Glucose Metabolism In Response Research Articles

The Role of AUF1 in Cytosolic DNA Induced Cellular Glucose Metabolic Response

The Role of AUF1 in Cytosolic DNA Induced Cellular Glucose Metabolic Response

Molecular Nexus between Insulin-like peptides and Downstream Kinases Regulate Glucose Homeostasis, Cell Survival and Growth in Drosophila

Drosophila is a versatile model organism to study metabolic disorders, one such being diabetes mellitus. Eight insulin-like peptides (ILPs) have been identified in Drosophila . ILPs are produced from paired Insulin-producing cells present in brain ganglia. Another protein called adipokinetic hormone (AKH) is homologous to mammalian glucagon and is released from the corpora cardiaca. Synergistic action of ILP and AKH maintains sugar homeostasis in Drosophila . ILP binds with insulin receptors on the adipocytes and trigger autophosphorylation and dimerization. The activated receptors then initiate a downstream signaling by various modulators to phosphorylate Akt (protein kinase B, a serine-threonine-specific protein kinase). Akt, when activated, targets multiple signaling molecules including Target of Rapamycin (TOR) that participates in glucose metabolism, protein synthesis, cell proliferation, neuroendocrine signaling, and stress response. Akt also phosphorylates transcription factor FOXO that promotes cell survival by up-regulating TRAIL, a pro-apoptotic protein. High lipid accumulation in the fat body is linked with insulin resistance in Drosophila . Drosophila reared on high lipid diet shows up-regulation in protein kinase C (PKC). PKC is known to antagonize insulin signaling in fruit flies. A clear concept regarding the complex process of glucose homeostasis can be generated through further investigations. Since Drosophila has several advantages over vertebrate models, it can be used to identify additional modulators of insulin biology and metabolism.

Effects of a multispecies synbiotic on glucose metabolism, lipid marker, gut microbiome composition, gut permeability, and quality of life in diabesity: a randomized, double-blind, placebo-controlled pilot study

PurposeDiabesity, the combination of obesity and type 2 diabetes, is an ever-growing global health burden. Diabesity-associated dysbiosis of the intestinal microbiome has gained attention as a potential driver of disease and, therefore, a possible therapeutic target by means of pro- or prebiotic supplementation. This study tested the effects of a multispecies synbiotic (i.e. a combination of probiotics and prebiotics) on glucose metabolism, gut microbiota, gut permeability, neutrophil function and quality of life in treatment-experienced diabesity patients.MethodsA randomized, double-blind, placebo-controlled pilot study with 26 diabesity patients was conducted in which patients received a daily dose of a multispecies probiotic and a prebiotic (or a placebo) for 6 months.ResultsThere were no changes in glucose metabolism or mixed meal tolerance test responses throughout the study. The analysis of secondary outcomes revealed beneficial effects on hip circumference [− 1 (95% CI − 4; 3) vs +3 (− 1; 8) cm, synbiotics vs. placebo, respectively, p = 0.04], serum zonulin [− 0.04 (− 0.2; 0.1) vs +0.3 (− 0.05; 0.6) ng/ml, p = 0.004)] and the physical role item of the SF36 quality of life assessment [+ 5.4 (− 1.7; 12.5) vs − 5.0 (− 10.1; 0.2) points, p = 0.02] after 3 months of intervention, and lipoprotein (a) [− 2.1 (− 5.7; 1.6) vs +3.4 (− 0.9; 7.9) mg/dl, p = 0.02] after 6 months. There were no significant differences in alpha or beta diversity of the microbiome between groups or time points.ConclusionsGlucose metabolism as the primary outcome was unchanged during the intervention with a multispecies synbiotic in patients with diabesity. Nevertheless, synbiotics improved some symptoms and biomarkers of type 2 diabetes and aspects of quality of life suggesting a potential role as adjuvant tool in the management of diabesity.Graphic abstract

β-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship to OGTT-time-to-glucose-peak.

In adults, the time-to-glucose-peak at or after 30 minutes during an oral glucose tolerance test (OGTT) identifies physiologically distinct groups with differences in insulin sensitivity, β-cell function and risk for type 2 diabetes. In obese non-diabetic adolescents, we investigated if the OGTT-time-to-glucose-peak also reflects incretin and free fatty acid (FFA) responses besides insulin sensitivity and β-cell function, measured by the clamp. Obese adolescents (n = 278) were categorized according to their OGTT-time-to-glucose-peak by Early-peak (at 30 minutes) vs Late-peak (>30 minutes) groups. Body composition, visceral adipose tissue, oral disposition index and OGTT-area under the curve (AUC) were examined. A subset of 102 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and β-cell function relative to insulin sensitivity. Compared with the Early-peak group, the Late-peak group had impaired β-cell function relative to insulin sensitivity, lower glucose-dependent insulinotropic polypeptide-AUC, and higher FFA-AUC despite higher insulin- and C-peptide-AUC. They also had lower hepatic and peripheral insulin sensitivity despite similar percent body fat and visceral adipose tissue, and had higher prevalence of impaired glucose tolerance (all P < .05). In obese non-diabetic youth, those with a Late-peak vs an Early-peak glucose during an OGTT showed diminished β-cell function, blunted incretin secretion, and lower insulin sensitivity of glucose and FFA metabolism. It remains to be determined if Late-peak glucose predicts the future development of type 2 diabetes in these high-risk youth.

Contribution of Non-canonical Cortisol Actions in the Early Modulation of Glucose Metabolism of Gilthead Sea Bream (Sparus aurata).

Teleost fish are exposed to diverse stressors in farming and wildlife conditions during their lifespan. Cortisol is the main glucocorticoid hormone involved in the regulation of their metabolic acclimation under physiological stressful conditions. In this context, increased plasma cortisol is associated with energy substrate mobilization from metabolic tissues, such as liver and skeletal muscle, to rapidly obtain energy and cope with stress. The metabolic actions of cortisol have primarily been attributed to its genomic/classic action mechanism involving the interaction with intracellular receptors, and regulation of stress-responsive genes. However, cortisol can also interact with membrane components to activate rapid signaling pathways. In this work, using the teleost fish gilthead sea bream (Sparus aurata) as a model, we evaluated the effects of membrane-initiated cortisol actions on the early modulation of glucose metabolism. For this purpose, S. aurata juveniles were intraperitoneally administrated with cortisol and with its membrane impermeable analog, cortisol-BSA. After 1 and 6 h of each treatment, plasma cortisol levels were measured, together with glucose, glycogen and lactate in plasma, liver and skeletal muscle. Transcript levels of corticosteroids receptors (gr1, gr2, and mr) and key gluconeogenesis (g6pc and pepck)- and glycolysis (pgam1 and aldo) related genes in the liver were also measured. Cortisol and cortisol-BSA administration increased plasma cortisol levels in S. aurata 1 h after administration. Plasma glucose levels enhanced 6 h after each treatment. Hepatic glycogen content decreased in the liver at 1 h of both cortisol and cortisol-BSA administration, while increased at 6 h due to cortisol but not in response to cortisol-BSA. Expression of gr1, g6pc, pgam1, and aldo were preferentially increased by cortisol-BSA in the liver. Taking all these results in consideration, we suggest that non-canonical cortisol mechanisms contribute to the regulation of the early glucose metabolism responses to stress in S. aurata.

Cytokines and Abnormal Glucose and Lipid Metabolism.

Clear evidence indicates that cytokines, for instance, adipokines, hepatokines, inflammatory cytokines, myokines, and osteokines, contribute substantially to the development of abnormal glucose and lipid metabolism. Some cytokines play a positive role in metabolism action, while others have a negative metabolic role linking to the induction of metabolic dysfunction. The mechanisms involved are not fully understood, but are associated with lipid accumulation in organs and tissues, especially in the adipose and liver tissue, changes in energy metabolism, and inflammatory signals derived from various cell types, including immune cells. In this review, we describe the roles of certain cytokines in the regulation of metabolism and inter-organ signaling in regard to the pathophysiological aspects. Given the disease-related changes in circulating levels of relevant cytokines, these factors may serve as biomarkers for the early detection of metabolic disorders. Moreover, based on preclinical studies, certain cytokines that can induce improvements in glucose and lipid metabolism and immune response may emerge as novel targets of broader and more efficacious treatments and prevention of metabolic disease.

Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain: PPARγ Agonists as a Promising Tool.

Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer agents, such as platinum- and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and paclitaxel). CINP may even be a factor of interruption of treatment and consequently increasing the risk of death. Besides that, it is important to take into consideration that the incidence of cancer is increasing worldwide, including colorectal, gastric, lung, cervical, ovary and breast cancers, all treated with the aforementioned drugs, justifying the concern of the medical community about the patient’s quality of life. Several physiopathological mechanisms have already been described for CINP, such as changes in axonal transport, mitochondrial damage, increased ion channel activity and inflammation in the central nervous system (CNS). Another less frequent event that may occur after chemotherapy, particularly under oxaliplatin treatment, is the central neurotoxicity leading to disorders such as mental confusion, catatonia, hyporeflexia, etc. To date, no pharmacological therapy has shown satisfactory effect in these cases. In this scenario, duloxetine is the only drug currently in clinical use. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors and are present in several tissues, mainly participating in lipid and glucose metabolism and inflammatory response. There are three PPAR isoforms: α, β/δ and γ. PPARγ, the protagonist of this review, is expressed in adipose tissue, large intestine, spleen and neutrophils. This subtype also plays important role in energy balance, lipid biosynthesis and adipogenesis. The effects of PPARγ agonists, known for their positive activity on type II diabetes mellitus, have been explored and present promising effects in the control of neuropathic pain, including CINP, and also cancer. This review focuses largely on the mechanisms involved in chemotherapy-induced neuropathy and the effects of the activation of PPARγ to treat CINP. It is the aim of this review to help understanding and developing novel CINP therapeutic strategies integrating PPARγ signalling.

High-dose Glycerol Monolaurate Up-Regulated Beneficial Indigenous Microbiota without Inducing Metabolic Dysfunction and Systemic Inflammation: New Insights into Its Antimicrobial Potential.

Glycerol monolaurate (GML) has potent antimicrobial and anti-inflammatory activities. The present study aimed to assess the dose-dependent antimicrobial-effects of GML on the gut microbiota, glucose and lipid metabolism and inflammatory response in C57BL/6 mice. Mice were fed on diets supplemented with GML at dose of 400, 800 and 1600 mg kg−1 for 4 months, respectively. Results showed that supplementation of GML, regardless of the dosages, induced modest body weight gain without affecting epididymal/brown fat pad, lipid profiles and glycemic markers. A high dose of GML (1600 mg kg−1) showed positive impacts on the anti-inflammatory TGF-β1 and IL-22. GML modulated the indigenous microbiota in a dose-dependent manner. It was found that 400 and 800 mg kg−1 GML improved the richness of Barnesiella, whereas a high dosage of GML (1600 mg kg−1) significantly increased the relative abundances of Clostridium XIVa, Oscillibacter and Parasutterella. The present work indicated that GML could upregulate the favorable microbial taxa without inducing systemic inflammation and dysfunction of glucose and lipid metabolism.

Effect of Laparoscopic Sleeve Gastrectomy on Static and Dynamic Measures of Glucose Homeostasis and Incretin Hormone Response 4-Years Post-Operatively

IntroductionThere is limited literature available on the long-term effect of bariatric surgery especially laparoscopic sleeve gastrectomy (LSG) on the incretin hormone response.AimOur primary aim was to investigate changes in glucose metabolism and incretin hormone responses in participants with impaired glucose regulation approximately 4 years after LSG. The secondary aim was to examine the long-term incretin hormone changes of biliopancreatic diversion (BPD).MethodA non-randomised prospective study comprising of 10 participants undergoing LSG and 6 participants undergoing BPD. Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were performed during an oral glucose tolerance test pre-operatively and 1 month, 6 months and at approximately 4–7 years post-operatively. Area under the curve (AUC) was examined at 60 and 120 min.ResultsIn the LSG group, a significant reduction in 2-h plasma glucose (2 h PG), HbA1c and HOMA-IR was observed at 4 years. Compared with pre-operative levels, significant increases in post-glucose GLP-1 secretion were observed at 1 and 6 months, but not maintained at 4 years. A linear increase was seen in post-glucose GIP response at 1 month and 6 months and 4 years. Within the BPD group, a reduction in HbA1c along with an increase GLP-1 response was observed at 7 years.ConclusionAn increase in GLP-1 response was not preserved at 4 years, but a significant increase in GIP response was observed along with improved glycaemic control following LSG.

Mapping genome-wide binding sites of endosperm specific expression transcription factor O2 using DAP-Seq

<p indent=0mm>Opaque2 (O2) is an important transcription factor regulating maize endosperm development, and mutation of the wild type O2 gene reduces the amount of zein and increases the lysine contents, thereby, leading to development of opaque and starchy endoplasm commonly referred to as <italic>o</italic>2 mutant. The opaque and starchy nature of the <italic>o</italic>2 mutant endosperm renders the kernels resistance to pests, diseases and mechanical damage caused during transportation besides having high nutritional quality. O2 regulates the genes involved in various biological functions or processes, including the synthesis and metabolism of proteins, carbohydrates and lipids. Previous studies have identified O2 target genes regulating different biological functions. However, the detailed information about the genome-wide analysis of O2 targets genes is insufficient and needs further investigation. Taking advantage of DNA affinity purification sequencing (DAP-Seq) over Chromatin Immunoprecipitation sequencing (ChIP-Seq) being a high throughput and easy approach to capturing whole genome transcription factor and DNA interaction profile, the gene regulatory network of O2 was investigated by coupling with mRNA abundance analyses. Using DAP-Seq, we detected a total of 11385 O2 binding sites throughout the genome. Genome-wide comparison of O2 TF showed that DAP-Seq peaks captured significant fractions of ChIP-Seq peaks (35.9%−50.54%), indicating the potential of DAP-seq to preferentially captures <italic>in vitro</italic> transcription factor binding sites. By integrating previously RNA-Seq analysis of wild type (B73) vs <italic>o</italic>2 mutant endosperm, we identified 317 directly bound target genes of O2 in this study, correlated with 97 target genes detected by ChIP-Seq and 220 additional target genes specifically detected by DAP-Seq. Among the direct target genes detected by DAP-Seq, 260 target genes were directly bound and activated by O2, including 20 zein gene, <italic>cyPPDK1/2</italic>, <italic>NF-YB16</italic> and <italic>ZmNAC111</italic>; and another 57 target genes were directly bound and repressed by O2, such as <italic>bt2</italic>, <italic>GAPDH</italic>, <italic>Orphan 154 </italic>etc. To further gain a comprehensive insight into the functions of the O2-regulated gene network, we performed Gene Ontology (GO) terms significantly enriched among O2 direct target genes using agriGO tool. The results indicated that O2 mainly regulates genes involved in endosperm storage product synthesis and accumulation, directly activates genes encoding storage proteins and enzymes involved in amino acid biosynthesis or metabolism in maize endosperm. Moreover, O2 also regulated genes involved in carbon partitioning between carbohydrates and proteins in maize endosperm. However, 220 O2 binding target gene specifically detected by DAP-Seq were also mainly involved in the glucose metabolism pathway and response to various stresses. To identify cis-regulatory sequences mediating O2 binding, we performed a de novo motif discovery on the O2 binding sites detected by DAP-Seq, using the MEME-ChIP program. We found that the most significant motif containing “CCACGTCA” sequence, the reported O2 cis motif, was enriched in the 400 bp region centered at the summits of peaks for 317 direct O2 target genes. In addition, the common cis-motif also enriched within 400 bp region centered at the summits of peaks for 220 specific binding target genes. The motif was shown to be centrally enriched in the analyzed genomic regions. Taken together, our results provide insight into the complexity of the O2 regulatory network, which validate and supplement the previous research findings.

1980-P: A Characterization of Postprandial Glucose Metabolism and Incretin Hormone Responses in Patients with Bile Acid Malabsorption

Bile acid malabsorption (BAM) is characterized by an excessive spill-over of bile acids to the colon leading to bile acid-induced diarrhea; the condition is usually treated with bile acid sequestrants. Bile acids have been demonstrated to modulate the secretion of the incretin hormone glucagon-like peptide 1 (GLP-1) and the aim of this study was to characterize postprandial glucose metabolism and incretin hormone responses in patients with BAM. Twelve patients with BAM (6 women; mean age 39.1 (SD 13.2); mean BMI 28.4 kg/m2 (SD 1.2); HbA1c 31.4 (SD 3.7)) and 12 healthy gender, age, BMI and HbA1c-matched controls (6 women; mean age 39.3 (SD 15.6); mean BMI 29,1 kg/m2 (SD 1.1); HbA1c 31.0 (SD 2.8)) were subjected to two 4-hour standardized liquid meal tests with double-blinded single-dose administration of the bile acid sequestrant colesevelam (3.75 g) and placebo, respectively, performed on separate days, and in randomized order. Fasting and postprandial plasma GIP and GLP-1 concentrations were comparable among patients with BAM and control subjects and unaffected by colesevelam administration. Peak plasma glucose concentrations were higher in BAM patients vs. control subjects, but area under curve for plasma glucose did not differ between the two groups. Patients with BAM exhibited significantly higher postprandial serum C-peptide concentrations and hyperglucagonemia compared to controls. Single-dose colesevelam had no effect on postprandial glucose or glucagon excursions in any of the groups but decreased the postprandial C-peptide response in BAM patients. Patients with BAM are characterized by elevated serum C-peptide concentrations and hyperglucagonemia whereas postprandial glucose tolerance and GLP-1 and GIP responses are similar to healthy controls. Disclosure M.L. Kårhus: None. D.P. Sonne: None. M.L. Thomasen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. A. Brønden: Other Relationship; Self; AstraZeneca. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding Novo Nordisk Foundation

Comparative analysis of glucose metabolism responses of large yellow croaker Larimichthys crocea fed diet with fish oil and palm oil.

In order to study the effects of dietary fatty acid compositions on glucose metabolism, large yellow croaker juveniles Larimichthys crocea (initial weight, 36.80 ± 0.39g) were fed with two experiment diets for 12weeks. The two diets contained 6.5% of fish oil (FO) and palm oil (PO), respectively. Results showed that the contents of saturated fatty acids in liver and muscle, levels of glucose, triglyceride (TG), non-esterified fatty acid (NEFA), and leptin in blood were significantly higher in PO group, while the hepatic glycogen and muscle glycogen significantly decreased (P <0.05). There were no significant differences in blood insulin and adiponectin levels between the two groups (P >0.05). Compared with the FO group, the expressions of glucokinase (GK), glucose-6-phosphate dehydrogenase, glycogen synthase (GYS), glucose transporter 2 (GLUT2), insulin receptor 1 (IR1), insulin receptor substrate 1 (IRS1), insulin receptor substrate (IRS2), and protein kinase B (AKT2) were significantly decreased, and the expressions of phosphoenolpyruvate carboxykinase (PEPCK) in liver were significantly increased in the PO group. Meanwhile, the expressions of GK, phosphofructokinase, GYS, GLUT4, and insulin receptor 2 (IR2) were significantly reduced, and the expressions PEPCK, fructose-1 and 6-diphosphatase in muscle were significantly increased in the PO group. In conclusion, palm oil in diet could inhibit the utilization of glucose and promote the endogenous glucose production in large yellow croaker by reducing the sensitivity of insulin, so as to increase the blood glucose level.

Hepatic gene expression in mouse models of non-alcoholic fatty liver disease after acute exercise.

Non-alcoholic fatty liver disease (NAFLD) patients benefit from physical exercise. This study aimed to investigate the effect of acute exercise on hepatic gene expression in different mouse models of NAFLD. C57BL/6J mice were fed with a control (CD) or a high fat (HFD) diet. AlbCrePtenflox/flox (Pten-KO) and Fxr-/- mice, two genetic models of NAFLD with insulin hypersensitivity and resistance, respectively, were fed with CD. After 4weeks, mice were randomly assigned to exercise or sedentariness. Mice were killed 15min or 3h after the running/sedentary period. Genome-wide hepatic gene expression was evaluated with the Illumina Micro-array platform. Quantitative polymerase chain reaction confirmed changes in gene expression. Acute exercise transiently affected the expression of genes involved in the immune response in C57BL/6 mice fed with CD and this effect normalized in the recovery phase. Acute exercise affected genes involved in gluconeogenesis in the insulin resistant Fxr-/- model. Genes involved in lipid metabolism were affected in C57BL/6 mice fed with CD, but not in mouse models of NAFLD. Genes involved in DNA damage response pathways were deregulated only in C57BL/6 mice fed with CD and not in mouse models of NAFLD. The simultaneous analysis of different NAFLD models revealed that an acute exercise bout affects hepatic gene expression differentially according to animal models and that most of the differentially expressed genes are involved in glucose and fatty acid metabolism, immune regulation, and DNA damage response.

Lipopolysaccharide (LPS) Aggravates High Glucose- and Hypoxia/Reoxygenation-Induced Injury through Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis in H9C2 Cardiomyocytes.

Diabetes aggravates myocardial ischemia-reperfusion (I/R) injury because of the combination effects of changes in glucose and lipid energy metabolism, oxidative stress, and systemic inflammatory response. Studies have indicated that myocardial I/R may coincide and interact with sepsis and inflammation. However, the role of LPS in hypoxia/reoxygenation (H/R) injury in cardiomyocytes under high glucose conditions is still unclear. Our objective was to examine whether lipopolysaccharide (LPS) could aggravate high glucose- (HG-) and hypoxia/reoxygenation- (H/R-) induced injury by upregulating ROS production to activate NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. H9C2 cardiomyocytes were exposed to HG (30 mM) condition with or without LPS, along with caspase-1 inhibitor (Ac-YVAD-CMK), inflammasome inhibitor (BAY11-7082), ROS scavenger N-acetylcysteine (NAC), or not for 24 h, then subjected to 4 h of hypoxia followed by 2 h of reoxygenation (H/R). The cell viability, lactate dehydrogenase (LDH) release, caspase-1 activity, and intracellular ROS production were detected by using assay kits. The incidence of pyroptosis was detected by calcein-AM/propidium iodide (PI) double staining kit. The concentrations of IL-1β and IL-18 in the supernatants were assessed by ELISA. The mRNA levels of NLRP3, ASC, and caspase-1 were detected by qRT-PCR. The protein levels of NF-κB p65, NLRP3, ASC, cleaved caspase-1 (p10), IL-1β, and IL-18 were detected by western blot. The results indicated that pretreatment LPS with 1 μg/ml not 0.1 μg/ml could efficiently aggravate HG and H/R injury by activating NLRP3 inflammasome to mediate pyroptosis in H9C2 cells, as evidenced by increased LDH release and decreased cell viability in the cells, and increased expression of NLRP3, ASC, cleaved caspase-1 (p10), IL-1β, and IL-18. Meanwhile, Ac-YVAD-CMK, BAY11-7082, or NAC attenuated HG- and H/R-induced H9C2 cell injury with LPS stimulated by reversing the activation of NLRP3 inflammasome-mediated pyroptosis. In conclusion, LPS could increase the sensitivity of H9C2 cells to HG and H/R and aggravated HG- and H/R-induced H9C2 cell injury by promoting ROS production to induce NLRP3 inflammasome-mediated pyroptosis.

Thiamine leads to oxidative stress resistance via regulation of the glucose metabolism

Thiamine diphosphate (ThDP) is an essential cofactor for important enzymes in carbohydrate, amino acid and lipid metabolisms. It is also known that thiamine plays an important role in stress response of some organisms. In this study, we focused on the effect of thiamine on stress responses triggered by various stress agents. For this purpose, firstly, viability of Schizosaccharomyces pombe cell cultures was examined under oxidative, osmotic and heat stresses. The highest tolerance observed in cell viability due to the presence of extracellular thiamine (1.5 µM) was found only against oxidative stress. Then, enzyme activity of catalase and superoxide dismutase (SOD) involved in antioxidant defense mechanism and the expression analysis of genes encoding enzymes related to glucose metabolism and stress response pathways were investigated under oxidative stress. In this condition, it was not observed any difference in SOD and catalase activities, and their gene expressions due to the presence of thiamine, whereas the upregulation of pyruvate dehydrogenase (pdb1), transketolase (SPBC2G5.05), fructose-1,6-bis-phosphatase (fbp1) and the downregulation of pyruvate decarboxylase (pdc201) were observed. In conclusion, these findings suggest that extracellular thiamine leading to oxidative stress resistance have an impact on the regulation of glucose metabolism by shifting the energy generation from fermentation to respiration.

Supplementation with cod protein hydrolysate in older adults: a dose range cross-over study

A large proportion of older adults are affected by impaired glucose metabolism. Previous studies with fish protein have reported improved glucose regulation in healthy adults, but the evidence in older adults is limited. Therefore, we wanted to assess the effect of increasing doses of a cod protein hydrolysate (CPH) on postprandial glucose metabolism in older adults. The study was a double-blind cross-over trial. Participants received four different doses (10, 20, 30 or 40 mg/kg body weight (BW)) of CPH daily for 1 week with 1-week washout periods in between. The primary outcome was postprandial response in glucose metabolism, measured by samples of serum glucose and insulin in 20 min intervals for 120 min. The secondary outcome was postprandial response in plasma glucagon-like peptide 1 (GLP-1). Thirty-one subjects aged 60-78 years were included in the study. In a mixed-model statistical analysis, no differences in estimated maximum value of glucose, insulin or GLP-1 were observed when comparing the lowest dose of CPH (10 mg/kg BW) with the higher doses (20, 30 or 40 mg/kg BW). The estimated maximum value of glucose was on average 0·28 mmol/l lower when the participants were given 40 mg/kg BW CPH compared with 10 mg/kg BW (P = 0·13). The estimated maximum value of insulin was on average 5·14 mIU/l lower with 40 mg/kg BW of CPH compared with 10 mg/kg BW (P = 0·20). Our findings suggest that serum glucose and insulin levels tend to decrease with increasing amounts of CPH. Due to preliminary findings, the results require further investigation.

Brain proteomics links oxidative stress with metabolic and cellular stress response proteins in behavioural alteration of Alzheimer's disease model rats.

Alzheimer's disease (AD) impairs memory and learning related behavioural performances of the affected person. Compared with the controls, memory and learning related behavioural performances of the AD model rats followed by hippocampal proteomics had been observed in the present study. In the eight armed radial maze, altered performance of the AD rats had been observed. Using liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), 822 proteins had been identified with protein threshold at 95.0%, minimum peptide of 2 and peptide threshold at 0.1% FDR. Among them, 329 proteins were differentially expressed with statistical significance (P < 0.05). Among the significantly regulated (P < 0.05) 329 proteins, 289 met the criteria of fold change (LogFC of 1.5) cut off value. Number of proteins linked with AD, oxidative stress (OS) and hypercholesterolemia was 59, 20 and 12, respectively. Number of commonly expressed proteins was 361. The highest amount of proteins differentially expressed in the AD rats were those involved in metabolic processes followed by those linked with OS. Most notable was the perturbed state of the cholesterol metabolizing proteins in the AD group. Current findings suggest that proteins associated with oxidative stress, glucose and cholesterol metabolism and cellular stress response are among the mostly affected proteins in AD subjects. Thus, novel therapeutic approaches targeting these proteins could be strategized to withstand the ever increasing global AD burden.

Glucose and lipid metabolic adaptations during postprandial starvation of Japanese flounder Paralichthys olivaceus previously fed different levels of dietary carbohydrates

Exogenous glucose loading is generally used to assess the capacity of glucose utilization in carnivorous fish. Examining the use of endogenous glucose during fasting provides a new perspective on assessing glucose metabolism in fish. Japanese flounder Paralichthys olivaceus, a marine carnivorous fish species, were starved for 3, 9, 24, 48 h, and 3, 7, 14, 21, 28 days, respectively, after a 10-week feeding trial with 12% (C12: 49.49% crude protein, 9.65% crude lipid and gross energy of 18.98 kJ g−1) and 20% (C20: 49.99% crude protein, 9.75% crude lipid and gross energy of 19.11 kJ g−1) of dietary carbohydrates (alpha-starch and corn starch). After feeding trial, fish fed different diets showed similar specific growth rate (3.62 vs 3.61) (P > .05). During starvation period, compared with 3 h, plasma glucose and insulin concentration increased at 9 h in both groups. A similar trend was found for the glycogen content and the mRNA levels of genes involved in glycolysis and pentose phosphate pathway in liver. And the gluconeogenic genes mRNA levels significantly increased since 9 h in C12 and 24 h in C20 (P < .05). Subsequently, liver glycogen in C12 fell significantly on the 3 d compared with 48 h and was depleted on the 7 d (P < .05). It significantly decreased on the 7 d compared with 3 d and was minimized on the 14 d in C20 (P < .05). Plasma glucose peaked at 48 h and 7 d in both groups. As for lipid metabolism, high levels of plasma triglyceride, cholesterol concentration and lipogenetic genes mRNA levels were observed within 9 h. Compared with 3 h, liver lipid significantly decreased on the 14 d in both groups (P < .05). The mRNA levels of genes related to beta-oxidation and ketogenesis was enhanced in later stages in both groups. In addition, in C20, greater changes of mRNA levels of genes involved in gluconeogenesis and lipolysis in liver were observed. It was concluded that primary substrate of energy sources switched from glycogen to lipid occurring on the 3 d-7 d in C12 and 7 d-14 d in C20. Besides, high dietary carbohydrate (C20) feeding activated greater gluconeogenesis and lipolysis during starvation. These observations demonstrated glucose and lipid metabolic responses of Japanese flounder during starvation were influenced by previous feeding with different levels of dietary carbohydrates.

P3.03-15 Lung Cancer Regulation of Glucose Metabolic Stress Response

Cancer cells have altered metabolism in order to accommodate for the increased metabolic needs required for oncogenic transformation, proliferation, development and survival. The metabolic profile observed in cancer cells often includes increased consumption of glucose and glutamine, increased glycolysis, changes in the use of metabolic enzyme isoforms, and increased secretion of lactate. In order to better understand this hallmark of cancer, we studied the regulation of pathways by microRNAs (miRNA) expression profile under normal or deprived glucose condition in different lung cancer cell lines. Two different NSCLC adenocarcinoma cell lines were tested in the study, A549, which is highly glycolytic (HG) and H358, which is low glycolytic (LG). Sequencing was performed using Illumina TruSeq RNA library preparation kit v2 with Illumina HiSeq 2500 sequencer using single-end 50bp protocol. Cell were analysed in two different conditions, under 24h of normal glucose concentration and under 24h glucose starvation. Samples were prepared in duplicates from the initial step of cell culturing summarizing to a total of eight samples. Differential expression analysis was performed using EdgeR algorithm with an adjusted p-value >0.05 and a log2 fold > 1.5. An opposite regulation profile was observed for miRNA of cells that are highly glycolytic (HG), A549, in comparison with low glycolytic, H358 cells. The formers presented 42 downregulated miRNAs from which 39 miRNAs were unique. Only 2 upregulated miRNAs, miR324 and miR616, were found significant in this cohort but they are also upregulated in the latter group. In comparison, from the 20 upregulated miRNAs found in high-glycolygic group from which 18 were unique to lower glycolytic cell line. Lower glycolytic cell lines show 4 downregulated miRNAs from which only one miRNA, miR205 was significantly uniquely downregulated, moreover, MIR205HG, which is miR205 host gene, is also found significantly downregulated, suggesting the strong involvement of miR205 in glucose metabolic stress response. Under glucose metabolic stress, miR205 and MIR205HG are uniquely downregulated in low glycolytic NSCLC adenocarcinoma cell line.

The Relationship Between Tumor Glucose Metabolism and Host Systemic Inflammatory Responses in Patients with Cancer: A Systematic Review

One of the most important and long recognized characteristics of tumor cells is their dysregulated cellular energetics with anaerobic driven glucose uptake. In patients with cancer, the prognostic value of the systemic inflammatory response has been well established, and the recent combination of PET and CT scanning combines the assessment of tumor physiologic activity with detailed anatomic localization. The aim of this study was to perform a systematic review of the assessment of the relationship between both the tumor and the host inflammatory responses using PET/CT. Methods: An extensive literature review using targeted subject headings was performed in the U.S. National Library of Medicine, the Excerpta Medica database, and the Cochrane Database of Systematic Reviews on March 31, 2018. On completion of the online search, the title and abstracts of each identified study were examined for relevance. Studies with duplicate datasets, not available in English, and that did not have full text availability were excluded. Full texts of relevant articles were obtained and were then examined to identify any further relevant articles. Results: Twelve studies containing 2,588 patients were included in the final analysis. All of the included studies used the 18F-FDG tracer in PET/CT imaging and had biochemical assessment of the systemic inflammatory response. Most studies showed a direct relationship between the tumor and bone marrow glucose uptake and host systemic inflammatory responses as measured by C-reactive protein (n = 2), albumin (n = 2), white cell count (n = 3), neutrophils (n = 2), and platelets (n = 2). Most of the studies (n = 8) also showed a direct relationship between tumor and bone marrow glucose uptake and poor outcomes. Conclusion: This review suggests a direct relationship between the tumor and bone marrow glucose uptake and host systemic inflammation. This may suggest new approaches for more optimal therapeutic targeting and monitoring strategies in patients with cancer.