory cell was used as mediators to estimate the mediating effects on the above associations. Isocarbophos and isofenphos were positively related with T2DM after adjusting for other factors. The odds ratio (95% confidence interval) (OR (95%CI)) for T2DM was 1.041 (1.015, 1.068) and for IFG was 1.066 (1.009, 1.127) per unit rise in ln-isocarbophos. The prevalence of T2DM increased by 6.4% for every 1 unit more of ln-isofenphos (OR (95% CI): 1.064 (1.041, 1.087)). Additionally, a 100% rise in ln-isocarbophos was linked to 3.3% higher ln-HOMA2IR and a 0.029 mmol/L higher glycosylated hemoglobin (HbA1c) (95% CI: 0.007, 0.051). While a 100% rise in ln-isofenphos was linked to increase in ln-HOMA2 and ln-HOMA2IR of 5.8% and 3.4%, respectively. Furthermore, white blood cell (WBC) and neutrophilic (NE) were found to be mediators in the relationship between isocarbophos and T2DM, and the corresponding proportions were 17.12% and 17.67%, respectively. Isofenphos and isocarbophos are associated with IFG and T2DM in the rural Chinese population, WBC and NE have a significant role in this relationship.

MMP-9 responsive hydrogel promotes diabetic wound healing by suppressing ferroptosis of endothelial cells.

Ferroptosis plays a crucial role in the progression of diabetic wounds, suggesting potential therapeutic strategies to target ferroptosis. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective calcium channel that acts as a receptor for a variety of physical or chemical stimuli. Cinnamaldehyde (CA) is a specific TRPA1 agonist. In in vitro experiments, we observed that high glucose (HG) treatment induced endothelial cell ferroptosis, impairing cell function. CA successfully inhibited endothelial cell ferroptosis, improving migration, proliferation, and tube formation. Further mechanistic studies showed that CA-activated TRPA1-induced Ca2+ influx promoted the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-E 2-related factor 2 (Nrf2) translocation, which contributed to the elevation of glutathione peroxidase 4 (GPX4), leading to the inhibition of endothelial cell ferroptosis. In addition, CA was incorporated into an MMP-9-responsive injectable duplex hybrid hydrogel (CA@HA-Gel), allowing its efficient sustained release into diabetic wounds in an inflammation-responsive manner. The results showed that CA@HA-Gel inhibited wound endothelial cell ferroptosis and significantly promoted diabetic wound healing. In summary, the results presented in this study emphasize the potential therapeutic application of CA@HA-Gel in the treatment of diseases associated with ferroptosis.

Indicadores de qualidade da atenção a usuários com diabetes na Atenção Primária à Saúde do Brasil: 2012 e 2018 / Quality indicators of care for users with diabetes in Primary Health Care in Brazil: 2012 and 2018 / Indicadores de calidad de la atención a usuarios con diabetes en Atención Primaria de Salud en Brasil: 2012 y 2018

Introdução: Diabetes mellitus (DM) é uma doença crônica, não transmissível, cuja prevalência tem aumentado mundialmente. Seu manejo adequado na Atenção Primária à Saúde (APS) pode reduzir suas complicações e as internações por condições sensíveis à atenção primária. Objetivo: Comparar indicadores de qualidade da atenção a pessoas com diabetes atendidas na rede básica de saúde do Brasil e suas diferenças por região. Métodos: Com delineamento transversal, utilizaram-se dados dos Ciclos I e III do Programa de Melhoria do Acesso e da Qualidade (PMAQ). Os desfechos foram indicadores sintéticos, operacionalizados a partir de 24 variáveis: i) acesso; ii) disponibilidade de insumos e equipamentos em condições de uso; iii) disponibilidade de medicamentos em quantidade suficiente; iv) organização e gestão; v) cuidado clínico; e vi) relato de cuidado adequado. Foram calculadas as diferenças em pontos percentuais (p.p.) dos indicadores entre 2012 e 2018, e os dados foram estratificados por região. Resultados: No geral, houve uma melhora no cuidado à pessoa com DM na APS do Brasil e regiões entre as equipes participantes do PMAQ, entre 2012 e 2018. As prevalências de acesso, disponibilidade de insumos/equipamentos, medicamentos, oferta, organização e gestão apresentaram aumento de, no mínimo, 10 p.p. no período de 6 anos, mas podem melhorar. Conclusões: Considerando que a ocorrência de DM está aumentando no país, faz-se necessário maior investimento na estrutura dos serviços e em programas de educação permanente dos profissionais de saúde.

Introduction: Diabetes Mellitus (DM) is a non-communicable chronic disease whose prevalence has been increasing worldwide. Its adequate management in Primary Health Care (PHC) can reduce complications and hospitalizations for conditions sensitive to primary care. Objective: To compare quality indicators for the care of people with diabetes treated in the basic health network in Brazil and their differences by region. Methods: With a cross-sectional design, data from Cycles I and III of the PMAQ were used. The outcomes were synthetic indicators, operationalized from 24 variables: i) access; ii) availability of supplies and equipment in usable conditions; iii) availability of medications in sufficient quantities; iv) organization and management; v) clinical care; and vi ) report of adequate care. Differences in percentage points (p.p.) of the indicators between 2012 and 2018 were calculated, and the data were stratified by region. Results: Overall, there was an improvement in the care of people with DM in PHC in Brazil and regions among the teams participating in PMAQ, between 2012 and 2018. The prevalence of access, availability of supplies/equipment, medications, demand, organization, and management showed an increase of at least 10 p.p. within six years, but they can improve. Conclusions: Considering that the occurrence of DM is increasing in the country, greater investment is necessary in the structure of services and in continuing education programs for health professionals.

La Diabetes Mellitus es una enfermedad crónica no transmisible cuya prevalencia ha aumentado en todo el mundo. Su manejo adecuado en la Atención Primaria puede reducir sus complicaciones y las hospitalizaciones por afecciones sensibles a la Atención Primaria. Objetivo: comparar indicadores de calidad de la atención a personas con diabetes atendidas en la red básica de salud de Brasil y sus diferencias por región. Métodos: Con delineamiento transversal, se utilizaron datos de los Ciclos I y III del PMAQ. Los defectos fueron indicadores sintéticos, operacionalizados a partir de 24 variables: i) acceso, ii) disponibilidad de insumos y equipos en condiciones utilizables, iii) disponibilidad de medicamentos en cantidad suficiente, iv) organización y gestión, v) atención clínica y vi) reporte de atención adecuada. Se calcularon las diferencias en puntos porcentuales (p.p.) de los indicadores entre 2012 y 2018, y los datos se estratificaron por regiones. Resultados: En general, hubo una mejora en la atención a las personas con DM en APS en Brasil y regiones entre los equipos participantes en el PMAQ entre 2012 y 2018. La prevalencia del acceso, la disponibilidad de insumos/equipos, los medicamentos, el suministro, la organización y la gestión mostraron un aumento de al menos 10 p.p. en el periodo de seis años, pero pueden mejorar. Conclusiones: Considerando que la ocurrencia de DM está aumentando en el país, es necesario invertir más en la estructura de los servicios y en programas de educación continuada para los profesionales de salud.

Artículos originales / Probability of anemia in pre-diabetics and diabetics: analytical study carried out in a medical center in Villa el Salvador, Lima-Peru

Resumen Introducción: la organización mundial de la salud estima que 2000 millones de personas padecen anemia, mientras que la pre-diabetes y la diabetes afectan aproximadamente a 352 y 460 millones de personas, respectivamente. La anemia es una complicación frecuente en la diabetes mellitus (DM). Objetivo: evaluar la asociación y probabilidad de alteraciones de la hemoglobina en pre-diabéticos y diabéticos. Metodología: estudio descriptivo, retorspectivo y transversal, la población fue de 1103 pacientes (211 prediabéticos, 223 diabéticos y 669 normoglucémicos), la muestra fue el total de la población que cumplió con los criterios de inclusión y exclusión: adultos normoglucémicos y pre-diabéticos sin presencia de enfermedad aguda o crónica al momento del examen. La asociación entre variables se realizó por medio de la prueba de chi-cuadrado y la probabilidad fue determinada por la prueba de Odds Ratio. Resultados: las mujeres pre-diabéticas tuvieron una probabilidad 1.72 mayor de anemia que mujeres no diabéticas. Los hombres pre-diabéticos tuvieron una probabilidad 2.80 veces mayor de anemia que los no diabéticos. Las mujeres diabéticas tuvieron una probabilidad 2,37 más alta de tener anemia, mientras que los hombres diabéticos tuvieron una probabilidad 4,41 veces más alta que lo hombres no diabéticos de padecer anemia. Conclusiones: pacientes pre-diabéticos tienen mayor probabilidad de anemia que en no diabéticos. Es posible que la hiperglucemia persistente en pre-diabéticos se asocie a cambios en la concentración de esta hemoproteína años antes del desarrollo de diabetes por mecanismos similares, pero de forma incipiente.

Abstract Introduction: The World Health Organization estimates that 2 billion people suffer from anemia, while pre-diabetes and diabetes affect approximately 352 and 460 million people, respectively. Anemia is a frequent complication in diabetes mellitus. Objective: To evaluate the association and probability of hemoglobin alterations in pre-diabetics and diabetics. Methodology: Descriptive, retrospective and cross-sectional study, the population was 1103 patients (211 prediabetics, 223 diabetics and 669 normoglycemics), the sample was the total population that met the inclusion and exclusion criteria: normoglycemic and prediabetic adults without presence of acute or chronic disease at the time of examination. The association between variables was performed using the chi-square test and the probability was determined by the Odds Ratio test. Results: Pre-diabetic women had a 1.72 higher probability of anemia than non-diabetic women. Pre-diabetic men were 2.80 times more likely to have anemia than non-diabetics. Diabetic women were 2.37 times more likely to have anemia, while diabetic men were 4.41 times more likely than non-diabetic men to have anemia. Conclusions: Pre-diabetic patients are more likely to have anemia than non-diabetics. It is possible that persistent hyperglycemia in pre-diabetics is associated with changes in the concentration of this hemoprotein years before the development of diabetes by similar mechanisms, but in an incipient manner.

Evaluating the Causal Effect of Type 2 Diabetes on Alzheimer's Disease Using Large-Scale Genetic Data.

BACKGROUND: Alzheimer's disease (AD) has a high comorbidity with type 2 diabetes (T2D). However, there is still some controversy over whether T2D has a causal impact on AD at present. OBJECTIVES: We aimed to reveal whether T2D has a causal effect on AD using large-scale genetic data. METHODS: Firstly, we performed a primary two-sample Mendelian randomization (MR) analysis to assess the potential causal effects of T2D on AD. For this analysis, we used the largest available genome-wide association studies (GWAS) T2D (T2D1, including 80,154 cases and 853,816 controls) and AD (AD1, including 111,326 cases and 677,663 controls) datasets. Additionally, we performed a validation MR analysis using two largely overlapping-sample datasets from FinnGen, including T2D (T2D2, including 57,698 cases and 308,252 controls) and AD (AD2, including 13,393 cases and 363,884 controls). In all MR analyses, the inverse variance-weighted method was used as the primary analysis method, supplemented by the weighted-median and MR-Egger techniques. RESULTS: In the primary analysis, we found that T2D was not associated with the risk of AD (OR: 0.98, CI: 0.95-1.01, P=0.241). Similarly, no significant association was detected in the validation MR analysis (OR: 0.97, CI: 0.64-1.47, P=0.884). CONCLUSION: Our findings provide robust evidence that T2D does not have a causal impact on AD. Future studies need to further explore the effect of T2D on the non-AD components of the dementia phenotype.

Therapeutic and Diagnostic Implications of Carbon Dot: An Advancement in the Avenue towards Cancer, Diabetes and Neurodegenerative Disorders.

INTRODUCTION: Carbon dots (CDs), by virtue of their electrical and optical properties, emit intense light and fluorescence. They have attributes like photostability, high quantum yield (QY), high emission, and scalability. In the recent past, theranostic-CDs have been widely used in sensing, imaging, and medication administration. Furthermore, CDs may provide significant promise to detect and ability to cross blood-brain barrier (BBB) along with a drug to treat numerous neurodegenerative disorders (ND), such as Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis. METHOD: This review aims at exploring the immense utility of CDs in the arena of theranostics. The immense utility of CDs was investigated through a systematic exploration of previously published data in the relevant field. The application of CDs is well extended to treat life-threatening disorders, like diabetes and cancer. In order to keep harmful substances out of the brain, the blood- -brain barrier (BBB) forms a defensive barrier. RESULTS: Water and gases being simple molecules can traverse the BBB without getting filtered out, but several large molecules suffer to reach the site of action owing to their poor solubility. CDs have recently been employed for delivering drugs to the brain and to assess the central nervous system. An in-depth study of relevant literature indicates that CDs are the next-generation carrier with an innate potential to subside the drawbacks of conventional nanoparticles. CONCLUSION: This review illustrates several biomedical applications of CDs, primarily focusing on neurological illnesses, diabetes, and cancers. It also confers the usefulness of CDs in diagnostic imaging.

Retinoic Acid Improves Vascular Endothelial Dysfunction by Inhibiting PI3K/AKT/YAP-Mediated Ferroptosis in Diabetes Mellitus.

BACKGROUND: Vascular endothelial dysfunction is the initial factor involved in cardiovascular injury in patients with diabetes. Retinoic acid is involved in improving vascular complications in patients with diabetes, but its protective mechanism is still unclear. This study aimed to evaluate the effect and mechanism of All-Trans Retinoic Acid (ATRA) on endothelial dysfunction induced by diabetes. METHODS: In the present study, streptozotocin (STZ)-induced diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs) were observed, and the effects of ATRA on HG-induced endothelial dysfunction and ferroptosis were evaluated. RESULTS: ATRA treatment improved impaired vasorelaxation in diabetic aortas in an endothelium-dependent manner, and this effect was accompanied by an increase in the NO concentration and eNOS expression. Ferroptosis, characterized by lipid peroxidation and iron overload induced by HG, was improved by ATRA administration, and a ferroptosis inhibitor (ferrostatin-1, Fer-1) improved endothelial function to a similar extent as ATRA. In addition, the inactivation of phosphoinositol-3-kinase (PI3K)/protein kinases B (AKT) and Yes-Associated Protein (YAP) nuclear localization induced by HG were reversed by ATRA administration. Vascular ring relaxation experiments showed that PI3K/AKT activation and YAP inhibition had similar effects on ferroptosis and endothelial function. However, the vasodilative effect of retinoic acid was affected by PI3K/AKT inhibition, and the inhibitory effects of ATRA on ferroptosis and the improvement of endothelial function were dependent on the retinoic acid receptor. CONCLUSION: ATRA could improve vascular endothelial dysfunction by inhibiting PI3K/AKT/YAP-mediated ferroptosis induced by HG, which provides a new idea for the treatment of vascular lesions in diabetes.

Effectiveness of the MyDiaMate application in reducing diabetes distress in adults with type 1 diabetes: Study protocol of the multi-national, randomised-controlled MyREMEDY trial.

AIMS: Diabetes distress is common among people with type 1 diabetes (T1D), negatively affecting quality of life, self management, and diabetes outcomes. E-health-based interventions could be an effective and low-cost way to improve the psychological care for people with T1D experiencing diabetes distress. The MyREMEDY study aims to test the effectiveness of the online unguided self-help intervention MyDiaMate in decreasing diabetes distress in adults with T1D. MyDiaMate is based on Cognitive Behavioural Therapy and consists of eight modules, each focusing on a different aspect of living with T1D that is often experienced as burdensome (e.g. hypoglycaemia, fatigue). METHODS: The effectiveness of MyDiaMate will be tested through a randomised-controlled trial across four European countries (the Netherlands, Germany, Spain and the United Kingdom). Six hundred and sixty adults (N = 165 per country) with T1D will be recruited and randomised with a balance of 2:1 into the intervention and care as usual groups. Intervention group members receive access to MyDiaMate for 6 months, care as usual group members receive access after 3 months for 3 months. Participants fill in questionnaires at 0 (baseline), 3 (effectiveness) and 6 months (follow-up). Primary outcome is diabetes distress at 3 months. Secondary outcomes are emotional well-being, psychological self-efficacy in relation to diabetes, social engagement, fatigue, and glycaemic outcomes. Moreover, logdata of MyDiaMate use is passively collected. Linear mixed model analyses will be used to test the effectiveness of MyDiaMate along with identifying which user subgroup benefits most from MyDiaMate use. TRIAL REGISTRATION: Clinicaltrials.gov NCT06308549.

Serum levels of the incretin-like peptide 26RFa are diminished in women living with obesity and diabetes and restored after sleeve gastrectomy: Results from the prospective pilot RFa-Ba-S study.

AIM: To investigate the evolution of the incretin-like peptide 26RFa in a prospective cohort of women living with obesity with or without type 2 diabetes (T2D) before and after sleeve gastrectomy (SG). METHODS: In this study, a total of 61 women were divided into three groups: women living with severe obesity without T2D (WlwOB group), women living with severe obesity and T2D (WlwOB-T2D group) and lean healthy volunteers (control group). Serum 26RFa concentrations were measured using a 26RFa enzyme-linked immunosorbent assay developed specifically for this study during meal tests before SG, and 30 and 180 days after SG. RESULTS: At baseline, serum 26RFa levels were reduced in the WlwOB (P < .05) and WlwOB-T2D (P < .01) groups compared with controls. In the WlwOB-T2D group, fasting 26RFa levels were found to increase throughout the entire follow-up period up to 6 months after the SG (P < .001). During the meal tests, serum 26RFa levels increased, especially in the WlwOB-T2D group at baseline. At the end of the follow-up, the profile of 26RFa concentrations obtained during the meal test in patients with severe obesity and T2D was similar to that of the controls. CONCLUSIONS: This prospective clinical study provides the first evidence that circulating 26RFa is altered mainly in WlwOB-T2D, and that these defects are partially reversed after SG.

Modified streptozotocin-induced diabetic model in rodents.

Streptozotocin (STZ)-induced type I diabetes mellitus (DM) models have been pivotal in diabetes research due to their ability to mimic the insulin-dependent hyperglycemia akin to human type I diabetes. However, these models often suffer from poor induction rates and low survival post-STZ induction, especially in long-term experiments, necessitating insulin supplementation, which introduces additional variables to experiments. To address this, we present a novel modification to the STZ-induced DM model in C57BL/6J mice to improve survival rates without insulin supplementation. Our method involves non-fasting, low-dose STZ injections dissolved in pH-neutral phosphate buffer saline instead of acidic sodium citrate buffer, administered over 5 days. We observed hyperglycemia induction in 94.28% of mice within a week post-injection, with stable high blood glucose levels, stable body weight, and minimal mortality up to 21 weeks. Notably, omitting 10% sucrose in water and fasting did not affect hyperglycemia induction. Our findings suggest that the modified protocol not only decreases the experimental effort of the researchers, but reduces animal stress and mortality, thus enhancing experimental outcomes and animal welfare. By optimizing the STZ-induced DM model in C57BL/6J mice, our study provides a valuable resource for researchers aiming to study diabetes and its complications while minimizing experimental variability and animal usage.

Molecular Docking, Pharmacophore Modeling, and ADMET Prediction of Novel Heterocyclic Leads as Glucokinase Activators.

BACKGROUND: A pivotal impetus has driven the development of numerous small molecules aiming to improve therapeutic strategies for type 2 diabetes. Glucokinase (GK) activation has been offered a new realm of therapeutic antidiabetic activity with novel heter-ocyclic derivatives. In the context of antidiabetic drug design, GK is an interesting and newly validated target. A key enzyme needed for blood glucose homeostasis is Glucokinase, which is dysfunctional in individuals with type 2 diabetes. Heterocyclic derivatives are utilized in this innovative approach to activate GK enzymes as medicinal agents that will significantly improve type 2 diabetes management. OBJECTIVE: To address type 2 diabetes, as well as minimize unwanted side effects, this research endeavor aimed to develop activators of glucokinase. METHODS: A rigorous scrutiny was conducted of the Maybridge online repository, which houses a formidable collection of 53,000 lead compounds. A collection of 125 compounds that contain the thiazolidinedione core was selected from this extensive collection. The struc-tures were generated using ChemDraw 2D, stabilized conformation with ChemBioDraw Ul-tra, and docked using Auto Dock Vina 1.5.6 in this methodology. In addition, log P was pre-dicted online using the Swiss ADME algorithm. The PKCSM software was used to predict the toxicity of the leading compounds. RESULTS: The highest binding affinity was found for AS72 and AS108 to GK receptors. GI absorption and excretion of these compounds were efficient due to Lipinski's Rule of Five compliance. When compared with the standard drugs Dorzagliatin (GKA) and MRK (co-crys-tallized ligand), these substances demonstrated a notable lack of AMES toxicity, skin sensiti-zation, and hepatotoxicity. CONCLUSION: In recent studies, lead molecules that possess enhanced pharmacokinetic profiles, increased binding affinity, and lower toxicity were developed to act as glucokinase activators.

Salivary microbiome and biomarker characteristics of diabetics with periodontitis.

OBJECTIVE: To examine the characteristics of the salivary microbiome in Type 2 diabetes mellitus (T2DM) patients with or without periodontitis. BACKGROUND: Periodontitis has been identified as clear sequelae of T2DM. This chronic oral disease also impacts the management of the clinical features of diabetes. The oral microbiome characteristics in T2DM with and without periodontitis, as well as the response of this oral microbiome to nonsurgical therapy have not been well described. Knowledge of key oral biological features could help address the observed poorer clinical presentation of T2DM patients. METHODS: The oral microbiome in saliva of adult cohorts periodontally healthy/non-diabetic (non-periodontitis; NP; n = 31), T2DM without periodontitis (DWoP; n = 32), and T2DM with periodontitis (DWP; n = 29) were characterized by microbial molecular analysis using V3-V4 sequencing and Luminex or ELISA techniques for salivary host analytes. RESULTS: Phyla distribution showed DWP with significantly lower levels of Firmicutes and Actinobacteria and higher levels of Fusobacteria and Spirochetes compared to the healthier groups. Approximately 10% of the detected microbial species showed significant differences in frequency and level of colonization among the DWP, DWoP, and NP samples. A subset of bacteria were significantly correlated with clinical disease features, as well as a specific repertoire of salivary analytes, in particular matrix metalloproteinase (MMP)8/MMP9, interleukin-1ß, B-cell activating factor, and resistin differed between the groups and were related to specific taxa. Principal component analysis that identified a majority of the DWP subjects microbiome was unique based upon an array of 27 taxa out of up to 255 detected in the saliva samples. CONCLUSION: T2DM patients with periodontitis show unique oral microbiome and salivary analyte composition compared to diabetics or non-diabetic persons without periodontitis. Specific members of the oral microbiome relate directly to the clinical disease features and/or salivary biomolecules in T2DM individuals.

Microcirculatory Dysfunction in Patients With Diabetes Mellitus Detected by a Distributed System of Wearable Laser Doppler Flowmetry Analysers.

The paper is devoted to the study of perfusion and amplitude-frequency spectra of laser Doppler flowmetry (LDF) signals in patients with diabetes mellitus (DM) in different skin areas of the upper and lower extremities using a distributed system of wearable LDF analysers. LDF measurements were performed in the areas of the fingers, toes, wrists and shins. The mean perfusion values, the amplitudes of blood flow oscillations in endothelial, neurogenic, myogenic, respiratory and cardiac frequency ranges, and the values of nutritive blood flow were analysed. The results revealed a decrease in tissue perfusion and nutritive blood flow in the lower extremities and an increase in these parameters in the upper extremities in patients with DM. A decrease in the amplitudes of endothelial and neurogenic oscillations was observed. The obtained results confirm the possibility of using wearable LDF analysers to detect differences in the blood flow regulation in normal and pathological conditions.

Association of hypertension and long-term blood pressure changes with new-onset diabetes in the elderly: A 10-year cohort study.

AIM: To explore the correlation between new-onset diabetes (NOD), hypertension and blood pressure management among elderly individuals in China. MATERIALS AND METHODS: A cohort analysis involved 1380 participants aged 60 years or older, initially free of diabetes in 2008, from the Chinese Longitudinal Healthy Longevity Survey. Follow-up assessments occurred every 2-3 years. The relationship between hypertension, blood pressure changes and NOD was analysed using multivariable-adjusted Cox regression. RESULTS: By 2018, 102 participants developed diabetes, while 1278 remained without diabetes. The cumulative diabetes prevalence increased from 3.1% at 3 years to 7.4% at 10 years. Hypertension prevalence increased from 20.9% at baseline to 41.0% at 10 years, with higher rates in those diagnosed with diabetes during follow-up. Multivariate analysis identified age, gender, baseline hypertension and systolic blood pressure (SBP) as independent predictors of NOD. Hypertension combined with overweight/obesity significantly increased the risk of NOD (hazard ratio [HR] 2.837; 95% confidence interval [CI], 1.680-4.792). We evaluated participants' blood pressure management levels in 2008 and 2011, then tracked the onset of diabetes from 2011 to 2018. Compared with participants with an average SBP below 120 mmHg in 2008 and 2011, those with SBP of 140 mmHg or higher had an 8-fold higher risk of developing NOD (adjusted HR8.492, 95% CI 2.048-35.217, P = .003), the highest risk group. Participants with SBP of 130-139.9 mmHg also had a significantly increased risk (adjusted HR 5.065, 95% CI 1.186-21.633, P = .029), while those with SBP of 120-129.9 mmHg showed no significant difference (HR 2.730, 95% CI 0.597-12.481, P = .195). Consistently high SBP (≥ 130 mmHg) further increased NOD risk (adjusted HR 3.464, 95% CI 1.464-8.196, P = .005). CONCLUSIONS: Significant predictors of NOD included age, gender, baseline hypertension and blood pressure management. Maintaining SBP consistently below 130 mmHg may be an effective strategy to reduce the incidence of NOD in the general elderly population.

Exposure to aircraft noise exacerbates cardiovascular and oxidative damage in three mouse models of diabetes.

BACKGROUND: Epidemiology links noise to increased risk of metabolic diseases like diabetes and obesity. Translational studies in humans and experimental animals showed that noise causes reactive oxygen species (ROS)-mediated cardiovascular damage. The interaction between noise and diabetes, specifically potential additive adverse effects, remains to be determined. METHODS AND RESULTS: C57BL/6 mice were treated with streptozotocin (i.p. injections, 50 mg/kg/d for 5d) to induce type-1 diabetes, with S961 (subcutaneous osmotic minipumps, 0.57 mg/kg/d for 7d) or fed a high-fat diet (HFD, 20 weeks) to induce type-2 diabetes. Control and diabetic mice were exposed to aircraft noise to an average sound pressure level of 72 dB(A) for 4d. While body weight was unaffected, noise reduced insulin production in all diabetes models. The oral glucose tolerance test showed only an additive aggravation by noise in the HFD model. Noise increased blood pressure and aggravated diabetes-induced aortic, mesenteric, and cerebral arterioles endothelial dysfunction. ROS formation in cerebral arterioles, the aorta, the heart, and isolated mitochondria was consistently increased by noise in all models of diabetes. Mitochondrial respiration was impaired by diabetes and noise, however without additive effects. Noise increased ROS and caused inflammation in adipose tissue in the HFD model. RNA sequencing data and alteration of gene pathway clusters also supported additive damage by noise in the setting of diabetes. CONCLUSION: In all three models of diabetes, aircraft noise exacerbates oxidative stress, inflammation, and endothelial dysfunction in mice with pre-existing diabetes. Thus, noise may potentiate the already increased cardiovascular risk in diabetic patients.

Traffic noise significantly contributes to an increased risk of cardiometabolic diseases (including diabetes and obesity) in the general population via stress hormones, inflammation and oxidative stress, all of which contribute to impaired vascular function and high blood pressure. However, the extent to which noise affects pre-existing diabetes is not sufficiently explained, which prompted us to investigate the molecular mechanisms responsible for noise-mediated exacerbation of cardiometabolic complications in three different animal models with diabetes mellitus: Noise exposure in diabetic mice caused further impairment of insulin signalling, increased blood pressure, and damage of small and large blood vessels as well as oxidative stress in the aorta, brain, and heart.Our functional observations were supported by gene analyses indicating combined effects of noise and diabetes on gene groups related to inflammation and metabolism, suggesting a need for further studies in humans to investigate how noise impacts cardiovascular risk in vulnerable groups such as patients with diabetes.

Associations between periodontal disease severity and selected cardiometabolic risk factors.

OBJECTIVES: To explore associations between periodontal disease (PD) severity and cardiometabolic risk factors, including body mass index (BMI), age, Type 2 Diabetes Mellitus (T2DM) risk, sex, and hypertension (HTN) in patients at an urban dental school clinic. METHODS AND MATERIALS: A cross-sectional study design was used to analyze electronic health record data, including periodontal status, demographic characteristics, cardiometabolic risk factors and the American Diabetes Association Diabetes Risk Test (DRT) Score. Chi-square tests and ordinal logistic regression were conducted using SAS 9.4. RESULTS: Of those with available data (n=6,778), 44% were male, 70.2% were overweight/obese, and the mean age was 50.9 (SD=16.6) years. Associations between PD severity and BMI, sex, age, DRT score, and HTN were statistically significant (all p<0.0001) in bivariate analyses. Using logistic regression, HTN (p=0.0006), sex (p<0.0001), and age (p<0.0001) were significant predictors of severe PD which was most common in those with HTN (35.9%), males (31.7%), those >60 years (36.6%). The odds of having severe PD for those with HTN were 1.2 times that of those without HTN. Males were 1.7 times more likely to have severe PD than females. Those aged 40-49 years, 50-59 years, and >60 years were 2.9, 4.2, and 4.3 times more likely to have severe PD than those who were 18-39 years, respectively. CONCLUSION: All cardiometabolic risk factors were associated with PD severity in bivariate analyses. In the logistic regression model, being older, male, and having HTN were significant predictors of PD severity. Future research is needed with a more diverse sample.