Altered Glucose Metabolism Research Articles

Chronic alcohol-induced mesenteric lymphatic leakage is associated with local and systemic metabolic dysregulation

Introduction: Chronic alcohol administration produces significant metabolic dysfunction as determined in pre-clinical and clinical studies. Our studies using a rodent model of chronic alcohol feeding showed that alcohol induces mesenteric lymphatic leakage and perilymphatic adipose tissue (PLAT) immunometabolic dysregulation. Specifically, chronic alcohol induced localized PLAT inflammation and decreased glucose uptake. Whether chronic alcohol-induced lymphatic leakage is also associated with altered systemic glucose/insulin dynamics remained to be determined. We hypothesized that chronic alcohol feeding impairs the endocrine response to a glucose tolerance test. Methods: Male Fischer 344 rats were randomized to a Lieber-DeCarli liquid diet containing 36% of calories from alcohol or pair-fed an isocaloric diet for 10 weeks. Animals consumed approximately 75 mL of diet per day. Body weights were not significantly different between groups; the average weights were 275.7 grams for control animals and 275.9 grams for alcohol-fed animals. Weights in both groups remained stable for the duration of the study. At 10 weeks, animals were fasted for 16 hours prior to intraperitoneal (IP) injections of 20% glucose solution (2g/kg). Blood samples were collected from the rat tail prior to and at 15-minute intervals following initial glucose injection for 2 hours. Blood glucose was tested at each interval using the AlphaTRAK glucometer. 2-way ANOVA and paired T-test were used to assess significant differences between groups. Results and Conclusion: Prior to IP glucose injection, blood glucose levels averaged 77 mg/dL for control animals and 71.5 mg/dL for alcohol-fed animals. Glucose levels in alcohol-fed animals averaged 38% higher at 15 minutes and 37% higher 30 minutes after IP glucose bolus than that of control animals. Total area under the curve (AUC) calculated from the glucose concentrations measured following IP glucose injection was significantly higher in alcohol-fed animals compared to control animals; average AUC for alcohol-fed animals was 26.8% higher than AUC for control animals. These results suggest that chronic alcohol-induced mesenteric lymphatic leakage and localized PLAT inflammation and altered glucose metabolism are also associated with disturbances in systemic glucose dysregulation. Future studies will examine the potential link between alcohol-induced PLAT immunometabolic dysregulation and alterations in systemic glucose metabolism. Supported by T32 (PM), K01 (FS). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Artificial non-nutritive sweeteners consumption is able to modulate glycemic control and body composition in healthy or diet-induced obese mice

Non-nutritive sweeteners (NNS) are among the most widely used food additives worldwide. Their substitution to sugar is presented as one of the solutions to prevent cardiometabolic disease, especially as they have a sweet taste but very low-energy content. However, several recent studies have questioned their physiological inactivity, which was the basis for their approval by health authorities. The main objective of this study was to evaluate the acute and chronic effects of artificial NNS consumption on glycemic control in lean and diet-induced mice models. Consequently, we evaluated the acute effects of NNS acesulfame-potassium (aceK) and sucralose on glucose tolerance, insulin sensitivity and insulin secretion measured in blood and at the beta-cells pancreatic level of mice. In another set of mice, we compared the effects of aceK or sucralose supplementations to sugar consumption during a 12 week long high-fat (HF) diet. At the end of the 12 weeks of supplementation, we evaluated the influence of these different conditions on glucose metabolism and body fat distribution. First, we reported, in our mice models, that oral glucose tolerance tests (OGTTs) after acute sucralose gavage were improved significantly compared to AceK gavage and control situation (vehicle). These acute effects on blood glucose levels after sucralose ingestion were not directly explained by a significant increase neither in beta cells insulin secretion nor in insulin sensitivity. Interestingly, we further demonstrated that both NNS chronic consumption were able to attenuate significantly the deleterious effect of HF diet on glycemic control (glucose tolerance and insulin sensitivity), independently of caloric intake. Moreover, we reported in HF mice supplemented with NNS a lower accumulation of adipose tissue in the inguinal and subcutaneous compartments which was associated with a reduction in body mass in these groups. Surprisingly, our results demonstrate that even an acute consumption of widely used NNS sucralose and AceK is able to alter glucose metabolism. When repeated over time, the consumption of these NNS also seems to be able to reduce deleterious effects of HF diet on glycemic control but also on body composition. These results may contribute to a better understanding of the effects of NNS on metabolic health, but further studies are needed to decipher underlying mechanisms.

Pancreatic fatty replacement as risk marker for altered glucose metabolism and cardiac iron and complications in thalassemia major

ObjectivesThis multicenter study assessed the extent of pancreatic fatty replacement and its correlation with demographics, iron overload, glucose metabolism, and cardiac complications in a cohort of well-treated patients with thalassemia major (TM).MethodsWe considered 308 TM patients (median age: 39.79 years; 182 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Magnetic resonance imaging was used to quantify iron overload (IO) and pancreatic fat fraction (FF) by T2* technique, cardiac function by cine images, and to detect replacement myocardial fibrosis by late gadolinium enhancement technique. The glucose metabolism was assessed by the oral glucose tolerance test.ResultsPancreatic FF was associated with age, body mass index, and history of hepatitis C virus infection. Patients with normal glucose metabolism showed a significantly lower pancreatic FF than patients with impaired fasting glucose (p = 0.030), impaired glucose tolerance (p < 0.0001), and diabetes (p < 0.0001). A normal pancreatic FF (< 6.6%) showed a negative predictive value of 100% for abnormal glucose metabolism. A pancreatic FF > 15.33% predicted the presence of abnormal glucose metabolism. Pancreas FF was inversely correlated with global pancreas and heart T2* values. A normal pancreatic FF showed a negative predictive value of 100% for cardiac iron. Pancreatic FF was significantly higher in patients with myocardial fibrosis (p = 0.002). All patients with cardiac complications had fatty replacement, and they showed a significantly higher pancreatic FF than complications-free patients (p = 0.002).ConclusionPancreatic FF is a risk marker not only for alterations of glucose metabolism, but also for cardiac iron and complications, further supporting the close link between pancreatic and cardiac disease.Key Points• In thalassemia major, pancreatic fatty replacement by MRI is a frequent clinical entity, predicted by a pancreas T2* < 20.81 ms and associated with a higher risk of alterations in glucose metabolism.• In thalassemia major, pancreatic fatty replacement is a strong risk marker for cardiac iron, replacement fibrosis, and complications, highlighting a deep connection between pancreatic and cardiac impairment.

Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome

The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.

Potassium Channels, Glucose Metabolism and Glycosylation in Cancer Cells.

Potassium channels emerge as one of the crucial groups of proteins that shape the biology of cancer cells. Their involvement in processes like cell growth, migration, or electric signaling, seems obvious. However, the relationship between the function of K+ channels, glucose metabolism, and cancer glycome appears much more intriguing. Among the typical hallmarks of cancer, one can mention the switch to aerobic glycolysis as the most favorable mechanism for glucose metabolism and glycome alterations. This review outlines the interconnections between the expression and activity of potassium channels, carbohydrate metabolism, and altered glycosylation in cancer cells, which have not been broadly discussed in the literature hitherto. Moreover, we propose the potential mediators for the described relations (e.g., enzymes, microRNAs) and the novel promising directions (e.g., glycans-orinented drugs) for further research.

The Metabolic Switch of Physical Activity in Non-Obese Insulin Resistant Individuals.

Healthy non-obese insulin resistant (IR) individuals are at higher risk of metabolic syndrome. The metabolic signature of the increased risk was previously determined. Physical activity can lower the risk of insulin resistance, but the underlying metabolic pathways remain to be determined. In this study, the common and unique metabolic signatures of insulin sensitive (IS) and IR individuals in active and sedentary individuals were determined. Data from 305 young, aged 20-30, non-obese participants from Qatar biobank, were analyzed. The homeostatic model assessment of insulin resistance (HOMA-IR) and physical activity questionnaires were utilized to classify participants into four groups: Active Insulin Sensitive (ISA, n = 30), Active Insulin Resistant (IRA, n = 20), Sedentary Insulin Sensitive (ISS, n = 21) and Sedentary Insulin Resistant (SIR, n = 23). Differences in the levels of 1000 metabolites between insulin sensitive and insulin resistant individuals in both active and sedentary groups were compared using orthogonal partial least square discriminate analysis (OPLS-DA) and linear models. The study indicated significant differences in fatty acids between individuals with insulin sensitivity and insulin resistance who engaged in physical activity, including monohydroxy, dicarboxylate, medium and long chain, mono and polyunsaturated fatty acids. On the other hand, the sedentary group showed changes in carbohydrates, specifically glucose and pyruvate. Both groups exhibited alterations in 1-carboxyethylphenylalanine. The study revealed different metabolic signature in insulin resistant individuals depending on their physical activity status. Specifically, the active group showed changes in lipid metabolism, while the sedentary group showed alterations in glucose metabolism. These metabolic discrepancies demonstrate the beneficial impact of moderate physical activity on high risk insulin resistant healthy non-obese individuals by flipping their metabolic pathways from glucose based to fat based, ultimately leading to improved health outcomes. The results of this study carry significant implications for the prevention and treatment of metabolic syndrome in non-obese individuals.

The Role of a Ketogenic Diet in the Treatment of Dementia in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) shares a common molecular mechanism and underlying pathology with dementia, and studies indicate that dementia is widespread in people with T2DM. Currently, T2DM-induced cognitive impairment is characterized by altered insulin and cerebral glucose metabolism, leading to a shorter life span. Increasing evidence indicates that nutritional and metabolic treatments can possibly alleviate these issues, as there is a lack of efficient preventative and treatment methods. The ketogenic diet (KD) is a very high-fat, low-carbohydrate diet that induces ketosis in the body by producing a fasting-like effect, and neurons in the aged brain are protected from damage by ketone bodies. Moreover, the creation of ketone bodies may improve brain neuronal function, decrease inflammatory expression and reactive oxygen species (ROS) production, and restore neuronal metabolism. As a result, the KD has drawn attention as a potential treatment for neurological diseases, such as T2DM-induced dementia. This review aims to examine the role of the KD in the prevention of dementia risk in T2DM patients and to outline specific aspects of the neuroprotective effects of the KD, providing a rationale for the implementation of dietary interventions as a therapeutic strategy for T2DM-induced dementia in the future.

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses.

Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.

Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-β is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients' cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.

Overexpression of a Short Sulfonylurea Splice Variant Increases Cardiac Glucose Uptake and Uncouples Mitochondria by Regulating ROMK Activity.

The mitochondrial splice variant of the sulfonylurea receptor (SUR2A-55) is associated with protection from myocardial ischemia-reperfusion (IR) injury, increased mitochondrial ATP sensitive K+ channel activity (mitoKATP) and altered glucose metabolism. While mitoKATP channels composed of CCDC51 and ABCB8 exist, the mitochondrial K+ pore regulated by SUR2A-55 is unknown. We explored whether SUR2A-55 regulates ROMK to form an alternate mitoKATP. We assessed glucose uptake in mice overexpressing SUR2A-55 (TGSUR2A-55) compared with WT mice during IR injury. We then examined the expression level of ROMK and the effect of ROMK modulation on mitochondrial membrane potential (Δψm) in WT and TGSUR2A-55 mice. TGSUR2A-55 had increased glucose uptake compared to WT mice during IR injury. The expression of ROMK was similar in WT compared to TGSUR2A-55 mice. ROMK inhibition hyperpolarized resting cardiomyocyte Δψm from TGSUR2A-55 mice but not from WT mice. In addition, TGSUR2A-55 and ROMK inhibitor treated WT isolated cardiomyocytes had enhanced mitochondrial uncoupling. ROMK inhibition blocked diazoxide induced Δψm depolarization and prevented preservation of Δψm from FCCP perfusion in WT and to a lesser degree TGSUR2A-55 mice. In conclusion, cardio-protection from SUR2A-55 is associated with ROMK regulation, enhanced mitochondrial uncoupling and increased glucose uptake.

Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche

ABSTRACT Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 μg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 μg/dL] and High DHEAS (HD) [≥42 μg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.

Abnormal glucose metabolism in virus associated sepsis.

Sepsis is identified as a potentially lethal organ impairment triggered by an inadequate host reaction to infection (Sepsis-3). Viral sepsis is a potentially deadly organ impairment state caused by the host's inappropriate reaction to a viral infection. However, when a viral infection occurs, the metabolism of the infected cell undergoes a variety of changes that cause the host to respond to the infection. But, until now, little has been known about the challenges faced by cellular metabolic alterations that occur during viral infection and how these changes modulate infection. This study concentrates on the alterations in glucose metabolism during viral sepsis and their impact on viral infection, with a view to exploring new potential therapeutic targets for viral sepsis.

Association of dysphagia with altered brain glucose metabolism in Parkinson's disease.

Dysphagia is a major clinical concern in Parkinson's disease (PD). However, the relationship between the development of phase-specific dysphagia and the regional brain glucose metabolism remains unclear. Our objective was to investigate the distributions of brain glucose metabolism specific to oral and pharyngeal phases of dysphagia in PD. In this retrospective cross-sectional study, patients with PD who underwent videofluoroscopic swallowing study (VFSS) and 18 F-fluorodeoxy-glucose positron emission tomography at intervals of <1 month were included. Each swallow was assessed by the binarized Videofluoroscopic Dysphagia Scale with 14 subitems, seven each for the oral and pharyngeal phases. Metabolism mapping was performed by superimposing significant clusters of subitems belonging to each of the two phases using voxel-wise Firth's penalized binary logistic regression model, adjusting for age and PD duration at VFSS. Eighty-two patients with PD who met the inclusion criteria were included in the analysis. The oral phase dysphagia-specific overlap map showed hypermetabolism in the right inferior temporal gyrus, bilateral cerebellum, superior frontal gyrus, and anterior cingulate cortices. Hypometabolism in the bilateral orbital and triangular parts of the inferior to middle frontal gyrus was also correlated with the occurrence of oral phase dysphagia. The development of pharyngeal phase dysphagia was related to hypermetabolism of posterior aspects of the bilateral parietal lobes, cerebellum, and hypometabolism of the mediodorsal aspects of anterior cingulate and middle to superior frontal gyri. These findings suggest that phase-specific distribution of brain glucose metabolism may explain the dysphagia of PD.

Brain glucose metabolism and dopamine transporter changes in rats with morphine-induced conditioned place preference.

Addiction to morphine is a chronic brain disease leading to compulsive abuse. Drug addiction animal models with and without conditioned place preference (CPP) training have been used to investigate cue-elicited drug craving. We used 18 F-fluorodeoxyglucose (18 F-FDG) and 11 C-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (11 C-CFT) micro-PET/CT scans to examine the regional changes in brain glucose metabolism and dopamine transporter (DAT) availability to study their relationship underlying drug memory in morphine-treated rat models with and without CPP. Standardized uptake value ratio (SUVr) of 18 F-FDG significantly decreased in the medial prefrontal cortex (mPFC) and cingulate with short-term morphine administration compared with the baseline condition. Voxelwise analysis indicated glucose metabolism alterations in the somatosensory cortex, hippocampus and cingulate in morphine-treated rats and in the striatum, thalamus, medial prefrontal cortex, primary motor cortex and many regions in the cortex in the CPP group compared with the baseline condition. Alterative glucose metabolism was also observed in the striatum, primary somatosensory cortex and some cortical regions in the CPP group compared with morphine alone group. DAT expression alterations were only observed in the long-term morphine compared with the short-term morphine group. This study shows that cerebral glucose metabolism significantly altered during morphine administration and CPP process mainly in the mPFC, striatum and hippocampus, which indicates that the function of these brain regions is involved in cue-induced craving and memory retrieval.

Metabolic and Molecular Aspects of Schizophrenia: A Review

Despite decades of research, the causes and biology of schizophrenia remain unknown. The condition is associated with metabolic symptoms such as hyperinsulinemia, dyslipidaemia, type 2 diabetes (T2DM), and obesity. These sensations are a prevalent side effect of the new antipsychotic medications. Nevertheless, metabolic dysfunction in schizophrenia has been studied before the antipsychotic phase, and it has also been documented in patients with first- onset schizophrenia prior to antipsychotic treatment. We investigate the evidence for metabolic abnormalities in schizophrenia patients, both in the central and peripheral nervous systems. Post-mortem brain tissue molecular analysis indicated alterations in glucose metabolism and insulin signalling pathways, whereas blood-based molecular profiling revealed hyperinsulinemia and abnormalities in insulin and co-released factor synthesis after the development of symptoms. Yet, such features are not seen in all patients with the disorder, and not all people with such defects have schizophrenia symptoms. One explanation of these facts is the presence of an underlying metabolic sensitivity in a subset of persons that interacts with environmental or hereditary factors to create the disorder's overt symptoms.

Association of overexpressed carboxyl-terminal amyloid precursor protein in brains with altered glucose metabolism and liver toxicity

ABSTRACT Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. The deposition of amyloid plaques mainly composed of amyloid beta (Aβ) is observed in brain regions in AD patients. AD presents with similar pathophysiology to that of metabolic syndrome, including glucose and insulin resistance. In addition, epidemiological studies indicate diabetes, impaired glucose metabolism, and obesity increase the prevalence of AD. The liver is considered a key organ in the reciprocal relationship between AD and metabolic syndrome and is the major organ for the clearance of Aβ in the periphery. Furthermore, liver dysfunction aggravates Aβ-induced pathophysiology. Aβ is produced in the brain and peripheral tissues and penetrates the blood–brain barrier. However, in vivo evidence showing the effect of Aβ on the crosstalk between the brain and liver has not been reported yet. In the present study, we investigated the toxicity of brain-derived Aβ on glucose metabolism and the liver using transgenic mice overexpressing the carboxyl-terminal of amyloid precursor protein in the brain. The transgenic mice were overweight, which was associated with impaired glucose metabolism and insulin resistance, but not due to increased food intake. In addition, transgenic mice had enlarged livers and reduced gene expressions associated with glucose and lipid metabolism. Thus, overexpressed amyloid precursor protein in the brain may promote being overweight and glucose resistance, possibly through liver toxicity.

The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication.

Obviously, immune cells like T cells and macrophages play a major role in rheumatoid arthritis (RA). On one hand, the breakdown of immune homeostasis directly induces systemic inflammation; on the other hand, these cells initiate and perpetuate synovitis and tissue damages through the interaction with fibroblast-like synoviocytes (FLS). In recent years, the pathological link between metabolic disorders and immune imbalance has received increasing attention. High energy demand of immune cells leads to the accumulation of metabolic byproducts and inflammatory mediators. They act on various metabolism-sensitive signal pathways as well as relevant transcription factors, such as HIF-1α, and STATs. These molecular events will impact RA-related effectors like circulating immune cells and joint-resident cells in return, allowing the continuous progression of systemic inflammation, arthritic manifestations, and life-threatening complications. In other words, metabolic complications are secondary pathological factors for the progression of RA. Therefore, the status of energy metabolism may be an important indicator to evaluate RA severity, and in-depth explorations of the mechanisms underlying the mystery of how RA-related metabolic disorders develop will provide useful clues to further clarify the etiology of RA, and inspire the discovery of new anti-rheumatic targets. This article reviews the latest research progress on the interactions between immune and metabolism systems in the context of RA. Great importance is attached to the changes in certain pathways controlling both immune and metabolism functions during RA progression.

Dichloroacetophenone biphenylsulfone ethers as anticancer pyruvate dehydrogenase kinase inhibitors in non-small cell lung cancer models

Pyruvate dehydrogenase kinase 1 (PDK1) is an important metabolic enzyme which is often overexpressed in many types of cancers, including non-small-cell lung cancers (NSCLC). Targeting PDK1 appears to be an attractive anticancer strategy. Based on a previously reported moderate potent anticancer PDK1 inhibitor, 64, we developed three dichloroacetophenone biphenylsulfone ethers, 30, 31 and 32, which showed strong PDK1 inhibitions of 74%, 83% and 72% at 10 μM, respectively. Then we investigated the anticancer effects of 31 in two NSCLC cell lines, namely, NCI–H1299 and NCI–H1975. It was found that 31 exhibited sub-micromolar cancer cell IC50s, suppressed colony formation, induced mitochondrial membrane potential depolarization, triggered apoptosis, altered cellular glucose metabolism, with concomitant reductions in extracellular lactate levels and enhanced the generation of reactive oxygen species in NSCLC cells. Moreover, 31 significantly suppressed the tumor growth in an NCI–H1975 mouse xenograft model, outperforming the anticancer effects of 64. Taken together our results suggested that inhibition of PDK1 via dichloroacetophenone biphenylsulfone ethers may provide a novel direction leading to an alternative treatment option in NSCLC therapy.

Glucose induced-AKT/mTOR activation accelerates glycolysis and promotes cell survival in acute myeloid leukemia

Multiple studies have demonstrated that excessive glucose utilization is a common feature of cancer cells to support malignant phenotype. Acute myeloid leukemia (AML) is recognized as a heterogeneous disorder of hematopoietic stem cells characterized by altered glucose metabolism. However, the role of glucose metabolic dysfunction in AML development remains obscure. In this study, glucose and 2-Deoxy-D-glucose (2-DG) treatment were applied to analyze the relationship between glucose metabolism and cell survival. Cell Counting Kit-8 (CCK-8) and flow cytometry (FCM) assays were used to examine the cell viability and apoptosis rate. Glucose consumption and lactate production were measured to assess the glucose metabolism pathway. The results demonstrated that abnormally increased glucose effectively promoted proliferation of leukemic cells and inhibited cell apoptosis, while 2-DG ameliorated leukemic phenotypes. Importantly, glucose exposure induced active glycolysis by increasing glucose consumption and lactate production. Furthermore, the levels of key glycolysis-related genes glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1) were upregulated. Mechanistic investigations revealed that AKT/mTOR signaling pathway was activated in glucose condition. In conclusion, our findings indicate that glucose induced-AKT/mTOR activation plays a growth-promoting role in AML, highlighting that inhibition of glycolysis would be a vital adjuvant therapy strategy for AML.

Alteration of antioxidant status, glucose metabolism, and hypoxia signal pathway in Eirocheir sinensis after acute hypoxic stress and reoxygenation

Dissolved oxygen (DO) is crucial for the survival of Chinese mitten crab (Eirocheir sinensis); low DO levels adversely affect the health of these crabs. In this study, we evaluated the underlying response mechanism of E. sinensis to acute hypoxic stress by analyzing antioxidant parameters, glycolytic indicators, and hypoxia signaling factors. The crabs were exposed to hypoxia for 0, 3, 6, 12, and 24 h and reoxygenated for 1, 3, 6, 12, and 24 h. The hepatopancreas, muscle, gill, and hemolymph were sampled at different exposure times to detect the biochemical parameters and gene expression. The results showed that the activity of catalase, antioxidants, and malondialdehyde in tissues significantly increased under acute hypoxia and gradually decreased during the reoxygenation phase. Under acute hypoxic stress, glycolysis indices, including hexokinase (HK), phosphofructokinase, pyruvate kinase (PK), pyruvic acid (PA), lactate dehydrogenase (LDH), lactic acid (LA), succinate dehydrogenase (SDH), glucose, and glycogen in the hepatopancreas, hemolymph, and gills increased to varying degrees but recovered to the control levels after reoxygenation. Gene expression data showed that hypoxia signaling pathway-related genes, including hypoxia-inducible factor-1α/β (HIF1α/β), prolyl hydroxylase (PHD), factor inhibiting hypoxia-inducible factor (FIH), and glycolysis-related factors (HK and PK) were upregulated, showing that the HIF signaling pathway was activated under hypoxic conditions. In conclusion, acute hypoxic exposure activated the antioxidant defense system, glycolysis, and HIF pathway to respond to adverse conditions. These data contribute to elucidating the defense and adaptive mechanisms of crustaceans to acute hypoxic stress and reoxygenation.