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In this paper, we provide an overview of the evolution of the definition of hyperglycemia during the past century and the alterations in glucose dynamics that cause fasting and postprandial hyperglycemia. We discuss how extensive mechanistic, physiological research into the factors and pathways that regulate the appearance of glucose in the circulation and its uptake and metabolism by tissues and organs has contributed knowledge that has advanced our understanding of different types of hyperglycemia, namely prediabetes and diabetes and their subtypes (impaired fasting plasma glucose, impaired glucose tolerance, combined impaired fasting plasma glucose, impaired glucose tolerance, type 1 diabetes, type 2 diabetes, gestational diabetes mellitus), their relationships with medical complications, and how to prevent and treat hyperglycemia.

microRNAs (miRNAs) are recognized as diabetes mellitus type 2 (T2DM) biomarkers useful for disease metabolism comprehension and have great potential as therapeutics targets. BDNF and IGF1 increased expression are highly involved in the benefits of insulin and glucose paths, however, they are down-regulated in insulin resistance conditions, while their expression increase is correlated to the improvement of glucose and insulin metabolism. Studies suggest the microRNA regulation of these genes in several different contexts, providing a novel investigation approach for comprehending T2DM metabolism and revealing potential therapeutic targets. In the present study, we investigate in different animal models (human, rat, and mouse) miRNAs that target BDNF and IGF1 in skeletal muscle tissue with T2DM physiological conditions. Bioinformatics tools and databases were used to miRNA prediction, molecular homology, experimental validation of interactions, expression in the studied physiological condition, and network interaction. The findings showed three miRNAs candidates for IGF1(miR-29a, miR-29b, and miR-29c) and one for BDNF (miR-206). The experimental evaluations and the search for the expression in skeletal muscle from T2DM subjects confirmed the predicted interaction between miRNA-mRNA for miR-29b and miR-206 through human, rat, and mouse models. This interaction was reaffirmed in multiple network analyses. In conclusion, our results show the regulation relationship between miR-29b and miR-206 with the investigated genes, in several tissues, suggesting an inhibition pattern. Nevertheless, these data show a large number of possible interaction physiological processes, for future biotechnological prospects. Resumo Os microRNAs (miRNAs) são reconhecidos como biomarcadores do diabetes mellitus tipo 2 (DM2), úteis para a compreensão do metabolismo da doença, e possuem grande potencial como alvos terapêuticos. O aumento da expressão de BDNF e IGF1 está altamente envolvido nos benefícios as vias de insulina e glicose, porém, são regulados negativamente em condições de resistência à insulina, enquanto seu aumento de expressão está correlacionado com a melhora do metabolismo da glicose e da insulina. Estudos sugerem a regulação desses genes por microRNA em vários contextos diferentes, proporcionando uma nova abordagem de investigação para compreender o metabolismo do DM2 e revelar potenciais alvos terapêuticos. No presente estudo, investigamos em diferentes modelos animais (humanos, ratos e camundongos) miRNAs que têm como alvo BDNF e IGF1 em tecido muscular esquelético com condições fisiológicas de DM2. As análises foram realizadas utilizando ferramentas de bioinformática e bancos de dados para predição de miRNA, homologia molecular, validação experimental de interações, expressão na condição fisiológica estudada e interação em rede. Os resultados mostraram três candidatos a miRNAs para IGF1 (miR-29a, miR-29b e miR-29c) e um para BDNF (miR-206). As avaliações experimentais e a busca pela expressão no músculo esquelético de indivíduos com DM2 confirmaram a interação prevista entre miRNA-mRNA para miR-29b e miR-206 através de modelos humanos, ratos e camundongos. Essa interação foi reafirmada em múltiplas análises de rede. Em conclusão, nossos resultados mostram a relação de regulação entre miR-29b e miR-206 com os genes investigados, em diversos tecidos, sugerindo um padrão de inibição. Contudo, esses dados mostram um grande número de possíveis processos fisiológicos de interação para perspectivas biotecnológicas.

Secretion of insulin from the pancreas is pulsatile, driven by intrinsic oscillations within individual islets of Langerhans. The secretions are coordinated among the many islets distributed throughout the pancreas producing a synchronized rhythm in vivo that is essential for maintaining normal glucose levels. One hypothesized mechanism for the coordination of islet activity is negative feedback, whereby sequestration of glucose in response to elevated insulin leads to a reduction in the blood glucose level that is sensed by the islet population. This global signal of glucose then coordinates the individual islets. In this study, we tested how this coordination mechanism is affected by time delays in the negative feedback, using a microfluidic system to monitor Ca

Objectives: The purpose of the study is to investigate body awareness and body image perception of patients with type 2 diabetes mellitus (T2DM) and to explore the association between clinical parameters and body awareness. Methods: A total of 92 participants with T2DM (38 women and 54 men) aged 36–76 years were recruited. Biochemical measurements, including fasting blood glucose, postprandial blood glucose and hemoglobin A1c (HbA1c), were obtained from the patients’ blood sample records. The Body Awareness Questionnaire (BAQ), Body Cathexis Scale (BCS) and Awareness Body Chart (ABC) were filled in by all subjects. Results: Most participants had an above-average BAQ (81.5%) and BCS (87%) score. There was a significant correlation between body mass index and ABC pain subscale. HbA1c was significantly associated with the duration of diabetes and sleep-wake cycle, process domains and total BAQ score. The body awareness score for the lower leg and foot regions (ABC parts) was negatively correlated with fasting blood glucose and HbA1c levels, while body awareness in the foot region was negatively correlated with the duration of diabetes. There was no association between BCS and any clinical parameters. Conclusion: This study showed that body awareness is associated with diabetes-related clinical parameters, such as fasting blood glucose and HbA1c levels, and duration of diabetes in patients with T2DM. Following diabetes progression and an increase in blood glucose levels, body awareness tended to decrease, particularly in the lower leg and foot regions. These findings highlighted the importance of evaluating body awareness in patients with T2DM. © 2023 Elsevier Ltd

To examine type 2 diabetes mellitus incidence and associated risk factors among people with HIV (PWH).A retrospective clinical cohort study of PWH at a Southeastern US academic HIV clinic between 2008 and 2018.PWH who attended at least two clinic visits were evaluated with demographic and clinical data extracted from the electronic medical record (EMR). Diabetes was defined as: hemoglobin A1C ≥6.5% and/or 2 glucose results200 mg/dl (at least 30 days apart), diagnosis of diabetes in the EMR, or exposure to diabetes medication. Time to diabetes incidence was computed from the entire clinic population for each year. Multivariable Cox proportional hazard regression models with time-dependent covariates were created to evaluate the independent association between covariates and time to incident diabetes.Among 4113 PWH, we identified 252 incident cases of diabetes. Incidence increased from 1.04 incidents per 1000 person years (PY) in 2008, to 1.55 incidents per 1000 PY in 2018. Body mass index (hazard ratio [HR] 10.5 (6.2, 17.7)), liver disease (HR 1.9 (1.2, 3.1)), steroid exposure (HR 1.5 (1.1, 1.9)), and use of integrase inhibitors (HR 1.5 (1.1, 2.0)) were associated with incident diabetes. Additional associated factors included lower CD4 + cell counts, duration of HIV infection, exposure to nonstatin lipid-lowering therapy, and dyslipidemia.Rapidly increasing incident diabetes rates among PWH were associated with both traditional and HIV-related associated risk factors, particularly body weight, steroid exposure, and use of Integrase Inhibitors. Notably, several of the risk factors identified are modifiable and can be targeted for intervention.

While dietary changes are recommended to treat pediatric non-alcoholic fatty liver disease (NAFLD), the role of specific nutrients in disease progression is unclear. The objective of this study is to (1) assess the macronutrient and micronutrient intake in adolescents with liver biopsy proven NAFLD [with and without non-alcoholic steatohepatitis (NASH)] and lean controls; (2) determine nutritional predictors of disease severity amongst these groups.Adolescents with biopsy-proven NAFLD and lean controls completed the Harvard Food Frequency Questionnaire.Twenty-eight NAFLD and 15 lean controls were studied. NAFLD with (n = 20) and without NASH (n = 8) had similar total calorie, protein, fat, and carbohydrate intake. Subjects with NASH had higher total sugar (122.3 ± 48.3 vs 83.1 ± 38.8 g), glucose (24.3 ± 9.3 vs 15.2 ± 7.5 g), sucrose (42.3 ± 16.9 vs 28.8 ± 11.7 g), and fructose (29.4 ± 12.5 vs 18.1 ± 8.0 g) intake than those with NAFLD but without NASH ( P0.05). Both NAFLD groups had similar micronutrient intake. Alanine aminotransferase (ALT) correlated with total caloric intake ( ρ = 0.4; P = 0.04). Total carbohydrate calories correlated with a higher NAS summary score ( ρ = 0.38; P = 0.04) and lobular inflammation ( ρ = 0.50; P = 0.007). Percent calories from added sugar and glucose correlated with worsening NAS summary score ( ρ = 0.44, P = 0.02; ρ = 0.48, P = 0.009) and lobular inflammation ( ρ = 0.51, P = 0.006; ρ = 0.53, P = 0.004). Percent calories from fructose correlated with lobular inflammation ( ρ = 0.56; P = 0.002). Total daily calories, protein, fat, carbohydrate, and micronutrient intake were similar between NAFLD and lean controls.NASH patients consume similar total calories, protein, and fat as those without NASH, but have significantly higher sugar intake. NAFLD and lean children, however, have similar macro/micronutrient intake. Histologic disease severity correlates with total carbohydrate and added sugar intake, supporting a role for simple sugar intake in NAFLD progression.

The Medtronic advanced hybrid closed-loop (AHCL) and MiniMed™ 670G hybrid closed-loop (HCL) systems provide the option to temporarily increase the glucose target to 150 mg/dL (8.3 mmol/L). This analysis investigated the efficacy of the AHCL compared with that of the HCL after the use of this setting. Data from 60 participants in the Fuzzy Logic Automated Insulin Regulation (FLAIR) study were used to compare the AHCL and HCL systems after the use of the temporary target (TT), and during analogous periods where this setting was not used. Differences in time in range 70-180 mg/dL between the systems were similar after the use of the TT setting and during analogous non-TT periods (interaction

Genome sequencing of filamentous fungi has demonstrated that most secondary metabolite biosynthetic gene clusters (BGCs) are silent under standard laboratory conditions. In this work, we have established an in vitro CRISPR-Cas9 system in

Cancer cells deploy several glucose transport protein (GLUT) channels on the cell membranes to increase glucose uptake. Cancer cells die within 24 h in the absence of glucose. Thus, preventing the deployment of GLUT channels can deprive them of glucose, resulting in apoptosis within 24 h. Herein, we developed the

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One major goal of regenerative medicine is the production of pancreatic endocrine islets to treat insulin-dependent diabetic patients. Among the different methods developed to achieve this goal, a particularly promising approach is direct lineage reprogramming, in which non-β-cells are directly converted to glucose-responsive, insulin-secreting β-like cells. Efforts by different research groups have led to critical insights in the inducing factors necessary and types of somatic tissues suitable for direct conversion to β-like cells. Nevertheless, there is limited understanding of the molecular mechanisms underlying direct cell fate conversion. Significant challenges also remain in translating discoveries into therapeutics that will eventually benefit diabetic patients. This review aims to cover the advances made in the direct reprogramming of somatic cells into β-like cells and discuss the remaining challenges.

Glucose is the brain's primary energetic resource. The brain's use of glucose is dynamic, balancing delivery from the neurovasculature with local metabolism. Although glucose metabolism is known to differ in humans with and without methamphetamine use disorder (MUD), it is unknown how central glucose regulation changes with acute methamphetamine experience. Here, we determined how intravenous methamphetamine regulates extracellular glucose levels in a brain region implicated in MUD-like behavior, the lateral hypothalamus (LH). We measured extracellular LH glucose in awake adult male and female drug-naive Wistar rats using enzyme-linked amperometric glucose biosensors. Changes in LH glucose were monitored during a single session after

Repeated hypoglycemia exposure leads to impaired awareness of hypoglycemia (IAH) and the development of defective counterregulatory responses. To date, only pancreas or islet transplantation has demonstrated normalization of hypoglycemia awareness and the endogenous glucose production (EGP) response to defend against insulin-induced hypoglycemia in long-standing type 1 diabetes (T1D). This study aims to validate clinical metrics of IAH (Clarke score), hypoglycemia severity (HYPO score), glycemic lability (lability index), and continuous glucose monitoring (CGM) as predictors of absent autonomic symptom (AS) recognition and defective glucose counterregulation during insulin-induced hypoglycemia, thus enabling early identification of individuals with compromised physiologic defense against clinically significant hypoglycemia. Forty-three subjects with mean ± standard deviation age 43 ± 13 years and T1D duration 28 ± 13 years, including 32 with IAH and 11 with hypoglycemia awareness (Aware), and 12 nondiabetic control subjects, underwent single-blinded randomized-paired hyperinsulinemic-euglycemic and hypoglycemic clamp experiments. Receiver operating characteristic (ROC) curves and sensitivity analyses were performed to assess metric prediction of absent AS recognition and defective EGP responses to hypoglycemia. Clarke score and CGM measures of hypoglycemia exposure demonstrated good ability to predict absent AS recognition (area under the curve ≥0.80). A composite threshold of IAH-Clarke ≥4 with ROC curve-derived thresholds for CGM measures of hypoglycemia exposure showed high specificity and predictive value in identifying an absent AS response during the hypoglycemic clamp. Metrics demonstrated poor ability to predict defective glucose counterregulation by the EGP response, which was impaired even in the Aware group. Screening for IAH alongside assessment of CGM data can increase the specificity for identifying individuals with absent hypoglycemia symptom recognition who may benefit from further intervention.

Background: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between sodium-glucose cotransporter-2 inhibitor treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis–defined metabolite clusters that changed differentially with treatment and examined the relationship between change in metabolite clusters and change in Kansas City Cardiomyopathy Questionnaire scores and NT-proBNP (N-terminal probrain natriuretic peptide). Models were adjusted for relevant clinical covariates and nominal P P Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short-chain acylcarnitine as well as medium-chain acylcarnitine principal components analysis–defined metabolite clusters compared with placebo (nominal P =0.01, false discovery rate–adjusted P =0.08 for both clusters). However, ketosis (β-hydroxybutyrate levels >500 μmol/L) was achieved infrequently (3 [2.5%] in dapagliflozin arm versus 1 [0.9%] in placebo arm) and supraphysiologic levels were not observed. Increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in Kansas City Cardiomyopathy Questionnaire scores (ie, worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of sodium-glucose cotransporter-2 inhibitors in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with sodium-glucose cotransporter-2 inhibitors in patients with HFrEF. Only physiologic levels of ketosis were observed. In addition, we identified several metabolic biomarkers associated with adverse HFrEF outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02653482.

Background: An ancient family of arrestin-fold proteins, termed alpha-arrestins, may have conserved roles in regulating nutrient transporter trafficking and cellular metabolism as adaptor proteins. One alpha-arrestin, TXNIP (thioredoxin-interacting protein), is known to regulate myocardial glucose uptake. However, the in vivo role of the related alpha-arrestin, ARRDC4 (arrestin domain-containing protein 4), is unknown. Methods: We first tested whether interaction with GLUTs (glucose transporters) is a conserved function of the mammalian alpha-arrestins. To define the in vivo function of ARRDC4, we generated and characterized a novel Arrdc4 knockout (KO) mouse model. We then analyzed the molecular interaction between arrestin domains and the basal GLUT1. Results: ARRDC4 binds to GLUT1, induces its endocytosis, and blocks cellular glucose uptake in cardiomyocytes. Despite the closely shared protein structure, ARRDC4 and its homologue TXNIP operate by distinct molecular pathways. Unlike TXNIP, ARRDC4 does not increase oxidative stress. Instead, ARRDC4 uniquely mediates cardiomyocyte death through its effects on glucose deprivation and endoplasmic reticulum stress. At baseline, Arrdc4 -KO mice have mild fasting hypoglycemia. Arrdc4 -KO hearts exhibit a robust increase in myocardial glucose uptake and glycogen storage. Accordingly, deletion of Arrdc4 improves energy homeostasis during ischemia and protects cardiomyocytes against myocardial infarction. Furthermore, structure-function analyses of the interaction of ARRDC4 with GLUT1 using both scanning mutagenesis and deep-learning Artificial Intelligence identify specific residues in the C-terminal arrestin-fold domain as the interaction interface that regulates GLUT1 function, revealing a new molecular target for potential therapeutic intervention against myocardial ischemia. Conclusions: These results uncover a new mechanism of ischemic injury in which ARRDC4 drives glucose deprivation-induced endoplasmic reticulum stress leading to cardiomyocyte death. Our findings establish ARRDC4 as a new scaffold protein for GLUT1 that regulates cardiac metabolism in response to ischemia and provide insight into the therapeutic strategy for ischemic heart disease.

Interscapular brown adipose tissue (BAT) plays an important role in controlling glucose homeostasis. Increased glucose entry and glycolysis in BAT result in lactate production and release. The adipose tissue expresses the lactate receptor hydrocarboxylic acid receptor 1 (HCAR1), markedly downregulated in male diet-induced obese (DIO) and

In nondiabetic rats, the Na+-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin increased vasopressin-related stimulation of fluid intake and free water reabsorption and maintained fluid balance and serum creatinine, whereas the loop diuretic furosemide reduced vasopressin and induced a negative fluid balance followed by a subsequent increase in serum creatinine. This study suggests that differences in vasopressin secretion in response to a SGLT2 inhibitor or loop diuretic may contribute to differences in body fluid status and subsequent renal function.

Renal blood flow represents >20% of total cardiac output and with this comes the great responsibility of maintaining homeostasis through the intricate regulation of solute handling. Through the processes of filtration, reabsorption, and secretion, the kidneys ensure that solutes and other small molecules are either returned to circulation, catabolized within renal epithelial cells, or excreted through the process of urination. Although this occurs throughout the renal nephron, one segment is tasked with the bulk of solute reabsorption—the proximal tubule. Among others, the renal proximal tubule is entirely responsible for the reabsorption of glucose, a critical source of energy that fuels the body. In addition, it is the only other site of gluconeogenesis outside of the liver. When these processes go awry, pathophysiological conditions such as diabetes and acidosis result. In this review, we highlight the recent advances made in understanding these processes that occur within the renal proximal tubule. We focus on the physiological mechanisms at play regarding glucose reabsorption and glucose metabolism, emphasize the conditions that occur under diseased states, and explore the emerging class of therapeutics that are responsible for restoring homeostasis.

This study examined the dynamic, real-time associations between partner involvement in diabetes self-care and continuous glucose monitor (CGM) metrics in adults with type 2 diabetes.For 1 week, 63 participants wore Dexcom G4 CGMs and provided momentary reports of partner involvement in diabetes self-care five times per day. Dynamic structural equation models were used to estimate the reciprocal lagged effects of partner involvement on next-hour CGM metrics (and vice versa).Partner involvement predicted improved next-hour glucose control for five of six CGM metrics in analyses adjusted for time-varying covariates. The hour after partner involvement, the model predicted a 26.34 mg/dl decrease in glucose level (standardized β = -0.19), 30% greater odds of meeting target time in target range ( β = 0.07), 48% higher odds of target time below target range (TBR; β = 0.04; the only nonsignificant effect), 47% greater odds of target time above target range (β = 0.11), a 4.20 unit decrease in glucose standard deviation ( β = -0.19), and a 0.01 unit decrease in glucose coefficient of variation ( β = -0.08; all p values.05). There was less consistent support for the reverse pathway, with only two metrics significantly related to next-hour partner involvement: glucose level ( β = 0.15) and TBR ( β = 0.21), such that having higher levels and meeting target TBR were significantly predictive of next-hour partner involvement.This is the first study showing that partner involvement in daily diabetes management predicts short-term glucose control. More research is needed to understand how partners influence glycemic control and evaluate interventions that promote their involvement in diabetes care.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

Achieving quantification of biomarkers in body fluids is crucial to the indication of the state of a person’s body and health. Wearable sensors could offer a convenient, fast and painless sensing strategy. In this work, we fabricated a wearable electrochemical patch sensor for simultaneous detection of dopamine and glucose in sweat. The sensor was printed on a flexible PDMS substrate with a simple screen-printed method. This prepared four-electrode sensor integrated two working electrodes for dopamine and glucose electrochemical sensing, one Ag/AgCl reference electrode and one carbon counter electrode, respectively. Cyclic voltammetry, differential pulse voltammetry and chronoamperometry were used for the evaluation of the wearable electrochemical patch sensor. It exhibits good sensitivity, wide linear range, low limit of detection, good anti-interference and reproducibility toward dopamine and glucose sensing in PBS and sweat.

Amaç: Proteinlerin besin kaynağından dolayı tokluk üzerine etkileri de farklı olabilmektedir. Bu çalışmada iki farklı protein kaynaklı kahvaltının tokluk belirteçleri, serum insülin ve glikoz üzerine etkisini incelemek amaçlandı. Yöntem: Bu çalışma 18-45 yaş arası 31 sağlıklı birey ile randomize çapraz geçişli olarak yürütüldü. Çalışmada farklı protein kaynağına sahip iki farklı kahvaltı bireylere sunuldu. Kahvaltılar bitkisel ve hayvansal kaynaklı besinlerden oluşturuldu. Bireylere kahvaltı sonrasında tokluk durumunu ölçmeyi amaçlayan VAS skalası 30 dakikalık aralıklar ile uygulandı. Bireylerden kahvaltılar sonrası serum insülin ve glikoz seviyesinin ölçümü için 30 dakika aralıklar ile kan numunesi alındı. Bireylerin kahvaltı sonrası ad libitium beslenme ile enerji alım miktarları BEBİS programı ile saptandı ve karşılaştırıldı. Bulgular: İki farklı kahvaltı sonrası bireylerin kombine tokluk skorları arasında 30.,60.,90. ve 210. dakikalardaki farklılıklar istatiksel olarak anlamlı bulundu (p

Glucose is the most abundant monosaccharide in nature and is an important energy source for living organisms. Glucose exists primarily as oligomers or polymers and organisms break it down and consume it. Starch is an important plant-derived α-glucan in the human diet. The enzymes that degrade this α-glucan have been well studied as they are ubiquitous throughout nature. Some bacteria and fungi produce α-glucans with different glucosidic linkages compared with that of starch, and their structures are quite complex and not fully understood. Compared with enzymes that degrade the α-(1→4) and α-(1→6) linkages in starch, biochemical and structural studies of the enzymes that catabolize α-glucans from these microorganisms are limited. This review focuses on glycoside hydrolases that act on microbial exopolysaccharide α-glucans containing α-(1→6), α-(1→3), and α-(1→2) linkages. Recently acquired information regarding microbial genomes has contributed to the discovery of enzymes with new substrate specificities compared with that of previously studied enzymes. The discovery of new microbial α-glucan-hydrolyzing enzymes suggests previously unknown carbohydrate utilization pathways and reveals strategies for microorganisms to obtain energy from external sources. In addition, structural analysis of α-glucan degrading enzymes has revealed their substrate recognition mechanisms and expanded their potential use as tools for understanding complex carbohydrate structures. In this review, the author summarizes the recent progress in the structural biology of microbial α-glucan degrading enzymes, touching on previous studies of microbial α-glucan degrading enzymes.

OBJECTIVE: The aim of this study was to investigate glucose tolerance, glucagon response, and beta cell function during a 1-year maintenance period with either exercise, the glucagon-like peptide-1 receptor agonist liraglutide, or the combination after diet-induced weight loss.METHODS: In this randomized placebo-controlled trial, adults with obesity (BMI: 32-43 kg/m 2 ) without diabetes underwent an 8-week low-calorie diet (800 kcal/d) and were randomized to 52 weeks of aerobic exercise, liraglutide 3.0 mg/d, exercise and liraglutide combined, or placebo. Change in glucose and glucagon response to a 3-hour mixed meal test and disposition index, as a measure of beta cell function, were measured. RESULTS: A total of 195 participants were randomized. After 1 year of treatment, the combination group had decreased postprandial glucose response by -9% (95% CI: -14% to -3%; p = 0.002), improved beta cell function by 49% (95% CI: 16% to 93%; p = 0.002), and decreased glucagon response by -18% (95% CI: -34% to -3%; p = 0.024) compared with placebo. Compared with placebo, liraglutide alone improved postprandial glucose response by -7% (95% CI: -12% to -1%; p = 0.018), but not beta cell function or glucagon. Exercise alone had similar postprandial glucose response, beta cell function, and glucagon response as placebo.CONCLUSIONS: Only the combination of exercise and liraglutide improved glucose tolerance, beta cell function, and glucagon responses after weight loss.

Fatty acids (FAs) rapidly and efficiently reduce cardiac glucose uptake in the Randle cycle or glucose-FA cycle. This fine-tuned physiological regulation is critical to allow optimal substrate allocation during fasted and fed states. However, the mechanisms involved in the direct FA-mediated control of glucose transport have not been totally elucidated yet. We previously reported that leucine and ketone bodies, other cardiac substrates, impair glucose uptake by increasing global protein acetylation from acetyl-CoA. As FAs generate acetyl-CoA as well, we postulated that protein acetylation is enhanced by FAs and participates in their inhibitory action on cardiac glucose uptake. Here, we demonstrated that both palmitate and oleate promoted a rapid increase in protein acetylation in primary cultured adult rat cardiomyocytes, which correlated with an inhibition of insulin-stimulated glucose uptake. This glucose absorption deficit was caused by an impairment in the translocation of vesicles containing the glucose transporter GLUT4 to the plasma membrane, although insulin signaling remained unaffected. Interestingly, pharmacological inhibition of lysine acetyltransferases (KATs) prevented this increase in protein acetylation and glucose uptake inhibition induced by FAs. Similarly, FA-mediated inhibition of insulin-stimulated glucose uptake could be prevented by KAT inhibitors in perfused hearts. To summarize, enhanced protein acetylation can be considered as an early event in the FA-induced inhibition of glucose transport in the heart, explaining part of the Randle cycle. Our results show that cardiac metabolic overload by oleate or palmitate leads to increased protein acetylation inhibiting GLUT4 translocation to the plasma membrane and glucose uptake. This observation suggests an additional regulation mechanism in the physiological glucose-FA cycle originally discovered by Randle.

Males with diabetes mellitus have been reported to have low serum testosterone levels relative to the general population. This study aimed to explore the impact of glycemic control, duration of diabetes (in years), comorbidities, and diabetes complications on serum testosterone levels in different age groups. Using a cross-sectional study design, data were collected from the files and lab results of 350 diabetic male patients at King Salman Armed Forces Hospital in Saudi Arabia. We obtained data about their age, serum testosterone levels, hemoglobin A1c (HbA1c), the duration of diabetes (in years), coexisting comorbidities (if present), and diabetes mellitus complications. Patients in this study were found to have significantly lower serum testosterone levels than the average population and by looking at each factor independently, we come to find that glycemic control was the only factor found to substantially impact testosterone levels in diabetic males. Moreover, poor glycemic control (HbA1c ≥7%) Alone was associated with lower serum testosterone levels regardless of the presence of other factors such as the duration of diabetes (in years), age, comorbidities, and micro/macrovascular complications. In conclusion, the presence of the other factors was not found to have significant effect on serum testosterone levels unless accompanied with poor glycemic control. Along with this finding, further studies are required to better understand the exact mechanism of glycemic control’s impact on testosterone levels.

An improved oxygen availability in air–liquid interface (ALI) cultures of enterocytes of the small intestine seems to be primarily responsible for morphological, metabolic, and functional changes. Intestinal porcine epithelial cells 1 (IPEC-1) are less investigated and are rarely used as model for intestinal barrier but showed a profound change of cell shape during ALI cultivation. We aim to answer the following question: Are the observed morphological effects accompanied by changes in metabolic function? A microarray analysis of submerged culture (SMC) and ALI cultures identified 830 significantly regulated genes. Subsequent functional clustering revealed alterations in 31 pathways, with the highest number of regulated genes in metabolic pathways, carbon metabolism, glycolysis, and hypoxia-inducible factor (HIF) signaling. Furthermore, HIF-1α as a mediator of a metabolic switch between glycolysis and oxidative phosphorylation showed a trend of increased mRNA levels in ALI in contrast to a reduced nuclear HIF-1α content in the nucleus. Candidate genes of oxidative phosphorylation such as a mitochondrial marker exhibited enhanced mRNA levels, which was confirmed by western blot analysis. Cytochrome C oxidase (COX) subunit 5B protein was decreased in ALI, although mRNA level was increased. The oxidation of ferrocytochrome C to ferricytochrome C was used for detection of cytochrome C oxidase activity of isolated mitochondria and resulted in a trend of higher activity in ALI. Furthermore, quantification of glucose and lactate concentrations in cell culture medium revealed significantly reduced glucose levels and decreased lactate production in ALI. To evaluate energy metabolism, we measured cellular adenosine triphosphate (ATP) aggregation in homogenized cell suspensions showing similar levels. However, application of the uncoupling agent FCCP reduced ATP levels in ALI but not in SMC. In contrast, blocking with 2-desoxy-d-glucose (2DG) significantly reduced ATP content in ALI and SMC. These results indicate a metabolic shift in IPEC-1 cultured under ALI conditions enhancing oxidative phosphorylation and suppressing glycolysis.

The aim of this study was to compare the effect of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) with equal energy expenditure on glycaemic and cardiometabolic risk factors in people with Type 2 Diabetes Mellitus (T2DM) when compared to the control. Sixty-three people with T2DM were randomly assigned to HIIT, MICT, or non-exercising controls. Individuals were trained with HIIT at 90 and 30% of their VO(2)peak (1:2 min ratio) starting from 8 up to 16 intervals and MICT at 50% of VO(2)peak, on a cycle ergometer, 3 times/week for 12 weeks under supervision. The primary outcome measure was the change in HbA1c. Aerobic capacity, cardiovascular responses, anthropometric measures, body composition, glycaemic, and cardiometabolic risk factors were measured at the beginning and the end of the 12-week training period. There was no significant difference between HIIT and MICT or when compared to the control for HbA1c, glucose, insulin resistance, blood lipids, cardiovascular responses, anthropometric measures, body composition, and abdominal and visceral fat (p(adj )> 0.05). HIIT and MICT increased VO(2)peak significantly compared to controls (p < 0.05) but not to each other (p > 0.05). Both HIIT and MICT improved VO(2)peak and HbA1c after 12 weeks of training compared to their baseline, furthermore, only MICT caused additional improvements in cardiovascular responses, anthropometric measures, and abdominal fat compared to baseline (p < 0.05). As a conclusion, isoenergetic HIIT or MICT did not improve HbA1c. The two protocols were equally efficient for improvement in aerobic capacity but had little effect on other cardiometabolic factors.

Large amount of people having diabetics in the world, and it is increasing very rapidly. Diabetics should to check their blood glucose level at least four times a day. When controls are not done regularly, risk of hypoglycemia and hyperglycemia may arise. There are ongoing researches for developing non-invasive methods as an alternative to finger piercing, which is the most commonly used and painful method for patients. In this study, although a physical glucometer design has not been completed yet, it has been demonstrated which wavelength ranges and which parameters can be used for non-invasive device. Most importantly an empirical relationship has been established between the level of blood sugar and de-polarization disturbance seen in circularly polarized light. The proposed equation can estimate the blood glucose level based on de-polarization information with an average error rate of 1%.

Micro-electro-mechanical systems (MEMS)-based resonators have a wide range of current applications such as the detection of chemical and biological substances. Up to now, several studies have been done in the literature about the integration of conducting polymers with MEMS to design a sensing layer for the applications mentioned above. However, all studies have been carried out on the coating of MEMS cantilever which has some disadvantages for the mass sensor like position-depended sensing as a result of being not only a mechanical spring structure but also a proof mass. In this study, conductive polymers (CPs) have been coated on different MEMS lateral comb-drive resonator designs by an effortless and effective solution provided by the electrochemical polymerization technique for the first time in the literature. An aqueous dispersion of carboxymethyl cellulose (CMC) and pyrrole has been formed, and the PPy/CMC composite film has been homogeneously coated on the MEMS resonators by electrochemical polymerization. The integration of CPs with MEMS has not only benefited the mechanical advantages of the lateral resonator but also used optical, electrical, and functional properties of the CPs. To examine its utilization as a sensor, the designed resonators have been used in the detection of volatile organic compounds in open-air conditions. Due to the differences in intermolecular interaction according to the polymer and VOCs structure, discrimination and detection of the VOCs have been performed even in uncontrolled air conditions. [GRAPHICS]

Acute lower extremity ischemia (ALI) is a cardiovascular emergency resulting from embolic and thrombotic causes. Although endovascular techniques have advanced, surgical thromboembolectomy is still the gold standard. Emergency thromboembolectomy surgery involves an ischemia-reperfusion injury, which also poses a risk for acute renal injury (AKI). The stress hyperglycemia rate (SHR) has recently emerged as an important prognostic value in emergency cardiovascular events. In the present study, we aimed to analyze the impact of preoperative contrast-enhanced tomographic angiography (CTA) and the SHR value on postoperative AKI in emergency thromboembolectomy procedures in patients with insulin-dependent diabetes mellitus (DM). In this retrospective analysis, patients with DM who received emergency surgical thromboembolectomy after being hospitalized at our hospital with ALI between 20 October 2015, and 10 September 2022, were included. Patients were classified into two groups: Group 1 (N = 159), who did not develop AKI, and Group 2 (N = 45), who did. The 45 patients in Group 2 and the 159 patients in Group 1 had median ages of 59 (39–90) and 66 (37–93), respectively (p = 0.008). The percentage of patients in Group 2 with Rutherford class IIB and admission times longer than 6 h was higher (p = 0.003, p = 0.027, respectively). To determine the variables affecting AKI after surgical embolectomy procedures, multivariate logistic regression analysis was used. In multivariate analysis Model 1, age > 65 years (odds ratio [OR]: 1.425, 95% confidence interval [CI]: 1.230–1.980, p < 0.001), preoperative high creatinine (OR: 4.194, 95% CI: 2.890–6.156, p = 0.003), and Rutherford class (OR: 0.874, 95% CI: 0.692–0.990, p = 0.036) were determined as independent predictors for AKI. In Model 2, age > 65 years (OR: 1.224 CI: 1.090–1.679, p = 0.014), preoperative high creatinine (OR: 3.975, 95% CI: 2.660–5.486, p = 0.007), and SHR (OR: 2.142, CI: 1.134–3.968, p = 0.003), were determined as independent predictors for amputation. In conclusion, when an emergency thromboembolectomy operation is planned in insulin-dependent DM patients, renal risky groups can be identified, and renal protective measures can be taken. In addition, to reduce the renal risk, according to the suitability of the clinical conditions of the patients, the decision to perform a CTA with contrast can be taken by looking at the SHR value.

Objectives Investigating empirical relationships among laboratory measures in children with diabetic ketoacidosis (DKA) can provide insights into physiological alterations occurring during DKA. We determined whether alterations in laboratory measures during DKA conform to theoretical predictions. Methods We used Pearson correlation statistics and linear regression to investigate correlations between blood glucose, electrolytes, pH and PCO2 at emergency department presentation in 1,681 pediatric DKA episodes. Among children with repeat DKA episodes, we also assessed correlations between laboratory measures at the first vs. second episode. Results pH and bicarbonate levels were strongly correlated (r=0.64), however, pH and PCO2 were only loosely correlated (r=0.17). Glucose levels were correlated with indicators of dehydration and kidney function (blood urea nitrogen (BUN), r=0.44; creatinine, r=0.42; glucose-corrected sodium, r=0.32). Among children with repeat DKA episodes, PCO2 levels tended to be similar at the first vs. second episode (r=0.34), although pH levels were only loosely correlated (r=0.19). Conclusions Elevated glucose levels at DKA presentation largely reflect alterations in glomerular filtration rate. pH and PCO2 are weakly correlated suggesting that respiratory responses to acidosis vary among individuals and may be influenced by pulmonary and central nervous system effects of DKA.

Olive leaves extracts are known to exert potential pharmacological activities especially, antidiabetic and antiobesity. This study explores the anti-insulin resistant effect of olive leaves extracts and oleuropein in 3 T3-L1 cells and in high-fat diet fed rats. Our results showed that ethanol extract (EE) suppressed significantly ( P < 0.01 ) triacylglycerol accumulation. In preadipocytes cells, EE 1/100 decreased cell viability and induced apoptosis. Real-time PCR analysis showed that EE reduced the mRNA levels of adipogenesis (CEBP-α, PPARγ, SREBP-1c, and FAS) and proinflammatory (TNF-α and IL-6) genes. Moreover, the cotreatment of EE 1/1000 or oleuropein with insulin increased considerably the expression of p-IRS, p85-pI3K, and p-AKT. In vivo model, the oral administration of oleuropein at 50 mg/kg in rats fed with high fat diet for 8 weeks reduced inflammation in liver and adipose tissues (WAT), improved glucose intolerance, and decreased hyperinsulinemia. Furthermore, the immunohistochemistry revealed that the expression level of p-Akt, IRS1, and Glut-4 were significantly enhanced in liver and WAT tissues after oleuropein supplementation comparing with that in HFD group. Additionally, the expression of IRS1 was markedly ameliorated in pancreas. Our obtained results can be adopted as an approach to used olive leaves as complement to prevent insulin-resistance disease.

Some populations are recommended to consume low-fat dairy, although the evidence behind replacing high-fat with low-fat dairy products is limited. This exploratory sub-study investigated the effect of cheese with different fat content on postprandial changes in type-2-diabetes risk markers. Following 12-week cheese or jam intake, a 4 h meal test was conducted with 37 participants. Test meals included bread and either: 80 g regular-fat cheese (REG), 80 g reduced-fat cheese (RED) or 25 g jam (CHO). Postprandial blood was drawn and appetite sensations registered. Time-meal interactions were not observed for glucose and insulin, but for triglycerides (TG) and free fatty acids (FFA). Pairwise comparisons showed 0.17 ± 0.07 mmol/L (p = 0.044) and 0.25 ± 0.07 mmol/L (p = 0.002) higher TG at 180 and 240 min, respectively, and 94 ± 37 mmol/L (p = 0.029) higher FFA at 180 min for REG compared with RED. Compared with CHO, intake of both cheese meals reduced insulin and glucose (main effects of meal, both p ≤ 0.011) and increased FFA and TG at certain time points. In conclusion, intake of cheese with a regular, compared with reduced, fat content did not affect glucose, insulin and appetite, but increased TG and FFA.

Regulatory T cells overwhelm conventional T cells in the tumor microenvironment (TME) thanks to a FOXP3-driven metabolic program that allows them to engage different metabolic pathways. Using a melanoma model of adoptive T cell therapy (ACT), we show that FOXP3 overexpression in mature CD8 T cells improved their antitumor efficacy, favoring their tumor recruitment, proliferation, and cytotoxicity. FOXP3-overexpressing (Foxp3UP) CD8 T cells exhibited features of tissue-resident memory-like and effector T cells, but not suppressor activity. Transcriptomic analysis of tumor-infiltrating Foxp3UP CD8 T cells showed positive enrichment in a wide variety of metabolic pathways, such as glycolysis, fatty acid (FA) metabolism, and oxidative phosphorylation (OXPHOS). Intratumoral Foxp3UP CD8 T cells exhibited an enhanced capacity for glucose and FA uptake as well as accumulation of intracellular lipids. Interestingly, Foxp3UP CD8 T cells compensated for the loss of mitochondrial respiration-driven ATP production by activating aerobic glycolysis. Moreover, in limiting nutrient conditions these cells engaged FA oxidation to drive OXPHOS for their energy demands. Importantly, their ability to couple glycolysis and OXPHOS allowed them to sustain proliferation under glucose restriction. Our findings demonstrate a hitherto unknown role for FOXP3 in the adaptation of CD8 T cells to TME that may enhance their efficacy in ACT.

Astrocytes store glycogen as energy and promote neurometabolic stability through supply of oxidizable l-lactate. Whether lactate regulates ventromedial hypothalamic nucleus (VMN) glucostatic function as a metabolic volume transmitter is unknown. Current research investigated whether G protein-coupled lactate receptor GPR81 controls astrocyte glycogen metabolism and glucose-regulatory neurotransmission in the ventrolateral VMN (VMNvl), where glucose-regulatory neurons reside. Female rats were pretreated by intra-VMN GPR81 or scramble siRNA infusion before insulin or vehicle injection. VMNvl cell or tissue samples were acquired by laser-catapult- or micropunch microdissection for Western blot protein or uHPLC-electrospray ionization-mass spectrometric glycogen analyses. Data show that GPR81 regulates eu- and/or hypoglycemic patterns of VMNvl astrocyte glycogen metabolic enzyme and 5′-AMP-activated protein kinase (AMPK) protein expression according to VMNvl segment. GPR81 stimulates baseline rostral and caudal VMNvl glycogen accumulation but mediates glycogen breakdown in the former site during hypoglycemia. During euglycemia, GPR81 suppresses the transmitter marker neuronal nitric oxide synthase (nNOS) in rostral and caudal VMNvl nitrergic neurons, but stimulates (rostral VMNvl) or inhibits (caudal VMNvl) GABAergic neuron glutamate decarboxylase65/67 (GAD)protein. During hypoglycemia, GPR81 regulates AMPK activation in nitrergic and GABAergic neurons located in the rostral, but not caudal VMNvl. VMN GPR81 knockdown amplified hypoglycemic hypercorticosteronemia, but not hyperglucagonemia. Results provide novel evidence that VMNvl astrocyte and glucose-regulatory neurons express GPR81 protein. Data identify neuroanatomical subpopulations of VMNvl astrocytes and glucose-regulatory neurons that exhibit differential reactivity to GPR81 input. Heterogeneous GPR81 effects during eu- versus hypoglycemia infer that energy state may affect cellular sensitivity to or postreceptor processing of lactate transmitter signaling.

Receptor interacting serine/threonine kinase 1 (RIPK1) mediates apoptosis by regulating the classic proapoptotic effectors Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak). Although Bcl-2-related ovarian killer (Bok) is structurally similar to Bak and Bax, it is unclear whether it mediates apoptosis in skeletal muscle ischemia reperfusion (IR) injury. We hypothesized that by regulating Bok-mediated apoptosis, inhibiting RIPK1 with necrostatin-1 would reduce skeletal muscle IR injury.Rats were randomized into four groups: sham (SM), IR, IR treated with necrostatin-1 (NI), or vehicle dimethyl sulfoxide (DI). For the IR group, the right femoral artery was clamped for 4 hours and then reperfused for 4 hours, and for the NI and DI groups, necrostatin-1 (1.65 mg/kg) and the equal volume of dimethyl sulfoxide were intraperitoneally administered prior to IR induction. The structural damage of muscle tissue and protein expression of Bok, Bcl-2, and cleaved caspase-3 were investigated, and apoptotic cells were identified with terminal dUTP nick-end labeling (TUNEL) staining. In vitro, human skeletal muscle cells (HSMCs) were exposed to 6 hours of oxygen-glucose deprivation followed by normoxia for 6 hours to establish an oxygen-glucose deprivation/reoxygenation (OGD/R) model. To determine the role of Bok, cell viability, lactate dehydrogenase (LDH) release, and flow cytometry were examined to demonstrate the effects of necrostatin-1 and Bok knockdown on the OGD/R insult of HSMCs.Necrostatin-1 pretreatment markedly reduced IR-induced muscle damage and RIPK1, Bok, and cleaved caspase-3 expression, whereas upregualted Bcl-2 expression (p0.05). Furthermore, necrostatin-1 prevented mitochondrial damage and decreased TUNEL-positive muscle cells (p0.05). In vitro, HSMCs treated with necrostatin-1 showed reduced Bok expression, increased cell viability, and reduced LDH release in response to OGD/R (p0.05), and Bok knockdown significantly blunted the OGD/R insult in HSMCs.Necrostatin-1 prevents skeletal muscle from IR injury by regulating Bok-mediated apoptosis.

We aimed to determine whether the addition of yoga to a regular exercise training regimen improves cardiometabolic risk profile.Sixty individuals with diagnosed hypertension (≥ 140/90 mm Hg for 3 measurements on different days) were recruited in an exercise training program. In addition to aerobic exercise training, participants were randomised into either a yoga or a stretching control group. Participants, over the 3-month intervention regimen, performed 15 minutes of either yoga or stretching in addition to 30 minutes of aerobic exercise training 5 times weekly. Blood pressure, anthropometry, high-sensitivity C-reactive protein (hs-CRP), glucose, and lipid levels as well as the Framingham and Reynolds Risk Scores were measured.At baseline, there was no difference in age, sex, smoking status, body mass index, blood pressure, heart rate, lipid and glucose levels, and Framingham Risk Score between groups. After the 3-month intervention period, the decrement in systolic and diastolic blood pressures (before vs after stretching: 126 ± 11/76 ± 7 vs 122 ± 11/73 ± 8 mm Hg; before vs after yoga: 130 ± 13/77 ± 10 vs 119 ± 11/69 ± 8 mm Hg) and heart rate was greater (P0.001) in the yoga group, with similar decreases in lipid, glucose, and hs-CRP levels and Framingham Risk Score in both groups. Reynolds Risk Score decrement was higher in the yoga vs the control group (absolute reduction -1.2 ± 1.2 vs -0.6 ± 0.8; relative reduction 13.2 ± 11.8% vs 9.3 ± 6.5%; P0.05).In patients with hypertension, the practice of yoga incorporated in a 3-month exercise training program was associated with greater improvement in resting blood pressure and heart rate and Reynolds Risk Score compared with stretching.

Reproduction represents the most energetically demanding period of life for many organisms. Capital breeders, such as anadromous sea trout (Salmo trutta), provide a particularly interesting group of organisms to study within the context of reproduction because they rely on energy stores accrued before breeding to reproduce and sustain all phenotypic and behavioral changes related to reproduction. Energy allocation into current reproduction therefore cannot be mitigated via food intake, resulting in an important life history trade-off. For this reason, exploring indexes related to energetics in salmonids can provide powerful insights into the physiological costs of reproduction. In this study, we sampled blood from and PIT tagged 232 fish captured in the wild before the spawning season. We recaptured and resampled 74 individuals (53 females and 21 males) at the end of the spawning season. Females were further divided into spawning phases (nonspawned, partially spawned, and spawned individuals), though males could not be classified as such. We compared nutritional correlates (triglycerides, cholesterol, calcium, inorganic phosphorus, and total protein), stress correlates (cortisol, sodium, potassium, chloride, and glucose), and indexes of tissue damage (aspartate aminotransferase) between initial capture and recapture as well as among spawning phases in females. We found that nutritional status decreased in all fish throughout the spawning season but that it was substantially lower in females that had spawned. We further found that spawning itself appears stressful, with elevated glucose in partially spawned females and elevated cortisol in male sea trout at recapture. Our findings thus support the idea that the cost of reproduction is energetically high and that incurred stress and a decrease in nutritional status are important physiological costs.

Cancer is one of the biggest leading causes of death worldwide. With increased accumulation of environmental factors like radiation and mutagens, causative mutation in the gene pool is increasing day by day in the human population. Metastasis and its resistance to a wide variety of treatments are the reasons which make cancer difficult to treat. It has already been reported that cancer cells introduce smart modifications in their metabolism and signaling pathways which sense changes in cancer microenvironment and help them survive under harsh conditions. The pattern of expression of these signaling molecules and their structural counterparts involved in cancer metastasis need to be investigated. We used different approaches to study the effect of several levels of glucose deprivation on cancer metastasis in the highly resistant breast cancer model cell line MDA-MB-231 grown in high- (25-mM) and low- (5-mM) glucose medium. Microscopic observations have shown that these cancer cells attach to the surface faster in the presence of high-compared to low-glucose concentrations. These observations were supported by varied expression of genes involved in this morphological transition. Under low-glucose concentration, the expression of epithelial-to-mesenchymal transition (EMT) structural proteins and regulatory molecules such as SLUG, ZEB, HIFα1A, STAT3, and VIM was downregulated, whereas expression of G9a (a histone-modifying enzyme, histone methyl transferase inhibitor), Snail, FBPase, MMP13, and PKM2 was upregulated. This resulted in the turning on of resistance mechanisms in MDA-MB-231 cancer cells enabling them to cope with the stressed tumor microenvironments leading to increased cancer invasion and migration. The increased invasion as shown by trans-well study and loose spheroids in 3D spheroid study showed how metastasis is triggered in MDA-MB-231 under glucose starvation. Our data suggests the devastating outcome of nutrient deprivation on cancer progression, which was previously thought to be supportive in cancer control.

The objective of this observational study was to compare the metabolic status of dairy cows during the last 6 wk of gestation based on colostrum volume and Ig content. For this, healthy Holstein cows were randomly selected from 3 commercial herds in Michigan. In each farm, four cohorts of 21 cows (one per season), stratified by parity, were enrolled (n=228). Cows were blood sampled weekly during the last 6 wk of gestation, and biomarkers related to nutrient utilization, oxidant status, and inflammation were quantified in serum. Cows were milked within 6 h of calving and the volume of colostrum produced was recorded and an aliquot collected. Concentration of IgG, IgA, and IgM were measured by radial immunodiffusion. Cows were grouped into high colostrum producer (HCP) or low (LCP), high IgG (HIG) or low (LIG), high IgA (HIA) or low (LIA), and high IgM (HIM) or low (LIM). For volume category, we arbitrarily defined 6 L of colostrum (4 L for first and 2 L for second feeding of calves) as the cut-off point, whereas for IgG we used the industry standard of ≥ 50g/L. To create groups of low and high IgM or IgA, we used the median of these Ig as the cutoff point. Colostrum volume was lowest in winter, but no differences were observed among parity groups. Conversely, colostrum IgG concentration was highest in fall and winter, but colostrum IgM was lowest at these seasons. However, colostrum Ig content only showed a negative weak correlation with volume (Spearman rho < -0.28). Compared to LCP, HCP cows had higher concentrations of antioxidant potential, BHB and lower cholesterol and oxidant status index. HIG cows showed higher concentrations of glucose compared to LIG. HIA cows had higher concentrations of cholesterol, reactive oxygen and nitrogen species, oxidant status index, and total protein, while BHB, and glucose were lower compared with LIA. Biomarkers of metabolic stress were not significantly different between HIM and LIM. Nevertheless, the differences observed did not result in differences in inflammatory status between animals in any of the colostrum variable categories analyzed, suggesting that physiological homeostasis was not disrupted during late gestation in association with the colostrum variables studied. Overall, the great variability observed in colostrum variables suggests that colostrogenesis is a complex and multifactorial process. However, our results suggest that greater availability of antioxidants during late gestation could support the production of higher volumes of colostrum, which needs to be explored in future trials.INTERPRETIVE SUMMARYChanges in biomarkers of metabolic stress during late gestation of dairy cows associated with colostrum volume and immunoglobulins content.By Rossi et al., page XXXX. We investigated associations between metabolic stress during the last 6 wk of gestation and the volume and immunoglobulin content of the colostrum produced. We observed that cows producing more than 6 L of colostrum exhibited increased metabolic activity during late gestation. Also, a greater blood antioxidant activity throughout late gestation was observed in cows with higher yields of colostrum, suggesting that greater availability of antioxidants might support the production of higher volumes of colostrum. Therefore, further studies should evaluate whether supplementation with additional antioxidants supplement during late gestation can improve colostrum yield.

Despite large, randomized controlled trials and guideline recommendations, patients with heart failure with reduced ejection fraction (HFrEF) continue to receive suboptimal guideline-directed medical treatment (GDMT). This study aimed to evaluate the potential effect of inpatient initiation of sodium-glucose cotransport-2 (SGLT2) inhibitors on postdischarge prescribing rates and the downstream impact on clinical outcomes. The INitiation of SGlt2i in Hospital for HFrEF (INSIGHT-HF) study was a retrospective analysis of hospitalized patients older than 18 years with a left ventricular ejection fraction (LVEF) ≤40% conducted from July 2020 and July 2021. Our primary outcome was SGLT2i prescription rates at 30 days. Among 2,663 eligible patients with documented HFrEF, 177 (6.6%) had SGLT2i initiated during their index hospitalization. The rate of SGLT2i prescriptions at 30 days was significantly higher in those with inpatient initiation of SGLT2i compared with those who did not start while inpatient (96% vs 14.7%, p0.0001). The heart failure readmission rate in the first 30 days was significantly lower in those with inpatient initiation of SGLT2i compared with those who did not start during hospitalization. (9.3% vs 22.7%, p = 0.04). Cardiovascular mortality was numerically, but not significantly, different between groups (4% vs 10.7%, p = 0.21). Inpatient initiation of an SGLT2i was associated with a significantly higher postdischarge rate of SGLT2i prescriptions and significantly lower heart failure readmission rates at 30 days. In conclusion, these findings highlight the importance of initiating SGLT2i during inpatient hospitalization to improve the quality of care in patients with HFrEF.

A multi-functional nanocatalytic system based on combined therapies has attracted considerable research attention in recent years due to its potential in the treatment of cancer. Herein, ZnO

Improving the tailorability of hydrochar synthesis is an effective way to enhance its performance and utilization efficiency. In this study, the growth rate, morphology, and molecular structure of hydrochar were controlled by regulating the pH and temperature of the hydrothermal carbonization process. Growth process analysis indicates that hydrochar has three growth periods: induction, rapid, and stable growth periods. It is mainly controlled by 5-hydroxymethylfurfural (HMF), which is formed by converting glucose and its transformation products. The regulation of acid can significantly shorten the induction period of hydrochar, even under low-temperature conditions (180℃), and increase the growth rate of hydrochar. However, the degree of hydrochar adhesion varies: the lower the temperature, the greater the degree of its adhesion. Molecular structural analysis demonstrates that hydrochar mainly consists of furan structural domains and aromatic clusters, and its surface is rich in oxygen-containing functional groups. The degree at which hydrochar was aromatized was improved by increasing the reaction temperature (160-220℃); whereas the regulation of acid reduced it and increased the content of oxygen-containing functional groups on the hydrochar surface. Based on these results, it is proposed that hydrochar formation has five stages and three growth periods with or without acid regulation.

Blood gas analyzers employing glucose-oxidase biosensors under-recover glucose when pOWhole blood specimens were tested by GEM®Premier™ 4000 (GEM 4000) and 5000 (GEM 5000). Specimens with an incalculable ("incalc") error code for glucose result or that had a glucose ≥ 20 mmol/L were retested on a second analyzer of the same type within 5 min over the course of 30 months in 5 hospitals in Calgary, Alberta. Discordant retests were defined as either: 1) paired numeric results with a difference 10 %, or 2) an "incalc" code that yielded a numeric result upon retesting. Glucose recovery in relation to pOOf 1,776 glucose tests repeated on the GEM 5000 or 1,544 on GEM 4000, 10% were discordant. GEM 5000 produced twice as many discordant numeric retests versus the GEM 4000 [5.9% (98/1,651) vs 2.7% (38/1,391)]. The majority of "incalc" error codes repeated with a numeric glucose result on both GEM analyzers [(79.7% (122/153) vs 75.2% (94/125)]. Among specimens experimentally depleted of pOThe algorithm in the GEM®Premier

Following non-elective orthopaedic surgery, a 61-year-old man with poorly controlled type 2 diabetes mellitus on empagliflozin developed high anion gap metabolic acidosis in the high-dependency unit. Metabolic acidosis persisted despite intravenous sodium bicarbonate, contributing to tachycardia and a run of non-sustained ventricular tachycardia. He was euglycaemic throughout hospital admission. Investigations revealed elevated urine and capillary ketones, and a diagnosis of sodium–glucose cotransporter-2 inhibitor-associated euglycaemic diabetic ketoacidosis was made. He was treated with an intravenous sliding scale insulin infusion and concurrent dextrose 5% with potassium chloride. Within 24 hours of treatment, his arterial pH, anion gap and serum bicarbonate levels normalised. After a further 12 hours, the intravenous insulin infusion was converted to a basal/bolus regimen of subcutaneous insulin, and he was transferred to the general ward. He was discharged well on subcutaneous insulin 6 days postoperatively.

Immune dysfunction and chronic inflammation are characteristic of HIV infection and diabetes mellitus, with CD4 + T-cell metabolism implicated in the pathogenesis of each disease. However, there is limited information on CD4 + T-cell metabolism in HIV+ persons with diabetes mellitus. We examined CD4 + T-cell glucose metabolism in HIV+ women with and without diabetes mellitus.A case-control study was used to compare CD4 + T-cell glucose metabolism in women with HIV with or without diabetes mellitus.Nondiabetic (HIV+DM-, N = 20) or type 2 diabetic HIV+ women with (HIV+DM+, N = 16) or without (HIV+DMTx+, N = 18) antidiabetic treatment were identified from the WIHS and matched for age, race/ethnicity, smoking status and CD4 + cell count. CD4 + T-cell immunometabolism was examined by flow cytometry, microfluidic qRT-PCR of metabolic genes, and Seahorse extracellular flux analysis of stimulated CD4 + T cells.HIV+DM+ displayed a significantly elevated proportion of CD4 + T cells expressing the immunometabolic marker GLUT1 compared with HIV+DMTx+ and HIV+DM- ( P = 0.04 and P = 0.01, respectively). Relative expression of genes encoding key enzymes for glucose metabolism pathways were elevated in CD4 + T cells of HIV+DM+ compared with HIV+DMTx+ and HIV+DM-. T-cell receptor (TCR)-activated CD4 + T cells from HIV+DM+ showed elevated glycolysis and oxidative phosphorylation compared with HIV+DM-.CD4 + T cells from HIV+DM+ have elevated glucose metabolism. Treatment of diabetes mellitus among women with HIV may partially correct CD4 + T-cell metabolic dysfunction.

LncRNA ZNFX1 antisense RNA 1 (ZFAS1) could improve neuronal damage and inhibit inflammation and apoptosis. We conducted an in-depth exploration on the protective mechanism of ZFAS1 in cerebral ischemia-reperfusion injury. Overexpressed or silenced plasmids of ZFAS1 were transfected into the cells to analyze the effects of oxygen-glucose deprivation/reperfusion (OGD/R) treatment on the viability, apoptosis and related gene expressions of Neuro-2a cell by performing MTT assay, flow cytometry, qRT-PCR, and Western blot. Bioinformatic analysis, qRT-PCR, dual-luciferase reporter assay and RNA immunoprecipitation were used to screen and verify the miRNA(s) which could competitively bind with ZFAS1 and downstream mRNA(s) targeted by the miRNA(s). The effects of ZFAS1 and the above target miRNA(s) or gene(s) on the apoptosis of OGD/R-injured cells, apoptosis-related proteins, inflammatory factors and p65/IκBα pathway were further verified via the rescue test. The results from the middle cerebral artery occlusion (MCAO) mouse model

In fasted and fed states, blood insulin levels are oscillatory. While this phenomenon is well studied at high glucose levels, comparatively little is known about its origin under basal conditions. We propose a possible mechanism for basal insulin oscillations based on oscillations in glycolysis, demonstrated using an established mathematical model. At high glucose, this is superseded by a calcium-dependent mechanism.