Elevated Hemoglobin A1c and the Risk of Developing ARDS in Two Cohort Studies.

BACKGROUND: Only a subset of patients at risk for ARDS go on to develop it, and the contribution of preexisting comorbidities (eg, diabetes) to ARDS risk is not well understood. Prior studies of the association between diabetes and ARDS have yielded conflicting results. RESEARCH QUESTION: Does assessing ARDS risk based on hemoglobin A1c (HbA1c) as a marker of long-term blood glucose levels, rather than a charted diagnosis of diabetes, clarify the relationship between diabetes and ARDS? STUDY DESIGN AND METHODS: Using data from two prospective observational cohorts of critically ill adults (Validating Acute Lung Injury Biomarkers for Diagnosis [VALID] and Early Assessment of Renal and Lung Injury [EARLI]), we analyzed the association between clinical HbA1c category and development of ARDS in patients with a risk factor for ARDS and at least one clinical HbA1c measurement within the 180 days prior through 14 days after enrollment. RESULTS: A total of 599 patients in VALID and 276 in EARLI met inclusion criteria, of whom 164 and 58 developed ARDS, respectively. Patients with a charted diagnosis of diabetes were not shown to be more likely to develop ARDS (VALID: 24.6% ARDS in those categorized as nondiabetic vs 30.0% in those categorized as diabetic, P = .14; EARLI: 19.6% vs 22.8%, respectively; P = .55). However, in VALID, patients categorized as diabetic with inadequate glycemic control based on their HbA1c had an increased risk of developing ARDS compared with those with nondiabetic HbA1c (20.9% vs 34.0%, respectively; P = .0073), a finding that persisted in multivariable analysis (OR for those categorized as diabetic with inadequate glycemic control vs those categorized as nondiabetic range HbA1c, 1.25; 95% CI, 1.01-1.57). These findings were not reproduced in the smaller EARLI cohort, but were appreciated when the cohorts were combined for analysis. INTERPRETATION: Elevated HbA1c may be associated with risk of developing ARDS, independent of clinical diagnosis of diabetes, but prospective validation is needed. If confirmed, these findings suggest that inadequate glycemic control could be an unrecognized risk factor for ARDS.

Rapid correction of chronic hyperglycemia and bone remodeling, warning against overdoing.

It is widely recognized that chronic hyperglycemia decreases bone quality, although little is known about the impact of the rapid correction of chronic hyperglycemia on the quality of bone remodeling. This spotlight article explores this correlation by focusing on the stages of bone remodeling linked to glucose levels.

The integrated analysis and underlying mechanisms of FNDC5 on diabetic induced cognitive deficits.

OBJECTIVES: Chronic hyperglycemia is considered as an important factor to promote the neurodegenerative process of brain, and the synaptic plasticity as well as heterogeneity of hippocampal cells are thought to be associated with cognitive dysfunction in the early process of neurodegeneration. To date, fibronectin type III domain-containing protein 5 (FNDC5) has been highlighted its protective role in multiple neurodegenerative diseases. However, the potential molecular and cellular mechanisms of FNDC5 on synaptic plasticity regulation in cognitive impairment (CI) induced by diabetics are still need to known. METHODS/DESIGN: To investigate the heterogeneity and synaptic plasticity of hippocampus in animals with CI state induced by hyperglycemia, and explore the potential role of FNDC5 involved in this process. Firstly, the single cell sequencing was performed based on the hippocampal tissue from db diabetic mice induced CI and normal health control mice by ex vivo experiments; and then the integrated analysis and observations validation using Quantitative Real-time PCR, western blot as well as other in vitro studies. RESULTS: We observed and clarified the sub-cluster of type IC spiral ganglion neurons expressed marker genes as Trmp3 and sub-cluster of astrocytes with marker gene as Atp1a2 in hippocampal cells from diabetic animals induced CI and the effect of those on neuron-glial communication. We also found that FNDC5\BDNF-Trk axis was involved in the synaptic plasticity regulation of hippocampus. In high glucose induced brain injury model in vitro, we investigated that FNDC5 significantly regulates BDNF expression and that over-expression of FNDC5 up-regulated BDNF expression (p < 0.05) and can also significantly increase the expression of synapsin-1 (p < 0.05), which is related to synaptic plasticity, In addition, the unbalanced methylation level between H3K4 and H3K9 in Fndc5 gene promoter correlated with significantly down-regulated expression of FNDC5 (p < 0.05) in the hyperglycemia state. CONCLUSION: The current study revealed that the synaptic plasticity of hippocampal cells in hyperglycemia might be regulated by FNDC5\BDNF-Trk axis, playing the protective role in the process of CI induced by hyperglycemia and providing a target for the early treatment of hyperglycemia induced cognitive dysfunction in clinic.

Infecciones de la vias urinarias en pacientes diabéticos / Urinary tract infections in diabetic patients

Las infecciones del tracto urinario se encuentran entre las enfermedades infecciosas más comunes en todo el mundo, Los pacientes con diabetes mellitus suelen presentar una función inmune deteriorada y enfermedades infecciosas agravadas. La infección del tracto urinario es una de las principales complicaciones de la diabetes mellitus, aumenta la susceptibilidad a las infecciones, en parte debido a la alteración de la función de los granulocitos, un control glucémico inadecuado e hiperglucemia crónica que condiciona la presencia de microangiopatía diabética.

Urinary tract infections are among the most common infectious diseases worldwide. Patients with diabetes mellitus sometimes presented with impaired immune function and aggravated infectious diseases. Urinary tract infection is one of the main complications of diabetes mellitus; it increases susceptibility to infections, partly due to altered granulocyte function, inadequate glycemic control and chronic hyperglycemia that conditions the presence of diabetic microangiopathy.

Rapid correction of hyperglycemia: A necessity but at what price? A brief report of a patient living with type 1 diabetes.

BACKGROUND: The correction and control of chronic hyperglycemia are the management goals of patients living with diabetes. Chronic hyperglycemia is the main factor inducing diabetes-related complications. However, in certain situations, the rapid and intense correction of chronic hyperglycemia can paradoxically favor the onset of microvascular complications. CASE SUMMARY: In this case report, we describe the case of a 25-year-old woman living with type 1 diabetes since the age of 9 years. Her diabetes was chronic and unstable but without complications. During an unplanned pregnancy, her diabetes was intensely managed with the rapid correction of her hyperglycemia. However, over the following 2 years, she developed numerous degenerative microvascular complications: Charcot neuroarthropathy with multiple joint involvement, severe proliferative diabetic retinopathy, gastroparesis, bladder voiding disorders, and end-stage renal failure requiring hemodialysis. CONCLUSION: In the literature to date, the occurrence of multiple microvascular complications following the rapid correction of chronic hyperglycemia has been rarely described in the same individual.

Prevalence of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus.

Introduction: Cardiac autonomic neuropathy (CAN) is one of the microvascular complications of diabetes mellitus, which is due to the involvement of autonomic nerve fibers innervating the heart and blood vessels. CAN was found to have a greater degree of morbidity and mortality than their non-CAN counterparts as it is underdiagnosed. Hence, this study aims to determine the prevalence and severity of CAN in type 2 diabetics in the South Indian setting. Materials and Methods: Forty-two patients with type 2 diabetes mellitus were enrolled in the study. Patients underwent tests for CAN, with the severity of CAN estimated as a CAN score, which was the sum of the scores of the four cardiovascular autonomic function tests. Results: Out of the 42 patients, a total of 36 patients (85.7%) were diagnosed with CAN. Among those with CAN, 24 patients had early CAN (57.1%), and 12 were diagnosed with definite CAN (28.6%). Patients with any form of CAN (early and definite CAN) had higher HbA1c and mean glucose values than those without CAN. CAN was also found to be more severe among older patients with diabetes. Conclusion: In the present study, we found that more than 50% of the study population had early CAN and around 28.6% patients had definite CAN indicating higher prevalence of CAN in our population. Also, there was a positive correlation between the severity of CAN and the age of the patients. This study highlights the importance of understanding the importance of screening the diabetic patients for CAN to prevent adverse cardiovascular events.

An inducible model of chronic hyperglycemia.

Transgene driven expression of Escherichia coli nitroreductase (NTR1.0) renders animal cells susceptible to the antibiotic metronidazole (MTZ). Many NTR1.0/MTZ ablation tools have been reported in zebrafish, which have significantly impacted regeneration studies. However, NTR1.0-based tools are not appropriate for modeling chronic cell loss as prolonged application of the required MTZ dose (10 mM) is deleterious to zebrafish health. We established that this dose corresponds to the median lethal dose (LD50) of MTZ in larval and adult zebrafish and that it induced intestinal pathology. NTR2.0 is a more active nitroreductase engineered from Vibrio vulnificus NfsB that requires substantially less MTZ to induce cell ablation. Here, we report on the generation of two new NTR2.0-based zebrafish lines in which acute ß-cell ablation can be achieved without MTZ-associated intestinal pathology. For the first time, we were able to sustain ß-cell loss and maintain elevated glucose levels (chronic hyperglycemia) in larvae and adults. Adult fish showed significant weight loss, consistent with the induction of a diabetic state, indicating that this paradigm will allow the modeling of diabetes and associated pathologies.

Alterations of Spontaneous Cortical and Subcortical Activity in Type 2 Diabetes Mellitus with and without Depression.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) patients with depression have a higher risk of complications and mortality than T2DM without depression. However, the exact neuropathophysiological mechanism remains unclear. Consequently, the current study aimed to investigate the alteration of cortical and subcortical spontaneous neural activity in T2DM patients with and without depression. METHODS: The demographic data, clinical variables, neuropsychological tests, and functional and anatomical magnetic resonance imaging of depressed T2DM (n = 47) of non-depressed T2DM (n = 59) and healthy controls (n = 41) were collected and evaluated. The correlation analysis, stepwise multiple linear regression, and receiver operating characteristic curve were performed for further analysis. RESULTS: Abnormal neural activities in the bilateral posterior cingulate cortex (PCC) and hippocampus were observed in depressed and non-depressed T2DM and the right putamen of the depressed T2DM. Interestingly, the subcortical degree centrality (DC) of the right hippocampus and putamen were higher in depressed than non-depressed T2DM. Furthermore, the cortical amplitude of low-frequency fluctuation (ALFF) in PCC, subcortical DC in the putamen of depressed T2DM, and hippocampus of non-depressed T2DM was correlated with cognitive scores. In contrast, the cortical fractional ALFF in PCC of non-depressed T2DM was correlated with depression scores. CONCLUSIONS: The abnormalities of spontaneous cortical activity in PCC and subcortical activity in the hippocampus might represent the neurobiological feature of cerebral dysfunction in T2DM. Notably, the altered subcortical activity in the right putamen might mainly associate with negative emotion in T2DM, which could be a promising biomarker for recognizing early cerebral dysfunction in depressed T2DM. This study provided a novel insight into the neuropathophysiological mechanism of brain dysfunction in T2DM with and without depression.

Trends in the pathophysiology of Charcot neuroarthropathy.

The pathophysiology of Charcot neuroarthropathy (CN) includes a number of gray areas, particularly regarding the onset of inflammation which induces the disruption of the bone remodeling factor responsible for the onset of bone lysis. This clinical insight highlights a potential link between this inflammation and the rapid correction of chronic hyperglycemia (Dardari et al., 2022), which is known to be responsible for a particular type of neuropathy known as treatment-induced neuropathy of diabetes (TIND). Our description makes an additional contribution to shed light on the mysterious physiopathology of CN.

Oleanolic acid rescues critical features of umbilical vein endothelial cells permanently affected by hyperglycemia.

Skin wound healing is a physiological process that involves several cell types. Among them, endothelial cells are required for inflammation resolution and neo-angiogenesis, both necessary for tissue restoration after injury. Primary human umbilical vein endothelial cells (C-HUVECs) are derived from the umbilical cord. When women develop gestational diabetes, chronic exposure to hyperglycemia induces epigenetic modifications in these cells (GD-HUVECs), leading to a permanent pro-inflammatory phenotype and impaired angiogenesis in contrast to control cells. Oleanolic acid (OA) is a bioactive triterpenoid known for its epithelial cell migration promotion stimulation and higher tensile strength of wounds. However, the potentially anti-inflammatory and pro-angiogenic properties of OA are still under investigation. We tested OA on C- and GD-HUVECs under inflammatory conditions induced by low levels of the inflammatory cytokine TNF-α. Reduced expression of adhesion molecules VCAM1, ICAM1, and SELE was obtained in OA-pre-treated C- and GD-HUVECs. Additionally, protein VCAM1 levels were also decreased by OA. Coherently, monocyte adhesion assays showed that a lower number of monocytes adhered to GD-HUVEC endothelium under OA pre-treatment when compared to untreated ones. It is noteworthy that OA improved angiogenesis parameters in both phenotypes, being especially remarkable in the case of GD-HUVECs, since OA strongly rescued their poor tube formation behavior. Moreover, endothelial cell migration was improved in C- and GD-HUVECs in scratch assays, an effect that was further confirmed by focal adhesion (FA) remodeling, revealed by paxillin staining on immunocytochemistry assays. Altogether, these results suggest that OA could be an emergent wound healing agent due to its capacity to rescue endothelial malfunction caused by hyperglycemia.

Effect of aqueous extract of Scorodophloeuszenkeri bark on chronic hyperglycemia and its complications in a diabetic Wistar rat model induced by streptozotocin.

Diabetes and its complications represent a real major public health problem in the world because of its high rates of morbidity and mortality. Chronic hyperglycemia, oxidative stress, dyslipidemia and inflammation play a major role in the pathophysiology of diabetes and its vascular complications. The objective of this study was to evaluate the effect of aqueous extract of S. zenkeri on chronic hyperglycemia and its complications in a streptozotocin-induced diabetic Wistar rat model. The barks of S. zenkeri were washed, dried and crushed; the powder was dissolved in distilled water (1:10 weight/volume) then macerated and the filtrate obtained was dried in an oven. Subsequently, after quantification of the bioactive compounds (total polyphenols, flavonoids and alkaloids) present in the extract, an in vivo study was conducted in an animal model of streptozotocin-induced hyperglycemia. For this fact, the rats were divided into four groups of five rats as folow: a normoglycaemia group (NC), an untreated hyperglycaemia group (PC), two hyperglycaemia groups including a test group receiving by esophageal gavage, the aqueous extract of the bark of S zenkerii (AESZ) at a dose of 300 mg/kg body weight and a control group receiving metformin at a dose of 20 mg/kg body weight. During the treatment which lasted 21 days, the weights have been taken every two days and the blood sugar levels every week. At the end of the treatment, the rats were killed under light chloroform anesthesia; the plasma, hemolysate, serum and liver homogenate prepared were used to assay the biochemical parameters of oxidative stress (catalase, MDA), lipid profile (Triglycerides, total cholesterol and HDL-cholesterol) and immunological (CRP and NFS). It emerged that the extract limited weight loss and caused a reduction in blood sugar of -26.59% after 21 days of treatment; the extract caused an increase in the activity of erythrocyte catalase and a reduction in the concentration of hepatic MDA, as well as a very marked reduction in inflammatory cells and CRP. The extract also caused a reduction in dyslipidemiawhich was materialized by a reduction in CRR, AC, AIP and an increase in CPI. These results suggest that this extract contains bioactive compounds capable of reducing chronic hyperglycemia while preventing its complications, thus justifying its traditional use in the management of diabetes.

FEATURES OF SKIN WOUNDS HEALING UNDER CHRONIC HYPERGLYCEMIA AND IMPROVEMENT OF THEIR TREATMENT METHODS.

OBJECTIVE: The aim: The work was aimed to study the histological, morphometric and planimetric features of skin regeneration in mature rats with chronic hyperglycemia under the influence of platelet-rich plasma. PATIENTS AND METHODS: Materials and methods: 60 mature white laboratory rats were used. The animals were divided into three groups (I - control with mechanical skin injuries; II - rats with chronic hyperglycemia and modeled mechanical skin injuries; III - animals with the chronic hyperglycemia and modeled mechanical skin injuries which were injected with the platelet-rich plasma). The samples were studied using light microscopy.Statistical data processing was performed using SPSS-17. RESULTS: Results: On the 21st day, the epithelialization of control mature rats wound was almost complete. The epithelium contained all layers without pathological changes. The new dermis has been reorganized into papillary and reticular layers. On the 21st day, the wound of rats with chronic hyperglycemia was not completely covered with the epidermis. The connective tissue of the dermis was disorganized. On the 21st day, the wound epithelialization was also more complete in mature rats with chronic hyperglycemia received platelet-rich plasma compared to the rats with chronic hyperglycemia. The dermis contained a large number of blood vessels with normal, full-blooded lumens. CONCLUSION: Conclusions: The chronic hyperglycemia leads to disruption of epithelialization processes, angiogenesis, a delay in the reorganization of dermis connective tissue, and vascular remodeling. The injections of autologous platelet-rich plasma promote faster angiogenesis, reduce inflammation, and accelerate wound epithelialization.

Relationship between chronic hyperglycemia and contrast extravasation in revascularization of symptomatic intracranial atherosclerotic stenosis: A retrospective single-center study.

BACKGROUND AND PURPOSE: Contrast extravasation is one of the most common perioperative complications in symptomatic intracranial atherosclerotic stenosis (ICAS) patients after percutaneous transluminal angioplasty and/or stenting (PTAS). This study aimed to investigate the correlations between the relevant serum biochemical indicators of carbohydrate metabolism and the occurrence of contrast extravasation. METHODS: Patients' demographic characteristics, vascular risk factors and laboratory examination data were collected. Blood routine test, blood biochemical examination and hormone level test within 1 week before surgery were measured in all enrolled subjects. Patients underwent non-contrast CT scans immediately after the endovascular procedure. Follow-up non-contrast CT scans were performed in the next 24 h and repeated as per clinical condition. RESULTS: 104 patients who have undergone effective PTAS were involved in this study. 18 patients have identified as contrast extravasation and there was no obvious abnormality in another 86 cases. There were significant differences in the pre-operative HbA1c, fasting blood sugar and cortisol levels in the subjects regardless of gender between two groups (p < 0.001, p < 0.001 and p = 0.001, respectively). Furthermore, there were statistical differences in E2 and testosterone levels between two groups in both male population (p = 0.035 and p = 0.028, respectively) and female population (p = 0.036 and p = 0.003, respectively). Besides, the AUC value of HbA1c, fasting blood sugar and cortisol levels were all over 0.7 (0.858, 0.780 and 0.752, respectively). The highest AUC value of various combinations was obtained from the combination of HbA1c and cortisol level, which was 0.898. CONCLUSIONS: Patient with chronic hyperglycemia is closely related to contrast extravasation after PTAS. Specific mechanisms might be explored and regarded as promising candidates to prevent contrast extravasation.

High-Fat Diet Aggravates Cerebral Infarct, Hemorrhagic Transformation and Neuroinflammation in a Mouse Stroke Model.

BACKGROUND: Stroke in context of type 2 diabetes (T2D) is associated with a poorer outcome than in non-diabetic conditions. We aimed at creating a new reproducible mouse model of stroke in impaired glucose tolerance conditions induced by high-fat diet. METHODS: Adult C57BL6 mice were fed for 2 months with either normal diet (ND) or high-fat diet (HFD). We used a model of Middle Cerebral Artery Occlusion (MCAO) for 90 min. Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT) were used to assess pre-diabetic status. Brain infarct volume, hemorrhagic transformation (HT) as well as systemic and cerebral inflammatory markers were evaluated. RESULTS: HFD was associated with an increased body weight and glycemia following OGTT. The HFD group presented a significant increase in brain infarct volume (38.7 (IQR 30-46.7%) vs. 28.45 (IQR 21-30%); p = 0.016) and HT (HFD: 2 (IQR 1-5) vs. ND: 0 (IQR 0-1); p = 0.012) and higher levels of IL-6 and MCP-1 in infarcted hemisphere compared to the ND group. CONCLUSION: Two months of HFD in adult mice were sufficient to alter the lipid profile and the control of hyperglycemia. These metabolic perturbations were significantly associated with increased infarct volume and hemorrhagic complications.

Caracterización epidemiológica y clínica de pacientes con retinopatía diabética / Clinical and epidemiological characterization of diabetic retinopathy patients

Objetivo: Caracterizar los pacientes con retinopatía diabética desde el punto de vista epidemiológico y clínico. Métodos: Se realizó un estudio descriptivo y transversal en el Centro Oftalmológico de Santiago de Cuba, desde octubre del año 2017 hasta octubre de 2019, en una población de 42 pacientes diabéticos tipo 2. Resultados: Predominaron los pacientes con tiempo de diabetes mellitus mayor de 10 años, y edades de 55 años o más (60,0 por ciento); el mayor porcentaje correspondió al color de piel negra (66,7 por ciento ); la agudeza visual mayor de 0,6 se presentó en el 49,4 por ciento de los casos; la retinopatía diabética proliferativa fue la más presentada con 55,9 por ciento. Hubo predominio, además, de los valores de hemoglobina glicosilada por encima del 7 por ciento y de la normoalbuminuria con 46,7 y 66,7 por ciento, respectivamente, en ambos grupos. Conclusiones: Los valores elevados de hemoglobina glicosilada y la normoalbuminuria se asocian, desde el punto de vista clínico, a la retinopatía diabética proliferativa(AU)

Objective: Characterize diabetic retinopathy patients from a clinical and epidemiological point of view. Methods: A descriptive cross-sectional study was conducted of 42 type 2 diabetic patients at Santiago de Cuba Ophthalmology Center from October 2017 to October 2019. Results: A predominance was found of patients who had had diabetes mellitus for more than 10 years and were aged 55 years or over (60.0 percent); black skin color prevailed with 66.7 percent; visual acuity above 0.6 was present in 49.4 percent of the cases, and proliferative diabetic retinopathy was the most common type (55.9 percent). In both groups glycosylated hemoglobin values above 7 percent prevailed, whereas normal albuminuria was predominant with 46.7 percent and 66.7 percent, respectively. Conclusions: High glycosylated hemoglobin and normal albuminuria values are clinically associated to proliferative diabetic retinopathy(AU)

Hemoglobina glicosilada y albuminuria en la progresión de la retinopatía diabética / Glycosylated hemoglobin and albuminuria in the progression of diabetic retinopathy

RESUMEN Objetivo: Identificar la relación de la hemoglobina glicosilada y la albuminuria con la progresión de la retinopatía diabética. Métodos: Se realizó un estudio descriptivo y transversal en el Centro Oftalmológico de Santiago de Cuba desde octubre del año 2017 hasta octubre de 2019. La muestra fue de 42 pacientes diabéticos tipo 2. Resultados: Predominaron los pacientes con tiempo de diabetes mellitus mayor de 10 años y las edades de 55 años o más con el 60,0 por ciento. El color de piel negra fue mayor con 66,7 por ciento; la agudeza visual mayor de 0,6 se presentó en el 49,4 por ciento y la retinopatía diabética proliferativa fue la más presentada con 55,9 por ciento. Predominaron además valores de hemoglobina glicosilada mayores de 7 por ciento en ambos grupos y la normoalbuminuria fue la que predominó en ambos grupos con 46,7 y 66,7 por ciento. Conclusiones: Los valores elevados de hemoglobina glicosilada y la normoalbuminuria se asocian de forma clínica a retinopatía diabética proliferativa(AU)

ABSTRACT Objective: Identify the relationship of glycosylated hemoglobin and albuminuria to progression of diabetic retinopathy. Methods: A descriptive cross-sectional study was conducted at Santiago de Cuba Ophthalmology Center from October 2017 to October 2019. The sample was 42 type 2 diabetic patients. Results: A predominance was found of patients with diabetes mellitus for more than 10 years and the 55 years and over age group (60.0 percent). Black skin color prevailed with 66.7 percent, visual acuity above 0.6 was present in 49.4 percent, and proliferative diabetic retinopathy was the most common type (55.9 percent). In both groups glycosylated hemoglobin values above 7 percent prevailed and normal albuminuria was predominant with 46.7 percent and 66.7 percent. Conclusions: High glycosylated hemoglobin and normal albuminuria values are clinically associated to proliferative diabetic retinopathy(AU)

Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer's disease mouse model.

During aging, lifestyle-related factors shape the brain's response to insults and modulate the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). This is the case for chronic hyperglycemia associated with type 2 diabetes, which reduces the brain's ability to handle the neurodegenerative burden associated with AD. However, the mechanisms behind the effects of chronic hyperglycemia in the context of AD are not fully understood. Here, we show that newly generated neurons in the hippocampal dentate gyrus of triple transgenic AD (3xTg-AD) mice present increased dendritic arborization and a number of synaptic puncta, which may constitute a compensatory mechanism allowing the animals to cope with a lower neurogenesis rate. Contrariwise, chronic hyperglycemia decreases the complexity and differentiation of 3xTg-AD newborn neurons and reduces the levels of ß-catenin, a key intrinsic modulator of neuronal maturation. Moreover, synaptic facilitation is depressed in hyperglycemic 3xTg-AD mice, accompanying the defective hippocampal-dependent memory. Our data suggest that hyperglycemia evokes cellular and functional alterations that accelerate the onset of AD-related symptoms, namely memory impairment.

Higher Hemoglobin A1c Level Is Associated With Poor Outcome of Intracerebral Hemorrhage.

Background: Pre-morbid chronic hyperglycemia is associated with the poor outcome of ischemic stroke, but the association between chronic hyperglycemia, and the long-term outcome of acute intracerebral hemorrhage is still poor understood. Methods: Data on patients with acute intracerebral hemorrhage in the ACROSS-China registry (Abnormal Glucose Regulation in Patients With Acute Stroke Across China) were reviewed. Elevated hemoglobin A1c (HbA1c) level on admission was indicative of chronic hyperglycemia. According to the clinical categories of HbA1c, patients were divided into three groups. Multivariable logistic regression or Cox method was performed to analyze the association of HbA1c and the prognosis of patients with acute intracerebral hemorrhage (poor functional outcome [modified Rankin scale score 3-6] and mortality) at 1 year. Results: A total of 416 patients were included in this study. Fifty-two (12.5%) patients died and 130 (31.8%) had poor functional outcome at 1-year follow-up. The higher levels of HbA1c (≥6.5%) was associated with a poor functional outcome (OR 2.35, 95% CI, 1.28-4.29) and increased mortality (OR 2.63, 95% CI 1.34-5.15), compared with the lowest category. When further stratified by diabetic or non-diabetic medical history, higher HbA1c (≥6.5%) still increased the risk of poor functional outcome (OR 3.42, 95% CI 1.39-8.44) and mortality (OR 4.48, 95% CI 1.64-12.24) in patients with non-diabetic medical history. However, higher HbA1c didn't have the association with the increased risk of poor functional outcome (OR 1.06, 95% CI 0.37-3.03) and mortality (OR 1.20, 95% CI 0.39-3.72) in patients with diabetic medical history. Conclusions: Higher HbA1c was associated with a higher risk of death and poor functional outcome 1 year after intracerebral hemorrhage, especially in patients without a diabetic history.

Glycemic control and its impact on oxidative stress biomarkers in type 2 diabetic patients treated with metformin: a cross-sectional analysis / Controle glicêmico e seu impacto em biomarcadores de estresse oxidativo em pacientes diabéticos tipo 2 tratados com metformina: uma análise transversal

AIMS: Evidence shows that diabetic patients may be predisposed to oxidative stress owing to increased glyco-oxidation and lipid peroxidation processes in consequence of chronic hyperglycemia. However, there is dearth of information whether glycemic control positively affects the antioxidant defense system in type 2 diabetes mellitus (T2DM). We investigated the potential association between glycemic control and oxidative stress biomarkers in controlled and uncontrolled diabetic states. METHODS: After obtaining ethical clearance, we included patients receiving metformin with glycated hemoglobin A1c ˂7.0% (glycemic control); newly diagnosed T2DM patients without glycemic control with hemoglobin A1c ˃7.0%; and apparently healthy normoglycemic individuals. The following biomarkers were determined: fasting glycemia level, malondialdehyde, glutathione peroxidase activity, catalase activity, total antioxidant capacity and total cholesterol level. The comparisons between the groups were made by ANOVA. RESULTS: The participants were 260 in number: 80 with controlled diabetes, 80 uncontrolled and 100 controls. All participants were between 40 and 71 years old. Fasting glycemia level and hemoglobin A1c showed significant reductions (p<0.05) in controlled T2DM against the uncontrolled T2DM group, all the same both were significantly higher (p<0.05) against the controls. Likewise, malondialdehyde levels showed significant elevations (p<0.05) correspondingly in both uncontrolled and controlled T2DM against the controls, accompanied with significant reductions (p<0.05) in the antioxidative enzyme activities (glutathione peroxidase activity and catalase activity) and total antioxidant capacity levels against the controls. In addition, total cholesterol was significantly reduced (p<0.05) in controlled T2DM against both uncontrolled T2DM and controls, respectively. There were significant correlations between hemoglobin A1c and oxidative stress biomarkers (p<0.05). CONCLUSION: There was no remarkable difference in oxidative stress states between glycemic controlled and uncontrolled T2DM, despite differences in their fasting glycemia and glycated hemoglobin levels. Our data, therefore, suggest that chronic hyperglycemia and possibly anti-diabetic medication may both equally associate with oxidative stress.

OBJETIVOS: Evidências mostram que pacientes diabéticos podem estar predispostos ao estresse oxidativo devido ao aumento dos processos de oxidação da glicose e peroxidação lipídica em consequência da hiperglicemia crônica. No entanto, há escassez de informações se o controle glicêmico afeta positivamente o sistema de defesa antioxidante no diabetes mellitus tipo 2. Esse estudo investiga a possível associação entre controle glicêmico e biomarcadores de estresse oxidativo em estados glicêmicos controlados e não controlados. MÉTODOS: Após a liberação da comissão de ética, o estudo incluiu pacientes em uso de medicação hipoglicemiante (metformina) com hemoglobina glicosilada A1c ˂7,0% (diabetes controlado), pacientes recém-diagnosticados com diabetes mellitus tipo 2 sem controle glicêmico e com hemoglobina A1c ˃7,0% e indivíduos normoglicêmicos aparentemente saudáveis. Foram determinados os seguintes biomarcadores: glicemia de jejum, malonaldeído, atividade da glutationa peroxidase, atividade de catalase, capacidade antioxidante total e nível de colesterol total. A comparação entre os grupos foi feita pela ANOVA. RESULTADOS: Foram incluídos 260 participantes: 80 com diabetes controlada, 80 não controlada e 100 controles. Todos os participantes tinham entre 40 e 71 anos. A glicemia de jejum e a hemoglobina glicosilada foram significativamente menores (p<0,05) nos diabéticos controlados comparado aos não controlados, e todos os diabéticos apresentaram valores significativamente maiores (p<0,05) que os controles. Da mesma forma, os níveis de malonaldeído foram significativamente maiores (p<0,05) nos diabéticos (controlados e não controlados), assim como valores das atividades antioxidantes (glutationa peroxidase e catalase) e nos níveis de capacidade antioxidante foram significativamente menores (p<0,05) frente aos controles. Além disso, o colesterol total foi significativamente menor (p<0,05) nos diabéticos controlados quando comparados aos não controlados e controles, respectivamente. Houve correlações significativas entre a hemoglobina glicosilada e do estresse oxidativo (p<0,05). CONCLUSÃO: Não houve diferença significativa nos estados de estresse oxidativo entre os diabéticos controlados e não controlados, apesar das diferenças nos níveis de glicose plasmática e hemoglobina glicosilada. Nossos dados, portanto, sugerem que a hiperglicemia crônica e, possivelmente, a medicação antidiabética pode associar-se igualmente ao estresse oxidativo.

Synthesis of thiobarbituric acid derivatives: In vitro α-glucosidase inhibition and molecular docking studies.

Synthesis, structure, and evaluation of in vitro α-glucosidase enzyme inhibition of a new class of diethylammonium salts of aryl substituted thiobarbituric acid is described. This protocol is straight, environmentally benign and efficient, involving Aldol-Michael addition reaction in one pot fashion. The 3D chemical structures of the synthesized compounds were assigned based on spectroscopic methods and X-ray single crystal diffraction analyses. All synthesized compounds 3a-3n were evaluated for their in vitro α-glucosidase enzyme inhibitory activity, whereas acarbose was used as the standard drug (IC50=840±1.73µM). All tested compounds were found to possess varying degree of α-glucosidase enzyme inhibition activity with (IC50=19.46±1.84-415.8±4.0µM). Compound3i(IC50=19.4±1.84µM) exhibited the highest activity. To the best of knowledge this is the first report of the in vitro α-glucosidase enzyme inhibition by the diethylamonium salts of aryl substituted thiobarbituric acid. Furthermore, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites.