Glucose Metabolites Research Articles

A novel serum metabolomic panel distinguishes IgG4-related sclerosing cholangitis from primary sclerosing cholangitis.

Background & AimsPrimary sclerosing cholangitis (PSC) and IgG4‐related sclerosing cholangitis (IgG4‐SC) are chronic fibro‐inflammatory immune‐mediated hepatobiliary conditions that are challenging to distinguish in a clinical setting. Accurate non‐invasive biomarkers for discriminating PSC and IgG4‐SC are important to ensure a correct diagnosis, prompt therapy and adequate cancer surveillance.MethodsWe performed nuclear magnetic resonance (NMR)‐based metabolomic profiling using serum samples collected prospectively from patients with PSC (n = 100), IgG4‐SC (n = 23) and healthy controls (HC; n = 16).ResultsMultivariate analysis of the serum metabolome discriminated PSC from IgG4‐SC with greater accuracy (AUC 0.95 [95%CI 0.90–0.98]) than IgG4 titre (AUC 0.87 [95%CI 0.79–0.94]). When inflammatory bowel disease (IBD) was excluded as a comorbid condition (IgG4‐SC n = 20, PSC n = 22), the diagnostic AUC increased to 1.0, suggesting that the metabolome differences identified are not a result of the increased prevalence of IBD in PSC relative to IgG4‐SC patients. Serum lactate (p < .0001), glucose (p < .01) and glutamine (p < .01) metabolites were increased in IgG4‐related disease (IgG4‐RD) and IgG4‐SC individuals compared to PSC, whereas mobile choline (p < .05), 3‐hydroxybutyric acid (p < .01) and ‐CH3 lipoprotein resonances (p < .01) were decreased.ConclusionsTaken together, serum metabolomic profiling has the potential to be incorporated as a diagnostic criterion, independent of IgG4 titre, to improve the diagnosis of IgG4‐RD and help distinguish IgG4‐SC from PSC.

ROS/PI3K/Akt and Wnt/\u03b2-catenin signalings activate HIF-1\u03b1-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer

BackgroundAcquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents to reduce resistance have not yielded success. Metabolic reprogramming is a key cancer hallmark and confers several tumor phenotypes including chemoresistance. Glucose metabolic reprogramming events of 5-FU resistance in CRC has not been evaluated, and whether abnormal glucose metabolism could impart 5-FU resistance in CRC is also poorly defined.MethodsThree separate acquired 5-FU resistance CRC cell line models were generated, and glucose metabolism was assessed by measuring glucose and lactate utilization, RNA and protein expressions of glucose metabolism-related enzymes and changes of intermediate metabolites of glucose metabolite pool. The protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients were detected by immunohistochemistry and immunofluorescence. Stable HIF1A knockdown in cell models was established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was evaluated in cell models in vivo and in vitro.ResultsThe abnormality of glucose metabolism in 5-FU-resistant CRC were described in detail. The enhanced glycolysis and pentose phosphate pathway in CRC were associated with increased HIF-1α expression. HIF-1α-induced glucose metabolic reprogramming imparted 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cell lines and clinical specimens, and increased HIF-1α levels were associated with failure of fluorouracil analog-based chemotherapy in CRC patients and poor survival. Upregulation of HIF-1α in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of β-catenin in the nucleus. Both HIF-1α gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU.ConclusionsHIF-1α is a potential biomarker for 5-FU-resistant CRC, and targeting HIF-1a in combination with 5-FU may represent an effective therapeutic strategy in 5-FU-resistant CRC.

Methylglyoxal Scavengers Attenuate Angiogenesis Dysfunction Induced by Methylglyoxal and Oxygen-Glucose Deprivation.

Cerebral endothelial cells play an essential role in brain angiogenesis, and their function has been found to be impaired in diabetes. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite of glucose formed mainly during glycolysis, and its levels can be elevated in hyperglycemic conditions. MG is a potent precursor of AGEs (advanced glycation end-products). In this study, we investigated if MG can induce angiogenesis dysfunction and whether MG scavengers can ameliorate angiogenesis dysfunction induced by MG. Here, we used cultured human brain microvascular endothelial cells (HBMECs) treated with MG and oxygen-glucose deprivation (OGD) to mimic diabetic stroke in vitro. We also used the MG challenged chicken embryo chorioallantoic membrane (CAM) to study angiogenesis in vivo. Interestingly, administration of MG significantly impaired cell proliferation, cell migration, and tube formation and decreased protein expression of angiogenesis-related factors, which was rescued by three different MG scavengers, glyoxalase 1 (GLO1), aminoguanidine (AG), and N-acetyl cysteine (NAC). In cultured CAM, MG exposure significantly reduced angiogenesis and the angiogenesis-related dysfunction could be attenuated by pretreatment with AG or NAC. Treatment of cultured HBMECs with MG plus OGD increased cellular apoptosis significantly, which could be prevented by exposure to GLO1, AG, or NAC. We also noted that administration of MG increased cellular oxidative stress as measured by reactive oxygen species (ROS) generation, enhanced AGE accumulation, and receptor for advanced glycation end-product (RAGE) expression in the cultured HBMECs, which were partially reversed by GLO1, AG, or NAC. Taken together, our findings demonstrated that GLO1, AG, or NAC administration can ameliorate MG-induced angiogenesis dysfunction, and this can be mainly attributed to attenuated ROS production, reduced cellular apoptosis, and increased levels of angiogenic factors. Overall, this study suggested that GLO1, AG, or NAC may be promising candidate compounds for the treatment of angiogenesis dysfunction caused by hyperglycemia in diabetic ischemic stroke.

Fuzzy Planar Cell Polarity Gene (FUZ) Promtes Cell Glycolysis, Migration, and Invasion in Non-small Cell Lung Cancer via the Phosphoinositide 3-Kinase/Protein Kinase B Pathway.

Purpose: Fuzzy planar cell polarity gene (FUZ) is regarded as a planar cell polarity effector that controls multiple cellular processes during vertebrate development. The role of FUZ in glucose metabolism, invasion, and metastasis of non-small cell lung cancer (NSCLC) is unclear. The aims of this study were to investigate the relationship between FUZ and glucose metabolism and its mechanism of action.Materials and methods: Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to detect FUZ expression in A549 and H1299 cells. Additionally, qRT-PCR and western blot analysis were used to detect the expression of related glucose metabolism indicators, and lactate and 18 Fluorine fludeoxyglucose (18F-FDG) uptake assays used to detect changes in glucose metabolites. Further, cell invasion and migration behavior were evaluated by transwell and wound healing assays. In vivo tumor growth assay was conducted to assess the effect of FUZ.Results: We found that FUZ was significantly upregulated in the NSCLC cell lines compared to that in the normal HBE cells. FUZ was found to promote energy metabolism through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, and overexpression of FUZ increased both lactic acid and 18F-FDG uptake. Moreover, FUZ knockdown significantly inhibited the migration and invasion of NSCLC cells. In vivo, FUZ knockdown can significantly inhibit tumor proliferation in the xenograft model, which was well identified by Micro-PET scan.Conclusion: The present finding in vitro and vivo show that FUZ is involved in NSCLC cell energy metabolism, invasion and migration via the PI3K/AKT signaling pathway, suggesting that FUZ can be a potential therapeutic target for NSCLC.

Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

Methylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.

Glucose Conferred Irinotecan Chemoresistance through Divergent Actions of Pyruvate and ATP in Cell Death and Proliferation of Colorectal Cancer

Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). This study aimed to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of various concentrations of glucose, pyruvate, or ATP-encapsulated liposomes. In this study, human CRC cell lines treated with irinotecan in high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in normal glucose concentrations. Irinotecan induced apoptosis and necroptosis, both mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it did not affect necroptosis. In contrast, pyruvate attenuated the receptor-interacting protein kinase 1/3-dependent necroptosis via free radical scavenging without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated the irinotecan-induced G0/G1 shift, whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere size while pyruvate prevented the deformation of spheroid mass. Glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to a quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, contributing to tumor recurrence. Our findings challenged the traditional view of ATP as the main factor for irinotecan chemoresistance and provided novel insights of pyruvate acting as an antioxidant responsible for drug insensitivity, which may shed light on the development of new therapies against recalcitrant cancers.

Non-metabolic functions of pyruvate kinase M2: PKM2 in tumorigenesis and therapy resistance.

Cancer is the disease of uncontrollably dividing cells in the body. As cancer cells proliferate at higher rates, they need more energy in a short time necessitating deregulation of energy-generating pathways for their benefit. Although oxidative phosphorylation generates more energy from a glucose molecule, cancer cells have a tendency to enhance aerobic glycolysis by consuming more glucose and producing lactate as a by-product even if oxygen is present. In addition to the generation of rapid energy to fulfill their increasing demands, this strategy also provides the use of glucose metabolites such as lactate as a source for the synthesis of anabolic molecules, such as nucleotides, amino acids, and lipids during the rapid phase of the proliferation. Pyruvate kinase M2 (PKM2) is an isoform of pyruvate kinase, which mediates the balancing of energy generation mechanisms during the anabolic and catabolic events. Due to its vital role in glycolysis, PKM2 has been investigated to target cancer cell metabolism for several years. However, recent studies demonstrate that PKM2 may also promote cancer progression by regulating core steps in metastasis such as migration, angiogenesis, and stemness. Of note, it is estimated that 90% of cancer-related deaths are due to metastasis. This review is intended to summarize the recent advances in the non-metabolic roles of PKM2 in cancer progression and to indicate its potential uses for the development of new treatment strategies.

Green Alga Enteromorpha prolifera Oligosaccharide Ameliorates Ageing and Hyperglycemia through Gut–Brain Axis in Age‐Matched Diabetic Mice

To investigate the anti-ageing and anti-diabetic effects of Enteromorpha prolifera oligosaccharide (EPO) in age-matched streptozocin-induced diabetic mice. LC-MS metabolomics and 16S rRNA sequencing is used to identify the brain metabolites and gut microbiota, respectively. EPO could significantly improve glucose metabolism and activity of total superoxide dismutase in serum. It also could regulate the tricarboxylic acid cycle, arginine, and inosine-related metabolic pathways in the brain of aged diabetic mice. Inosine is found to enhance the relative expressions of daf-2, daf-16, and skn-1 in insulin-resistant Caenorhabditis elegans. Additionally, EPO could alter the composition and diversity of gut microbiota in mice. It could upregulate the Signal Transducer and Activator of Transcription 3/Forkhead Box O1 (FOXO1)/B cell lymphoma 6 (Bcl-6) pathways in the brain and the c-Jun N-terminal Kinase (JNK)/FOXO1/Bcl-6 signaling axis in the intestine to regulate glucose metabolite status and ageing in mice. EPO could also improve the levels of glucagon-like peptide type 1 (GLP1) expression in the gut, thereby inducing high expression of GLP1 receptor in the brain to control glucose metabolites through the brain-gut axis. Enterococcus is negatively correlated with AMP in the brain and could be a potential hallmark species in age-related diabetes. These results suggest that EPO could be a potential novel natural drug for the treatment of diabetes in the elderly.

Integrative analysis of multiomics data identified acetylation as key variable of excessive energy metabolism in hyperthyroidism-induced osteoporosis rats

BackgroundResults from the previous experiment have demonstrated bone loss and excess metabolism in Hyperthyroidism-induced rats. Thus, an underlying relationship between metabolism and bone loss was speculated. In addition, previous studies have shown the influence of acetylation on metabolism in tissues and diseases. The hypothesis from this case study suggests that excessive metabolism is induced by acetylation of vital metabolism enzymes. ResultsIn the case study, a HYP-induced osteoporosis rat model was used and the glucose metabolite was tested through the acetylation of proteins by the mass spectrometer. The results showed that pivotal enzymes of Glycolysis-Tricarboxylic acid cycle-Oxidative phosphorylation were acetylated along with upregulated metabolites. With all acetyly-lysine sites of related enzymes listed, the results in this study showed that bone loss in HYP rats was accompanied by the upregulation of CREB-binding protein (Crebbp, CBP). Furthermore, it is also indicated that CBP has a close relationship with the enhancement of LDHA which promotes glucose metabolism. ConclusionsAcetylation is highly correlated with excessive energy metabolism in HYP-induced osteoporotic rats, where a representation relationship between CBP and LDHA is demonstrated. SignificanceHyperthyroidism may lead to osteoporosis. Our study found an interesting phenomenon of hyperthyroidism induced-osteoporosis is that osteoporosis is accompanied by excessive glucose metabolism. In this process, some molecular mechanisms are still unclear. This study indicates a high degree of acetylation of metabolic enzymes, which may be closely related to excessive glucose metabolism. The relationship between CBP and LDHA was also investigated in this study, which showed that CBP and LDHA had some extent interaction. Glucose metabolism and acetylation maybe all associated with hyperthyroidism induced-osteoporosis. This data provides new insights into the molecular mechanisms of hyperthyroidism induced-osteoporosis.

Hydropinotherapy with Sulphurous Mineral Water as Complementary Treatment to Improve Glucose Metabolism, Oxidative Status, and Quality of Life.

Hydropinotherapy is a salus per aquam (Spa) treatment suitable as a complementary approach to treat several diseases, which strongly affect the quality of life (QoL). Hydropinotherapy with sulphurous mineral water exerts benefits thanks to components, such as hydrogen sulphide, which is considered mainly responsible for antioxidant and hypoglycaemic effects. Such properties, linked from each other, could favour an improvement in patients’ QoL. However, data on humans are scarce. This study aimed to investigate whether a cycle of sulphurous hydropinotherapy was able to modify plasma levels of glucose and reactive oxygen metabolites (ROMs) and improve QoL in patients suffering from several chronic disorders. A prospective, observational study involved patients with gastrointestinal diseases who received a prescription of a cycle of sulphurous hydropinotherapy (S-HT). Age- and sex-matched control group was enrolled (No S-HT). Glycaemia and plasma concentration of ROMs were measured in all subjects. The impact of spa treatment on the QoL was assessed using the Short Form 36 Health Status Survey questionnaire (SF-36). All parameters were measured at baseline and at the end of a 2-week treatment. Between the groups, no differences were found in glycaemia and ROMs at baseline. In the S-HT group, a reduction in glycaemia and ROMs, both in respect to baseline (p = 0.005 and p = 0.031, respectively) and to control group, as shown by the delta value calculated, as the difference between the values at 2 weeks and baseline (p = 0.0009 and p = 0.0001, respectively). In the S-HT, delta ROMs was the best predictor of delta glycaemia with a direct linear correlation (beta = 0.559, 95% CI 0.471 to 0.647, p < 0.0001). In the S-HT, the SF-36 total score was improved both when compared with baseline (p = 0.002) and with No S-HT (p = 0.001). Sulphurous hydropinotherapy induces a decrease in glycaemia and ROM levels, also ameliorating the patients’ QoL. Therefore, it could be considered a useful complementary therapeutic approach.

Glycation and Glycosylation in Cardiovascular Remodeling: Focus on Advanced Glycation End Products and O-Linked Glycosylations as Glucose-Related Pathogenetic Factors and Disease Markers.

Glycation and glycosylation are non-enzymatic and enzymatic reactions, respectively, of glucose, glucose metabolites, and other reducing sugars with different substrates, such as proteins, lipids, and nucleic acids. Increased availability of glucose is a recognized risk factor for the onset and progression of diabetes-mellitus-associated disorders, among which cardiovascular diseases have a great impact on patient mortality. Both advanced glycation end products, the result of non-enzymatic glycation of substrates, and O-linked-N-Acetylglucosaminylation, a glycosylation reaction that is controlled by O-N-AcetylGlucosamine (GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), have been shown to play a role in cardiovascular remodeling. In this review, we aim (1) to summarize the most recent data regarding the role of glycation and O-linked-N-Acetylglucosaminylation as glucose-related pathogenetic factors and disease markers in cardiovascular remodeling, and (2) to discuss potential common mechanisms linking these pathways to the dysregulation and/or loss of function of different biomolecules involved in this field.

Induction of RAGE-NFkB signalling axis enhances SHP-2 tyrosine phosphatase expression resulting in deviant activation of diabetic monocytes

Abstract Purpose Aberrant activation of Type 2 Diabetes mellitus (T2DM) monocytes is an important pathomechanism leading to restricted arteriogenesis and augmented atherosclerosis, hereby, accelerating CAD and PAD. Tyrosine phosphatase SHP-2 was found to be upregulated in T2DM-monocytes. This study aimed to identify the pathways regulating SHP-2 expression in T2DM-monocytes. Methods Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Monocytes were incubated with Methylglyoxal (MG), a highly reactive side product of glycolysis, Receptor for advanced glycation end product (RAGE) ligand AGE-bovine serum (AGE-BSA) or TNFα for 24 hours. Transwell migration assays were used to analyse the migratory potential of monocytes. Western Blot, RT-qPCR and FACS were performed to quantify the expression of relevant molecules. Pharmacological inhibitors were used to study functional relevance of the RAGE-NFκB-SHP-2 signalling axis. Results Significantly enhanced SHP-2 expression was detected in monocytes, which were incubated with TNFα, MG or AGE-BSA, respectively. Co-incubation of these molecules with NFκB-inhibitor blocked SHP-2 upregulation. Pharmacological inhibition of RAGE reversed the MG or AGE-BSA induced SHP-2 expression and activity in monocytes. RAGE expression on monocytes was upregulated after the incubation with MG or AGE-BSA, consistent with enhanced RAGE mRNA levels in T2DM monocytes. Besides, we also detected elevated SHP-2 transcripts in monocytes of T2DM patients which was more pronounced in monocytes with augmented TNFα expression. Furthermore, MG and AGE-BSA provoked the enhanced migration of monocytes which could be significantly reduced after the application of an allosteric SHP-2 inhibitor. Interestingly, pharmacological inhibition of RAGE in these conditions alone was sufficient to block the elevated monocyte migration. Moreover, monocytes isolated from T2DM patients revealed a comparable pro-migratory phenotype, which was completely restored after the pharmacological inhibition of SHP-2. Conclusions This study identified the upstream signalling mediators that contribute to SHP-2 dependent monocyte activation in T2DM conditions. Glucose metabolite (MG) or RAGE ligand (AGE-BSA) alone were sufficient to induce a pro-migratory phenotype in monocytes by upregulating SHP-2. Of note, an inflammatory state seems to accelerate this effect since enhanced TNFα levels were found to be positively correlated with the augmented SHP-2 expression. Moreover, we identified the RAGE-NFκB signalling axis through which the SHP-2 upregulation is conveyed when augmented accumulation of glucose metabolites occur. These findings reveal a basis for potential new therapeutic approaches to prevent accelerated CAD and PAD in diabetic patients since independent pharmacological inhibition of every step in the RAGE-NFκB-SHP-2 axis was sufficient to reset the aberrant monocyte activation. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Interdisciplinary Center for Clinical Research of the Medical Faculty of the University of Münster

Long-term melatonin treatment attenuates body weight gain with aging in female mice.

Women usually experience body weight gain with aging, which can put them at risk for many chronic diseases. Previous studies indicated that melatonin treatment attenuates body weight gain and abdominal fat deposition in several male animals. However, it is unclear whether melatonin affects female animals in the same way. This study investigated whether long-term melatonin treatment can attenuate body weight gain with aging and, if it does, what the mechanism is. Ten-week-old female ICR mice were given melatonin-containing water (100 μg/mL) or only water until 43 weeks. Melatonin treatment significantly attenuated body weight gain at 23 weeks (control; 57.2 ± 2.0 g vs melatonin; 44.4 ± 3.1 g), 33 weeks (control; 65.4 ± 2.6 g vs melatonin; 52.2 ± 4.2 g) and 43 weeks (control; 66.1 ± 3.2 g vs melatonin; 54.4 ± 2.5 g) without decreasing the amount of food intake. Micro-CT analyses showed that melatonin significantly decreased the deposition of visceral and s.c. fat. These results suggested that melatonin attenuates body weight gain by inhibiting abdominal fat deposition. Metabolome analysis of the liver revealed that melatonin treatment induced a drastic change in the metabolome with the downregulation of 149 metabolites, including the metabolites of glucose and amino acids. Citrate, which serves as a source of de novo lipogenesis, was one of the downregulated metabolites. These results show that long-term melatonin treatment induces drastic changes in metabolism and attenuates body weight gain and fat deposition with aging in female mice.

Late Breaking Abstracts

Late Breaking Abstracts

The Type 2 Diabetes Factor Methylglyoxal Mediates Axon Initial Segment Shortening and Alters Neuronal Function at the Cellular and Network Levels.

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or location along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. To determine the key type 2 diabetes-related factor that produces AIS shortening we modified levels of insulin, glucose, or the reactive glucose metabolite methylglyoxal in cultures of dissociated cortices from male and female mice and quantified AIS geometry using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification altered AIS length. Exposure to 100 but not 1 or 10 μm methylglyoxal for 24 h resulted in accumulation of the methylglyoxal-derived advanced glycation end-product hydroimidazolone and produced reversible AIS shortening without cell death. Methylglyoxal-evoked AIS shortening occurred in both excitatory and putative inhibitory neuron populations and in the presence of tetrodotoxin (TTX). In single-cell recordings resting membrane potential was depolarized at 0.5–3 h and returned to normal at 24 h. In multielectrode array (MEA) recordings methylglyoxal produced an immediate ∼300% increase in spiking and bursting rates that returned to normal within 2 min, followed by a ∼20% reduction of network activity at 0.5–3 h and restoration of activity to baseline levels at 24 h. AIS length was unchanged at 0.5–3 h despite the presence of depolarization and network activity reduction. Nevertheless, these results suggest that methylglyoxal could be a key mediator of AIS shortening and disruptor of neuronal function during type 2 diabetes.

Metabolomics profiling of valproic acid-induced symptoms resembling autism spectrum disorders using 1H NMR spectral analysis in rat model

ABSTRACT Prenatal exposure to valproic acid (VPA) has been implicated in the manifestation of autism spectrum disorder (ASD)-like behavioral and functional changes both in human and rodents including mice and rats. The objective of this study was to determine metabolomics profiling and biomarkers related to VPA-induced symptoms resembling ASD using proton nuclear magnetic resonance (1H-NMR) spectral data. VPA was administered to pregnant rats at gestation day 12.5 and effects measured subsequently in male 4-week-old offspring pups. The sociability of VPA-treated animals was significantly diminished and exhibited ASD-like behavior as evidenced by reduction of social adaptation disorder and lack of social interactions. To find biomarkers related to ASD, the following were collected prefrontal brain cortices, urine bladder and blood samples directly from heart puncture. In all samples, principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) displayed significant clustering pattern differences between control and treated groups. Valine, taurine, myo-inositol, 3-hydroxybutyrate and 1,3-dihydroxyacetone were significantly decreased in brain cortices in treated rats. Serum metabolites of glucose, creatine phosphate, lactate, glutamine and threonine were significantly increased in VPA-administered animals. Urinary metabolites of pimelate, 3-hydroxyisovalerate and valerate were significantly reduced in VPA-treated rat, whereas galactose and galactonate levels were elevated. Various metabolites were associated with mitochondrial dysfunction metabolism and central nervous system disorders. Data demonstrated that VPA-induced alterations in endogenous metabolites of serum, urine, and brain cortex which might prove useful as biomarkers for symptoms resembling ASD as a model of this disorder.

Research progress on the roles and mechanisms underlying metabolic molecules involved in nutrition therapy and immune regulation in sepsis

The pathology of sepsis is extremely complex. Pathogen invasion, inflammatory factors secretion, coagulation disorder and microcirculation disturbance lead to metabolic disorder and organ dysfunction. In recent years, immunometabolism has aroused continuous attention in aspect of nutrition therapy and immune intervention for sepsis. Nutrition metabolites include amino acids, fatty acids, and glucose metabolites, which are not only the nutritional ingredients, but also the regulators of innate immune and adaptive immune. Fatty acids and glucose metabolites are involved in regulation of immune response mainly via free fatty acid receptors and AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. Here, we summarized the research progress on the roles of nutrition metabolites in nutrition therapy and immune regulation during sepsis, which could provide a new direction for the development of metabolic therapy for sepsis.

Increased glycolysis in skeletal muscle coordinates with adipose tissue in systemic metabolic homeostasis.

Insulin‐independent glucose metabolism, including anaerobic glycolysis that is promoted in resistance training, plays critical roles in glucose disposal and systemic metabolic regulation. However, the underlying mechanisms are not completely understood. In this study, through genetically manipulating the glycolytic process by overexpressing human glucose transporter 1 (GLUT1), hexokinase 2 (HK2) and 6‐phosphofructo‐2‐kinase‐fructose‐2,6‐biphosphatase 3 (PFKFB3) in mouse skeletal muscle, we examined the impact of enhanced glycolysis in metabolic homeostasis. Enhanced glycolysis in skeletal muscle promoted accelerated glucose disposal, a lean phenotype and a high metabolic rate in mice despite attenuated lipid metabolism in muscle, even under High‐Fat diet (HFD). Further study revealed that the glucose metabolite sensor carbohydrate‐response element‐binding protein (ChREBP) was activated in the highly glycolytic muscle and stimulated the elevation of plasma fibroblast growth factor 21 (FGF21), possibly mediating enhanced lipid oxidation in adipose tissue and contributing to a systemic effect. PFKFB3 was critically involved in promoting the glucose‐sensing mechanism in myocytes. Thus, a high level of glycolysis in skeletal muscle may be intrinsically coupled to distal lipid metabolism through intracellular glucose sensing. This study provides novel insights for the benefit of resistance training and for manipulating insulin‐independent glucose metabolism.

Repeated hypoxia exposure induces cognitive dysfunction, brain inflammation, and amyloidβ/p-Tau accumulation through reduced brain O-GlcNAcylation in zebrafish

Repetitive hypoxia (RH) exposure affects the initiation and progression of cognitive dysfunction, but little is known about the mechanisms of hypoxic brain damage. In this study, we show that sublethal RH increased anxiety, impaired learning and memory (L/M), and triggered downregulation of brain levels of glucose and several glucose metabolites in zebrafish, and that supplementation of glucose or glucosamine (GlcN) restored RH-induced L/M impairment. Fear conditioning (FC)-induced brain activation of and PKA/CREB signaling was abrogated by RH, and this effect was reversed by GlcN supplementation. RH was associated with decreased brain O-GlcNAcylation and an increased O-GlcNAcase (OGA) level. RH increased brain inflammation and p-Tau and amyloid β accumulation, and these effects were suppressed by GlcN. Our observations collectively suggest that changes in O-GlcNAc flux during hypoxic exposure could be an important causal factor for neurodegeneration, and that supplementation of the HBP/O-GlcNAc flux may be a potential novel therapeutic or preventive target for addressing hypoxic brain damage.

Daily Inclusion of Potatoes Into a Dietary Guidelines for Americans-Based Dietary Pattern Does Not Adversely Impact Cardiometabolic Risk in Adults With Metabolic Syndrome

Abstract Objectives Observational studies suggest that the regular ingestion of potatoes adversely affects cardiometabolic health, but controlled studies in humans are needed to establish causality. Our objective was to assess whether daily inclusion of non-fried potato foods as part of a Dietary Guidelines for Americans (DGA)-based dietary pattern would impair cardiometabolic health in adults with metabolic syndrome (MetS). Methods In a 2-arm, randomized controlled, crossover trial separated by a 2-wk washout period, MetS adults were provided a eucaloric DGA-based dietary pattern containing potato (350 g with 17.5 g/d resistant starch; POTATO) or an energy-matched bagel (0 g/d resistant starch; CON) for 14 d. Fasting blood was collected on d 0 and 14. On d 14, after a 75 g oral glucose tolerance test, brachial artery flow-mediated dilation (FMD) was measured and blood was collected at 30 min intervals for 2 h to assess vascular endothelial function and metabolic excursions, respectively. Circulating endotoxin, glucose, insulin, and nitric oxide metabolites (NOx) were assessed by spectrophotometry, and malondialdehyde (MDA) and arginine and its metabolites by HPLC. Data were analyzed using two-way repeated measures ANOVA. Results MetS adults (n = 27; 32.5 ± 1.3 y; 35.0 ± 1.0 kg/m2) completed the study with no adverse effects or significant changes in body weight. The 14-d DGA-based dietary pattern had a small but significant effect to decrease glucose (107 ± 1.9 vs. 102 ± 1.7 mg/dL; P = 0.04) and insulin (19 ± 2.9 vs. 14 ± 1.5 μIU/mL; P = 0.03), but these were unaffected by POTATO. Fasting endotoxin, NOx, and MDA and FMD were also unaffected by POTATO compared to CON, as were postprandial AUC0–2h of FMD, insulin, glucose, arginine, MDA, endotoxin, and NOx. Conclusions Findings of this acute controlled trial, which require long-term validation, support that a DGA-based dietary pattern may help to improve insulin resistance and that potatoes can be effectively incorporated into the diet without compromising vascular endothelial function or cardiometabolic health in persons with MetS. Funding Sources Alliance for Potato Research and Education.