Asociación entre Glucemia inestable, tiempo de estancia y mortalidad de pacientes en estado críticos: Estudio de cohorte / Associação Entre Glicemia Instável, Tempo de Permanência e Mortalidade de Pacientes Críticos: Estudo de Coorte / Relationships between unstable Glycemia, Hospital Length Of Stay, and mortality In Critically Ill patients: A cohort study

Resumen Introducción: El control y la evaluación de los niveles glucémicos de pacientes en estado críticos es un desafío y una competencia del equipo de enfermería. Por lo que, determinar las consecuencias de esta durante la hospitalización es clave para evidenciar la importancia del oportuno manejo. Objetivo: Determinar la asociación entre la glucemia inestable (hiperglucemia e hipoglucemia), el resultado de la hospitalización y la duración de la estancia de los pacientes en una unidad de cuidados intensivos. Metodología: Estudio de cohorte prospectivo realizado con 62 pacientes a conveniencia en estado crítico entre marzo y julio de 2017. Se recogieron muestras diarias de sangre para medir la glucemia. Se evaluó la asociación de la glucemia inestable con la duración de la estancia y el resultado de la hospitalización mediante ji al cuadrado de Pearson. El valor de p<0.05 fue considerado significativo. Resultados: De las 62 personas participantes, 50 % eran hombres y 50 % mujeres. La edad media fue de 63.3 años (±21.4 años). La incidencia de glucemia inestable fue del 45.2 % y se asoció con una mayor duración de la estancia en la UCI (p<0.001) y una progresión a la muerte como resultado de la hospitalización (p=0.03). Conclusión: Entre quienes participaron, la glucemia inestable se asoció con una mayor duración de la estancia más prolongada y con progresión hacia la muerte, lo que refuerza la importancia de la actuación de enfermería para prevenir su aparición.

Resumo Introdução: O controle e avaliação dos níveis glicêmicos em pacientes críticos é um desafio e uma competência da equipe de enfermagem. Portanto, determinar as consequências da glicemia instável durante a hospitalização é chave para evidenciar a importância da gestão oportuna. Objetivo: Determinar a associação entre glicemia instável (hiperglicemia e hipoglicemia), os desfechos hospitalares e o tempo de permanência dos pacientes em uma unidade de terapia intensiva. Métodos: Um estudo de coorte prospectivo realizado com 62 pacientes a conveniência em estado crítico entre março e julho de 2017. Foram coletadas amostras diariamente de sangue para medir a glicemia. A associação entre a glicemia instável com o tempo de permanência e o desfecho da hospitalização foi avaliada pelo teste qui-quadrado de Pearson. O valor de p <0,05 foi considerado significativo. Resultados: Das 62 pessoas participantes, 50% eram homens e 50% mulheres. A idade média foi de 63,3 anos (±21,4 anos). A incidência de glicemia instável foi de 45,2% e se associou a um tempo de permanência mais prolongado na UTI (p <0,001) e uma progressão para óbito como desfecho da hospitalização (p = 0,03). Conclusão: Entre os participantes, a glicemia instável se associou a um tempo mais longo de permanência e com progressão para óbito, enfatizando a importância da actuação da equipe de enfermagem para prevenir sua ocorrência.

Abstract Introduction: The control and evaluation of glycemic levels in critically ill patients is a challenge and a responsibility of the nursing team; therefore, determining the consequences of this during hospitalization is key to demonstrate the importance of timely management. Objective: To determine the relationship between unstable glycemia (hyperglycemia and hypoglycemia), hospital length of stay, and the hospitalization outcome of patients in an Intensive Care Unit (ICU). Methods: A prospective cohort study conducted with 62 critically ill patients by convenience sampling between March and July 2017. Daily blood samples were collected to measure glycemia. The correlation of unstable glycemia with the hospital length of stay and the hospitalization outcome was assessed using Pearson's chi-square. A p-value <0.05 was considered significant. Results: Among the 62 patients, 50% were male and 50% were female. The mean age was 63.3 years (±21.4 years). The incidence of unstable glycemia was 45.2% and was associated with a longer ICU stay (p<0.001) and a progression to death as a hospitalization outcome (p=0.03). Conclusion: Among critically ill patients, unstable glycemia was associated with an extended hospital length of stay and a progression to death, emphasizing the importance of nursing intervention to prevent its occurrence.

Metabolomics for early pancreatic cancer detection in plasma samples from a Swedish prospective population-based biobank.

Background: Pancreatic ductal adenocarcinoma (pancreatic cancer) is often detected at late stages resulting in poor overall survival. To improve survival, more patients need to be diagnosed early when curative surgery is feasible. We aimed to identify circulating metabolites that could be used as early pancreatic cancer biomarkers. Methods: We performed metabolomics by liquid and gas chromatography-mass spectrometry in plasma samples from 82 future pancreatic cancer patients and 82 matched healthy controls within the Northern Sweden Health and Disease Study (NSHDS). Logistic regression was used to assess univariate associations between metabolites and pancreatic cancer risk. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to design a metabolite-based risk score. We used receiver operating characteristic (ROC) analyses to assess the discriminative performance of the metabolite-based risk score. Results: Among twelve risk-associated metabolites with a nominal P value <0.05, we defined a risk score of three metabolites [indoleacetate, 3-hydroxydecanoate (10:0-OH), and retention index (RI): 2,745.4] using LASSO. A logistic regression model containing these three metabolites, age, sex, body mass index (BMI), smoking status, sample date, fasting status, and carbohydrate antigen 19-9 (CA 19-9) yielded an internal area under curve (AUC) of 0.784 [95% confidence interval (CI): 0.714-0.854] compared to 0.681 (95% CI: 0.597-0.764) for a model without these metabolites (P value =0.007). Seventeen metabolites were significantly associated with pancreatic cancer survival [false discovery rate (FDR) <0.1]. Conclusions: Indoleacetate, 3-hydroxydecanoate (10:0-OH), and RI: 2,745.4 were identified as the top candidate biomarkers for early detection. However, continued efforts are warranted to determine the usefulness of these metabolites as early pancreatic cancer biomarkers.

The impact of the stress hyperglycemia ratio on the risk of contrast-associated acute kidney injury in patients undergoing coronary angiography: a large real-world cohort study.

BACKGROUND: Contrast-associated acute kidney injury (CA-AKI) is an important complication in the perioperative period of coronary angiography (CAG). Dysglycemia is closely associated with the occurrence of CA-AKI. However, the association between stress hyperglycemia and CA-AKI in patients undergoing CAG remains unclear. The study aims to investigate the association of the stress hyperglycemia ratio (SHR) and CA-AKI under CAG in a large real-world cohort. METHODS: This was a retrospective observational study, and patients undergoing CAG were enrolled. SHR is calculated by dividing the random blood glucose with the estimated average glucose derived from the glycosylated hemoglobin (HbA1c), and subjects were divided into five groups according to SHR. The outcome was CA-AKI defined as an increase in serum creatinine of ≥ 0.3 mg/dL (26.5 µmol/L) or 1.5-fold higher than normal levels in 48 h. The association was assessed with logistic regression and restricted cubic spline analysis. RESULTS: In 19,965 participants (men: 73.3%, mean age: 63.1 ± 10.8 years) undergoing CAG, a total of 1,621 CA-AKI cases occurred. There were reverse J-shaped associations between the SHR and CA-AKI after adjustment for other confounding factors. Moreover, SHR improved the predictive effectiveness of the traditional Mehran score (AUC 0.65 vs 0.63, P < 0.001), a predictive model of CA-AKI in patients undergoing percutaneous coronary intervention. CONCLUSIONS: There were reverse J-shaped associations of SHR with CA-AKI risk among patients undergoing CAG, and the assessment of SHR before CAG may assist clinicians in identifying patients at higher risk of CA-AKI.

Hyperglycemia facilitates EV71 replication: Insights into miR-206-mediated regulation of G3BP2 promoting EV71 IRES activity.

Background: Neurotropic virus infections actively manipulate host cell metabolism to enhance virus neurovirulence. Although hyperglycemia is common during severe infections, its specific role remains unclear. This study investigates the impact of hyperglycemia on the neurovirulence of enterovirus 71 (EV71), a neurovirulent virus relying on internal ribosome entry site (IRES)-mediated translation for replication. Methods: Utilizing hSCARB2-transgenic mice, we explore the effects of hyperglycemia in EV71 infection and elucidate the underlying mechanisms. Results: Remarkably, administering insulin alone to reduce hyperglycemia in hSCARB2-transgenic mice results in a decrease in brainstem encephalitis and viral load. Conversely, induced hyperglycemia exacerbates neuropathogenesis, highlighting the pivotal role of hyperglycemia in neurovirulence. Notably, miR-206 emerges as a crucial mediator induced by viral infection, with its expression further heightened by hyperglycemia and concurrently repressed by insulin. The use of antagomiR-206 effectively mitigates EV71-induced brainstem encephalitis and reduces viral load. Mechanistically, miR-206 facilitates IRES-driven virus replication by repressing the stress granule protein G3BP2. Conclusions: Novel therapeutic approaches against severe EV71 infections involve managing hyperglycemia and targeting the miR-206-stress granule pathway to modulate virus IRES activity.

Endothelial dysfunction: mechanisms and contribution to diseases.

The endothelium, lining the inner surface of blood vessels and spanning approximately 3 m2, serves as the largest organ in the body. Comprised of endothelial cells, the endothelium interacts with other bodily components including the bloodstream, circulating cells, and the lymphatic system. Functionally, the endothelium primarily synchronizes vascular tone (by balancing vasodilation and vasoconstriction) and prevents vascular inflammation and pathologies. Consequently, endothelial dysfunction disrupts vascular homeostasis, leading to vascular injuries and diseases such as cardiovascular, cerebral, and metabolic diseases. In this opinion/perspective piece, we explore the recently identified mechanisms of endothelial dysfunction across various disease subsets and critically evaluate the strengths and limitations of current therapeutic interventions at the pre-clinical level.

Continuous Glucose Monitoring Using the Dexcom G6 in Cardiac Surgery During the Postoperative Period.

OBJECTIVE: Cardiac surgery is associated with hyperglycemia, which in turn is associated with adverse postsurgical outcomes such as wound infections, acute renal failure, and mortality. This pilot study seeks to determine if Dexcom G6Pro continuous glucose monitor (Dexcom G6Pro CGM) is accurate during the postoperative cardiac surgery period when fluid shifts, systemic inflammatory response syndrome, and vasoactive medications are frequently encountered, compared to standard glucose monitoring techniques. METHODS: This study received institutional review board approval. In this prospective study, correlation between clinical and Dexcom glucose readings was evaluated. Clinical glucose (blood gas, metabolic panel, and point of care) data set included 1428 readings from 29 patients, while the Dexcom G6Pro CGM data included 45 645 data points following placement to upper arm. Additionally, average clinical measurements of day and overnight temperatures and hemodynamics were evaluated. Clinical and Dexcom data were restricted to being at least 1 hour after prior clinical reading Matching Dexcom G6Pro CGM data were required within 5 minutes of clinical measure. Data included only if taken at least 2 hours after Dexcom G6Pro CGM insertion (warm-up time) and analyzed only following intensive care unit (ICU) admission. Finally, a data set excluding the first 24 hours after ICU admission was created to explore stability of the device. Patients remained on Dexcom G6Pro CGM until discharge or 10 days postoperatively. RESULTS: The population was 71% male, 14% with known diabetes; 66% required intravenous insulin infusion. The Clarke error grid plot of all measures post-ICU admission showed 53.5% in zone A, 45.9% in zone B, and 0.6% (n = 5) in zones D or E. The restricted dataset that excluded the first 24 hours post-ICU admission showed 55.9% in zone A, 43.9% in zone B, and 0.2% in zone D. Mean absolute relative difference between clinical and Dexcom G6Pro CGM measures was 20.6% and 21.6% in the entire post-ICU admission data set, and the data set excluding the first 24 hours after ICU admission, respectively. In the subanalysis of the 12 patients who did not have more than a 5-minute tap in the operating room, a consensus error grid, demonstrated that after ICU admission, percentage in zone A was 53.9%, zone B 45.4%, and zone C 0.7%. Similar percentages were obtained removing the first 24 hours post-ICU admission. These numbers are very similar to the entire cohort. A consensus error grid created post-ICU admission demonstrated: (zone A) 54%, (zone B) 45%, (zone C) 0.9%, and the following for the dataset created excluding the first 24 hours: (zone A) 56%, (zone B) 44%, (zone C) 0.4%, which demonstrated very close agreement with the original Clarke error grid. No adverse events were reported. CONCLUSIONS: Almost 100% of Dexcom G6Pro CGM and clinical data matching points fell within areas considered as giving clinically correct decisions (zone A) and clinically uncritical decisions (zone B). However, the relatively high mean absolute relative difference precludes its use for both monitoring and treatment in the clinical context. As technology evolves, interstitial glucose monitoring may become an important tool to limit iatrogenic anemia and mitigate glycemic fluctuations.

Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment.

BACKGROUND: Vasculopathy is the most common complication of diabetes. Endothelial cells located in the innermost layer of blood vessels are constantly affected by blood flow or vascular components; thus, their mechanosensitivity plays an important role in mediating vascular regulation. Endothelial damage, one of the main causes of hyperglycemic vascular complications, has been extensively studied. However, the role of mechanosensitive signaling in hyperglycemic endothelial damage remains unclear. METHODS: Vascular endothelial-specific Piezo1 knockout mice were generated to investigate the effects of Piezo1 on Streptozotocin-induced hyperglycemia and vascular endothelial injury. In vitro activation or knockdown of Piezo1 was performed to evaluate the effects on the proliferation, migration, and tubular function of human umbilical vein endothelial cells in high glucose. Reactive oxygen species production, mitochondrial membrane potential alternations, and oxidative stress-related products were used to assess the extent of oxidative stress damage caused by Piezo1 activation. RESULTS: Our study found that in VECreERT2;Piezo1flox/flox mice with Piezo1 conditional knockout in vascular endothelial cells, Piezo1 deficiency alleviated streptozotocin-induced hyperglycemia with reduced apoptosis and abscission of thoracic aortic endothelial cells, and decreased the inflammatory response of aortic tissue caused by high glucose. Moreover, the knockout of Piezo1 showed a thinner thoracic aortic wall, reduced tunica media damage, and increased endothelial nitric oxide synthase expression in transgenic mice, indicating the relief of endothelial damage caused by hyperglycemia. We also showed that Piezo1 activation aggravated oxidative stress injury and resulted in severe dysfunction through the Ca2+-induced CaMKII-Nrf2 axis in human umbilical vein endothelial cells. In Piezo1 conditional knockout mice, Piezo1 deficiency partially restored superoxide dismutase activity and reduced malondialdehyde content in the thoracic aorta. Mechanistically, Piezo1 deficiency decreased CaMKII phosphorylation and restored the expression of Nrf2 and its downstream molecules HO-1 and NQO1. CONCLUSION: In summary, our study revealed that Piezo1 is involved in high glucose-induced oxidative stress injury and aggravated endothelial dysfunction, which have great significance for alleviating endothelial damage caused by hyperglycemia.

Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy.

BACKGROUND: Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA. METHODS: To identify DMRs, we employed the bump hunter method in samples from young (9-16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28-33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle. RESULTS: One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring's own adiposity. CONCLUSIONS: Our results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease.

Effect of Elevated Blood Glucose on Postoperative Complications Among Diabetic Patients After Surgical Treatment of Torsional Ankle Fracture.

BACKGROUND: This study aims to evaluate the association of elevated blood glucose and postoperative complications among diabetic patients after surgical treatment of torsional ankle fracture. METHODS: This was a retrospective study of consecutive diabetic patients treated surgically for a torsional ankle injury between January 2017 and December 2021 at a large tertiary hospital. All patients who met inclusion and exclusion criteria were divided into a high-HbA1c group or a low-HbA1c group according to the HbA1c cutoff of 7.0% within 3 months of operation, then a propensity score match was performed to control potential confounding factors. The primary outcomes were postoperative complications, and secondary outcomes were unplanned secondary procedures. RESULTS: A matched cohort of 238 patients was finally included, with 119 patients with high HbA1c levels and 119 with low HbA1c levels. Patients with high HbA1c levels experienced more complications (31.1% vs 18.5%, P < .01) and more secondary procedures (22.7% and 8.4%, P < .01) than those with low HbA1c levels. Multivariate logistic regression indicated that patients with high HbA1c levels were significantly associated with higher proportions of any complications (OR 2.25, 95% CI 1.08-4.69; P = .03), superficial infection (OR 4.03, 95% CI 2.13-5.41; P < .01), deep infection (OR 1.42, 95% CI 1.23-2.02; P < .01), and any unplanned secondary operations (OR 3.72, 95% CI 1.62-8.52; P < .01) compared with those with low HbA1c levels after controlling for potential confounders. Multivariate linear regression showed that high HbA1c levels were significantly associated with a higher number of complications (ß = 4.61, 95% CI 2.63-18.18; P < .01) and a higher number of secondary procedures (ß = 4.44, 95% CI 2.79-10.87; P < .01). CONCLUSION: Patients with an HbA1c >7.0% within 3 months of operation are more likely to have a wound issue/infection and more likely to undergo a secondary procedure after surgical treatment of torsional ankle fractures in diabetic patients than patients with an HbA1c ≤7.0% within 3 months of operation. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

The potential association between metabolic disorders and pulmonary tuberculosis: a Mendelian randomization study.

BACKGROUND: Metabolic disorders (MetDs) have been demonstrated to be closely linked to numerous diseases. However, the precise association between MetDs and pulmonary tuberculosis (PTB) remains poorly understood. METHOD: Summary statistics for exposure and outcomes from genome-wide association studies (GWASs) for exposures and outcomes were obtained from the BioBank Japan Project (BBJ) Gene-exposure dataset. The 14 clinical factors were categorized into three groups: metabolic laboratory markers, blood pressure, and the MetS diagnostic factors. The causal relationship between metabolic factors and PTB were analyzed using two-sample Mendelian Randomization (MR). Additionally, the direct effects on the risk of PTB were investigated through multivariable MR. The primary method employed was the inverse variance-weighted (IVW) model. The sensitivity of this MR analysis was evaluated using MR-Egger regression and the MR-PRESSO global test. RESULTS: According to the two-sample MR, HDL-C, HbA1c, TP, and DM were positively correlated with the incidence of active TB. According to the multivariable MR, HDL-C (IVW: OR 2.798, 95% CI 1.484-5.274, P = 0.001), LDL (IVW: OR 4.027, 95% CI 1.140-14.219, P = 0.03) and TG (IVW: OR 2.548, 95% CI 1.269-5.115, P = 0.009) were positively correlated with the occurrence of PTB. TC (OR 0.131, 95% CI 0.028-0.607, P = 0.009) was negatively correlated with the occurrence of PTB. We selected BMI, DM, HDL-C, SBP, and TG as the diagnostic factors for metabolic syndrome. DM (IVW, OR 1.219, 95% CI 1.040-1.429 P = 0.014) and HDL-C (IVW, OR 1.380, 95% CI 1.035-1.841, P = 0.028) were directly correlated with the occurrence of PTB. CONCLUSIONS: This MR study demonstrated that metabolic disorders, mainly hyperglycemia, and dyslipidemia, are associated with the incidence of active pulmonary tuberculosis.

N-p-coumaroyloctopamine ameliorates hepatic glucose metabolism and oxidative stress involved in a PI3K/AKT/GSK3ß pathway.

Type 2 diabetes mellitus is regarded as a chronic metabolic disease characterized by hyperglycemia. Long-term hyperglycemia may result in oxidative stress, damage pancreatic ß-cell function and induce insulin resistance. Herein we explored the anti-hypoglycemic effects and mechanisms of action of N-p-coumaroyloctopamine (N-p-CO) in vitro and in vivo. N-p-CO exhibited high antioxidant activity, as indicated by the increased activity of SOD, GSH and GSH-Px in HL-7702 cells induced by both high glucose (HG) and palmitic acid (PA). N-p-CO treatment significantly augmented glucose uptake and glycogen synthesis in HG/PA-treated HL-7702 cells. Moreover, administration of N-p-CO in diabetic mice induced by both high-fat diet (HFD) and streptozotocin (STZ) not only significantly increased the antioxidant levels of GSH-PX, SOD and GSH, but also dramatically alleviated hyperglycemia and hepatic glucose metabolism in a dose-dependent manner. More importantly, N-p-CO upregulated the expressions of PI3K, AKT and GSK3ß proteins in both HG/PA-induced HL-7702 cells and HFD/STZ-induced mice. These findings clearly suggest that N-p-CO exerts anti-hypoglycemic and anti-oxidant effects, most probably via the regulation of a PI3K/AKT/GSK3ß signaling pathway. Thus, N-p-CO may have high potentials as a new candidate for the prevention and treatment of diabetes.

Diabetic Ketoacidosis: A Rare Complication of Type 3c Diabetes.

Recently termed pancreoprivic diabetes, type 3c diabetes refers to high blood sugar values secondary to disease of the exocrine pancreas. The disease is most commonly misdiagnosed as type 2 diabetes mellitus (DM) and is overlooked by physicians and the general public. Chronic pancreatitis (CP) accounts for most cases of type 3c diabetes. Diabetic ketoacidosis (DKA) is a rare occurrence in type 3c diabetes as both alpha and beta cell dysfunction occur concurrently. In this case, the major hormones involved in lipolysis and ketone body production would be catecholamines, cortisol, and growth hormone. We report a case of a 37-year-old female with a history of endocrine pancreatic insufficiency secondary to CP who presented with DKA, one of the life-threatening but preventable complications of diabetes. Noncompliance with insulin and concurrent urinary tract infection were the inciting factors. Her condition improved with DKA management according to standard protocol, intravenous antibiotics, and other supportive care. She got discharged after optimization of insulin therapy, with proper advice for home blood sugar monitoring and regular follow-up. A patient with pancreatic pathology may present to the emergency with DKA as the first manifestation, and if not properly evaluated, the diagnosis of type 3c diabetes can be missed.

The protective role of resveratrol against high glucose-induced oxidative stress and apoptosis in HepG2 cells.

High glucose concentrations result in oxidative stress, leading to damage of cellular constituents like DNA, proteins, and lipids, ultimately resulting in apoptosis. Resveratrol, a polyphenol phytoalexin, has been studied for its potential therapeutic effects on diabetes. This study investigated the influence of high glucose (HG) on HepG2 cells and assessed resveratrol's effect on high-glucose-induced oxidative stress and apoptosis. HepG2 cells were cultured for 48 and 72 h with high glucose (40 mM), low resveratrol (25 µM), high resveratrol (50 µM), high glucose + low resveratrol, and high glucose + high resveratrol. After exposure, oxidative and apoptosis-related gene expression was evaluated using quantitative polymerase chain reaction (qPCR), and lactate dehydrogenase (LDH) release was measured using the supernatant. In HepG2 cells cultured with high glucose, all antioxidant enzymes (SOD, superoxide dismutase; GPx1, glutathione peroxidase 1; CAT, catalase; Nrf2, nuclear factor erythroid 2-related factor 2; and NQO1, NAD(P)H quinone oxidoreductase 1) were significantly reduced; however, when HepG2 cells were cultured with resveratrol (25 and 50 µM) and high glucose, the expression levels of all antioxidant enzymes were increased. The anti-apoptotic gene (B-cell lymphoma 2; Bcl2) and the DNA repair gene (Oxoguanine glycosylase-1, OGG1) were significantly decreased following high glucose exposure to HepG2 cells. Surprisingly, the expression levels of Bcl2 and OGG1 were notably elevated after resveratrol treatment. Furthermore, high glucose levels increased the LHD release in HepG2 cells, whereas resveratrol treatment reduced the LDH release. Our results demonstrate that resveratrol provides protection against oxidative stress and apoptosis induced by high glucose in HepG2 cells. Hence, resveratrol shows potential as an effective approach to address the impaired antioxidant response resulting from elevated glucose levels commonly observed in diabetes and metabolic disorders.

Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-ß in Type 2 Diabetes.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-ß peptides (Aß) play a key role in AD pathophysiology. Therefore, human studies on Aß metabolism and T2D are warranted. Objective: The objective of this study was to examine whether acute hyperglycemia affects plasma Aß 1-40 and Aß 1-42 concentrations in individuals with T2D and matched controls. Methods: Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aß 1-40, Aß 1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aß 1-40 and Aß 1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. Results: At baseline, Aß 1-40 and Aß 1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aß decreased in the control group, compared to the placebo clamp (Aß 1-40: p = 0.034, Aß 1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aß or IDE was noted in the T2D group. Conclusions: Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aß 40 and Aß 42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.

O-GlcNAcylation and immune cell signaling: A review of known and a preview of unknown.

The dynamic and reversible modification of nuclear and cytoplasmic proteins by O-GlcNAcylation significantly impacts the function and dysfunction of the immune system. O-GlcNAcylation plays crucial roles under both physiological and pathological conditions in the biochemical regulation of all immune cell functions. Three and a half decades of knowledge acquired in this field is merely sufficient to perceive that what we know is just the prelude. This review attempts to mark out the known regulatory roles of O-GlcNAcylation in key signal transduction pathways and specific protein functions in the immune system, and adumbrate ensuing questions toward the unknown functions.

Effect of High-Sucrose Diet on the Occurrence and Progression of Diabetic Retinopathy and Dietary Modification Strategies.

As the most serious of the many worse new pathological changes caused by diabetes, there are many risk factors for the occurrence and development of diabetic retinopathy (DR). They mainly include hyperglycemia, hypertension, hyperlipidemia and so on. Among them, hyperglycemia is the most critical cause, and plays a vital role in the pathological changes of DR. High-sucrose diets (HSDs) lead to elevated blood glucose levels in vivo, which, through oxidative stress, inflammation, the production of advanced glycation end products (AGEs) and vascular endothelial growth factor (VEGF), cause plenty of pathological damages to the retina and ultimately bring about loss of vision. The existing therapies for DR primarily target the terminal stage of the disease, when irreversible visual impairment has appeared. Therefore, early prevention is particularly critical. The early prevention of DR-related vision loss requires adjustments to dietary habits, mainly by reducing sugar intake. This article primarily discusses the risk factors, pathophysiological processes and molecular mechanisms associated with the development of DR caused by HSDs. It aims to raise awareness of the crucial role of diet in the occurrence and progression of DR, promote timely changes in dietary habits, prevent vision loss and improve the quality of life. The aim is to make people aware of the importance of diet in the occurrence and progression of DR. According to the dietary modification strategies that we give, patients can change their poor eating habits in a timely manner to avoid theoretically avoidable retinopathy and obtain an excellent prognosis.

Short- and long-term exposure to high glucose induces unique transcriptional changes in osteoblasts in vitro.

Bone is increasingly recognized as a target for diabetic complications. In order to evaluate the direct effects of high glucose on bone, we investigated the global transcriptional changes induced by hyperglycemia in osteoblasts in vitro. Rat bone marrow-derived mesenchymal stromal cells were differentiated into osteoblasts for 10 days, and prior to analysis, they were exposed to hyperglycemia (25 mM) for the short-term (1 or 3 days) or long-term (10 days). Genes and pathways regulated by hyperglycemia were identified using mRNA sequencing and verified with qPCR. Genes upregulated by 1-day hyperglycemia were, for example, related to extracellular matrix organization, collagen synthesis and bone formation. This stimulatory effect was attenuated by 3 days. Long-term exposure impaired osteoblast viability, and downregulated, for example, extracellular matrix organization and lysosomal pathways, and increased intracellular oxidative stress. Interestingly, transcriptional changes by different exposure times were mostly unique and only 89 common genes responding to glucose were identified. In conclusion, short-term hyperglycemia had a stimulatory effect on osteoblasts and bone formation, whereas long-term hyperglycemia had a negative effect on intracellular redox balance, osteoblast viability and function.

Glycated LDL generates reactive species that damage cell components, oxidize hemoglobin and alter surface morphology in human erythrocytes.

Low-density lipoprotein (LDL) transports cholesterol to various tissues via the blood. Glycation of LDL occurs during hyperglycemic condition which is characterised by persistently high blood glucose level. Circulating erythrocytes can come in direct contact with glycated LDL (G-LDL). The objective of this study was to investigate the effect of G-LDL on human erythrocytes, specifically on hemoglobin, intracellular generation of reactive species and the antioxidant defence system. Isolated erythrocytes were incubated with G-LDL (3 and 6 mg/ml) and native LDL (6 mg/ml) at 37 °C for 24 h. Native LDL and G-LDL untreated erythrocytes were similarly incubated at 37 °C and served as control. G-LDL treatment increased hemolysis compared to control and native LDL-treated erythrocytes. Incubation of erythrocytes with G-LDL led to an increase in protein oxidation and lipid peroxidation while greatly decreasing the total sulfhydryl content. It also significantly enhanced hemoglobin oxidation, heme degradation, and the release of free iron moiety. Treatment with G-LDL led to an appreciable increase in the production of reactive oxygen and nitrogen species. The antioxidant power and activities of major antioxidant enzymes were drastically reduced, while critical membrane-bound enzymes were inhibited. The surface morphology of G-LDL-treated erythrocytes was altered leading to the formation of echinocytes. Importantly, treatment of erythrocytes with native LDL did not significantly affect the above-mentioned parameters and values were similar to the corresponding controls. Thus, G-LDL is cytotoxic to human erythrocytes and causes oxidative damage to cell components. This can reduce the oxygen-transporting ability of blood and also result in red cell senescence and anemia.

Vaspin facilitates the proliferation and osteogenic differentiation of periodontal ligament stem cells.

OBJECTIVE: To investigate whether visceral adipose tissue-derived serine protease inhibitor (vaspin) can alleviate the inhibitory effect of high-glucose (HG) culture on the proliferation and osteogenic differentiation of human periodontal ligament stem cells (PDLSCs) and to preliminarily explore the underlying mechanisms. BACKGROUND: High glucose produces damage to the regeneration of periodontal tissue of PDLSCs. The expression level of vaspin in periodontal tissue is high in periodontitis patients and effectively reduced after initial therapy of periodontal diseases. However, the effect of vaspin on PDLSCs remains unknown. MATERIALS AND METHODS: PDLSCs were cultured in media augmented with 5.5 or 25.0 mM concentrations of glucose to elucidate the impact and mechanism of vaspin on PDLSCs under high glucose in vitro. Proliferation was measured by Cell Counting Kit-8 (CCK8) assay. Osteogenesis of PDLSCs was assessed by alkaline phosphatase (ALP) staining, ALP activity, and Alizarin Red staining. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) were used to investigate the osteo-specific markers. Then, the molecular impact of vaspin in the presence/absence of HG on PDLSCs physiology was determined with TGF-ß1/Smad signaling pathway as the main focus. RESULTS: It was revealed that the proliferation and osteogenic differentiation (OD) of PDLSCs under HG was reduced, and by adding vaspin the anti-osteogenic impact of HG was relieved. Moreover, vaspin enhanced TGF-ß1/Smad signaling pathway activity. Pretreatment with TGF-ß1 inhibitor blocked vaspin-triggered TGF-ß1/Smad signal activation and minimized the vaspin-induced protective effect against HG-inhibited growth and OD. CONCLUSIONS: In summary, vaspin observably reduces HG-mediated inhibition of PDLSCs OD by modulating the TGF-ß1/Smad signaling pathway. Vaspin may be a potential therapeutic for periodontal tissue regeneration in diabetic patients.

Hepatogenous Diabetes as Compared to Type-2 Diabetes Mellitus and Non-diabetes in Patients With Liver Cirrhosis: Magnitude, Characteristics, and Implications.

Aim: Hepatogenous diabetes (HD) is frequently underestimated among cirrhosis patients. The current study assessed the magnitude, clinical characteristics, and implications of HD in cirrhosis patients as compared to the patients with type-2 diabetes mellitus (T2DM) and non-diabetes (ND) cirrhosis. Methods: In a prospective observational study, 338 consecutive eligible cirrhosis patients were screened for diabetes mellitus. A 2-hour oral glucose tolerance test (OGTT) was used to detect HD. The clinical characteristics, complications, and outcomes were ascertained and compared amongst HD, T2DM, and ND patients. Results: In the final study cohort of 316 patients, the proportion of HD, T2DM, and ND was 22.5% (n = 71), 26.3% (n = 83), and 51.3% (n = 162), respectively. HD was the predominant form of diabetes (68.9%) in Child-Pugh class-C cirrhosis. The majority (73%) of HD patients had abnormal OGTT without fasting hyperglycaemia. A lower cut-off of 98.5 mg/dl for fasting blood glucose had a modest sensitivity (72%) and specificity (75%) for predicting HD. In comparison to T2DM patients, HD patients were younger, leaner, and had more advanced cirrhosis. In comparison to ND patients, HD patients were leaner but had higher glycemic indices, serum cholesterol, and arterial ammonia levels. During a median follow-up period of 12 (03-21) months, the frequency of hepatic encephalopathy and variceal haemorrhage were higher in HD and T2DM patients compared to that in the ND group. Conclusions: HD is prevalent in about one fifth of cirrhosis patients. It differs from T2DM and ND in a number of ways, and has association with complications of cirrhosis.