WorldWideScience
 
 
1

2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy.  

Science.gov (United States)

Cancer cells are characterized by altered glucose metabolism known as the Warburg effect in which aerobic glycolysis is increased. Glucose is converted to lactate even under sufficient oxygen tension. Interfering with this process may be a potential effective strategy to cause cancer cell death because these cells rely heavily on glucose metabolism for survival and proliferation. 2-Deoxy-D-glucose (2DG), a glucose analog, targets glucose metabolism to deplete cancer cells of energy. In addition, 2DG increases oxidative stress, inhibits N-linked glycosylation, and induces autophagy. It can efficiently slow cell growth and potently facilitate apoptosis in specific cancer cells. Although 2DG itself has limited therapeutic effect in many types of cancers, it may be combined with other therapeutic agents or radiotherapy to exhibit a synergistic anticancer effect. In this review, we describe the Warburg effect and discuss 2DG and its underlying mechanisms and potential application for cancer treatment. PMID:25218591

Zhang, Dongsheng; Li, Juan; Wang, Fengzhen; Hu, Jun; Wang, Shuwei; Sun, Yueming

2014-12-28

2

Glucose metabolism regulates T cell activation, differentiation, and functions.  

Science.gov (United States)

The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex and coordinated signals to drive the activation, proliferation, and differentiation of appropriate T cell subsets. It is now established that changes in cellular activation are coupled to profound changes in cellular metabolism. In addition, emerging evidence now suggest that specific metabolic alterations associated with distinct T cell subsets may be ancillary to their differentiation and influential in their immune functions. The "Warburg effect" originally used to describe a phenomenon in which most cancer cells relied on aerobic glycolysis for their growth is a key process that sustain T cell activation and differentiation. Here, we review how different aspects of metabolism in T cells influence their functions, focusing on the emerging role of key regulators of glucose metabolism such as HIF-1?. A thorough understanding of the role of metabolism in T cell function could provide insights into mechanisms involved in inflammatory-mediated conditions, with the potential for developing novel therapeutic approaches to treat these diseases. PMID:25657648

Palmer, Clovis S; Ostrowski, Matias; Balderson, Brad; Christian, Nicole; Crowe, Suzanne M

2015-01-01

3

Therapeutic potential of targeting glucose metabolism in glioma stem cells.  

Science.gov (United States)

Glioblastoma is a highly lethal cancer. Glioma stem cells (GSCs) are potentially an attractive therapeutic target and eradication of GSCs may impact tumor growth and sensitize tumors to conventional therapies. The brain is one of the most metabolically active organs with glucose representing the most important, but not the only, source of energy and carbon. Like all other cancers, glioblastoma requires a continuous source of energy and molecular resources for new cell production with a preferential use of aerobic glycolysis, recognized as the Warburg effect. As selected metabolic nodes are amenable to therapeutic targeting, we observed that the Warburg effect may causally contribute to glioma heterogeneity. This Editorial summarizes recent studies that examine the relationship between GSCs and metabolism and briefly provides our views for the future directions. The ultimate goal is to establish a new concept by incorporating both the cellular hierarchical theory and the cellular evolution theory to explain tumor heterogeneity. Such concept may better elucidate the mechanisms of how tumors gain cellular and molecular complexity and guide us develop novel and effective targeted therapies. PMID:25077882

Nakano, Ichiro

2014-11-01

4

Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells.  

Science.gov (United States)

To investigate sensitization of metformin-cytotoxicity, cancer cells were treated with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK). Metformin-cytotoxicity was mainly dependent on glucose availability and reducing power generated by pentose phosphate pathway, whereas DCA cotreatment enhanced metformin-cytotoxicity via reprogramming glucose metabolism by inhibiting PDK and increasing mitochondrial respiration. DCA cotreatment elicited cell death rather than cell survival despite high glucose and high GSH condition. In conclusion, DCA sensitized metformin-cytotoxicity by reprogramming glucose metabolism in part from aerobic glycolysis to mitochondrial oxidation, evidenced by measurements of glucose consumption, lactate release, and the ratio of oxygen consumption rate/extracellular acidification rate. PMID:24480191

Choi, Yong Won; Lim, In Kyoung

2014-05-01

5

Development of the method of determining the 3H-Glucose metabolism by tumor cells  

International Nuclear Information System (INIS)

Objective: To measure the glucose metabolic rate (GMR) in tumor cells. Methods: HCT116 cells were seeded in a density of 2 x 105 and grown to 90% confluence. Then 5- 3H-glucose was added into the medium. Thirty minutes later, cells were killed while 3H-H2O was separated from the labeled glucose by column chromatography. Radioactivity of 3H-H2O was counted using scintillation counter. At last glucose metabolic rate (GMR) in 30 minutes was calculated. Results: The chromatography column was found to exclude more than 99% of the total H-glucose from the perfusate if there was more than 5.0 ml of suspension loaded into the column. The glucose metabolic rate (GMR) of 3.7 x 105 HCT116 cells was 1.23% in 30 minutes. Conclusion: It is proved that by using this method one can determine the glucose metabolic rate precisely via adding 5-3H-glucose into the medium. Using this method, the tumor cells' glucose metabolism and energy providing will be studied better. (authors)

6

PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Insulin secretion from pancreatic beta cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1alpha, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1alpha pathway in ...

Zehetner, J.; Danzer, C.; Collins, S.; Eckhardt, K.; Gerber, Pa; Ballschmieter, P.; Galvanovskis, J.; Shimomura, K.; Ashcroft, Fm; Thorens, B.; Rorsman, P.; Krek, W.

2008-01-01

7

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic ? cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Insulin secretion from pancreatic ? cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1?, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL–HIF1? pathway in the co...

Zehetner, Jens; Danzer, Carsten; Collins, Stephan; Eckhardt, Katrin; Gerber, Philipp A.; Ballschmieter, Pia; Galvanovskis, Juris; Shimomura, Kenju; Ashcroft, Frances M.; Thorens, Bernard; Rorsman, Patrik; Krek, Wilhelm

2008-01-01

8

ChREBP, a glucose-responsive transcriptional factor, enhances glucose metabolism to support biosynthesis in human cytomegalovirus-infected cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Human cytomegalovirus (HCMV)-infected cells and tumor cells produce similar alterations in glucose metabolism, including increasing glucose uptake and glycolysis and redirecting glucose carbon to support synthesis of biomolecules. We show that HCMV infection induces the glucose-responsive transcriptional factor carbohydrate-response element binding protein to reprogram glucose metabolism to support lipid and nucleotide synthesis. This study provides insight into viral mechanisms of pathogenesis.

Yu, Yongjun; Maguire, Tobi G.; Alwine, James C.

2014-01-01

9

Glycated albumin suppresses glucose-induced insulin secretion by impairing glucose metabolism in rat pancreatic ?-cells  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Glycated albumin (GA is an Amadori product used as a marker of hyperglycemia. In this study, we investigated the effect of GA on insulin secretion from pancreatic ? cells. Methods Islets were collected from male Wistar rats by collagenase digestion. Insulin secretion in the presence of non-glycated human albumin (HA and GA was measured under three different glucose concentrations, 3 mM (G3, 7 mM (G7, and 15 mM (G15, with various stimulators. Insulin secretion was measured with antagonists of inducible nitric oxide synthetase (iNOS, and the expression of iNOS-mRNA was investigated by real-time PCR. Results Insulin secretion in the presence of HA and GA was 20.9 ± 3.9 and 21.6 ± 5.5 ?U/3 islets/h for G3 (P = 0.920, and 154 ± 9.3 and 126.1 ± 7.3 ?U/3 islets/h (P = 0.046, for G15, respectively. High extracellular potassium and 10 mM tolbutamide abrogated the inhibition of insulin secretion by GA. Glyceraldehyde, dihydroxyacetone, methylpyruvate, GLP-1, and forskolin, an activator of adenylate cyclase, did not abrogate the inhibition. Real-time PCR showed that GA did not induce iNOS-mRNA expression. Furthermore, an inhibitor of nitric oxide synthetase, aminoguanidine, and NG-nitro-L-arginine methyl ester did not abrogate the inhibition of insulin secretion. Conclusion GA suppresses glucose-induced insulin secretion from rat pancreatic ?-cells through impairment of intracellular glucose metabolism.

Muto Takashi

2011-04-01

10

Glucose promotes its own metabolism by acting on the cell-surface glucose-sensing receptor T1R3.  

Science.gov (United States)

A homodimer of taste type 1 receptor 3 (T1R3) functions as a sweet taste-sensing receptor in pancreatic ?-cells. This receptor is activated by various sweet molecules including sugars such as glucose. To determine the role of this receptor in glucose-induced insulin secretion, we addressed whether or not this receptor modulates glucose metabolism in MIN6 cells. We measured changes in intracellular ATP ([ATP]i) in MIN6 cells expressing luciferase. Sucralose, an agonist of T1R3, induced immediate and sustained elevation of [ATP]i in the presence of 5.5 mM glucose. The effect of sucralose was dose-dependent and, at 5 mM, was greater than that induced by 25 mM glucose. In contrast, carbachol, GLP-1 or high concentration of potassium did not reproduce the sucralose action. Sucralose facilitated the increase in [ATP]i induced by a mitochondrial fuel methylsuccinate, and potentiated glucose-induced elevation of [ATP]i. Administration of a non-metabolizable glucose analogue, 3-O-methylglucose, which acts as an agonist of T1R3, induced a small and transient increase in [ATP]i. 3-O-Methylglucose augmented elevation of [ATP]i induced by methylsuccinate, and also enhanced glucose-induced increase in [ATP]i. Knock down of T1R3 by using shRNA attenuated [ATP]i-response to high concentration of glucose and also reduced the glucose-induced insulin secretion. These results indicate that activation of the homodimer of T1R3 facilitates the metabolic pathway in mitochondria and augments ATP production. The results obtained by using 3-O-methylglucose suggest that glucose, by acting on the homodimer of T1R3, promotes its own metabolism. PMID:24200979

Nakagawa, Yuko; Ohtsu, Yoshiaki; Nagasawa, Masahiro; Shibata, Hiroshi; Kojima, Itaru

2014-01-01

11

Effect of epinephrine and insulin on glucose metabolism in isolated fat cells  

International Nuclear Information System (INIS)

Since epinephrine and insulin are known to counteract each other in several metabolic respects, it was found of interest to evaluate the interaction of these hormones on glucose metabolism in isolated fat cells. Results indicate that in spite of reduced lipolysis, insulin potentiates the conversion of glucose to glyceride-glycerol. This means that a certain degree of esterification of fatty acids must take place. So the low rate of lipolysis is sufficient to provide fatty acids for this esterification. (author)

12

Effect of epinephrine and insulin on glucose metabolism in isolated fat cells  

Energy Technology Data Exchange (ETDEWEB)

Since epinephrine and insulin are known to counteract each other in several metabolic respects, it was found of interest to evaluate the interaction of these hormones on glucose metabolism in isolated fat cells. Results indicate that in spite of reduced lipolysis, insulin potentiates the conversion of glucose to glyceride-glycerol. This means that a certain degree of esterification of fatty acids must take place. So the low rate of lipolysis is sufficient to provide fatty acids for this esterification.

Zewail, M.A. (National Research Centre, Cairo (Egypt)); Fahmy, N.M. (National Organisation for Drug Control and Research, Cairo (Egypt)); Nielsen, J.H. (Gentofte Hospital, Copenhagen (Denmark))

1984-08-01

13

Glucose metabolism is altered after loss of L cells and ?-cells but not influenced by loss of K cells.  

Science.gov (United States)

The enteroendocrine K and L cells are responsible for secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon like-peptide 1 (GLP-1), whereas pancreatic ?-cells are responsible for secretion of glucagon. In rodents and humans, dysregulation of the secretion of GIP, GLP-1, and glucagon is associated with impaired regulation of metabolism. This study evaluates the consequences of acute removal of Gip- or Gcg-expressing cells on glucose metabolism. Generation of the two diphtheria toxin receptor cellular knockout mice, TgN(GIP.DTR) and TgN(GCG.DTR), allowed us to study effects of acute ablation of K and L cells and ?-cells. Diphtheria toxin administration reduced the expression of Gip and content of GIP in the proximal jejunum in TgN(GIP.DTR) and expression of Gcg and content of proglucagon-derived peptides in both proximal jejunum and terminal ileum as well as content of glucagon in pancreas in TgN(GCG.DTR) compared with wild-type mice. GIP response to oral glucose was attenuated following K cell loss, but oral and intraperitoneal glucose tolerances were unaffected. Intraperitoneal glucose tolerance was impaired following combined L cell and ?-cell loss and normal following ?-cell loss. Oral glucose tolerance was improved following L cell and ?-cell loss and supernormal following ?-cell loss. We present two mouse models that allow studies of the effects of K cell or L cell and ?-cell loss as well as isolated ?-cell loss. Our findings show that intraperitoneal glucose tolerance is dependent on an intact L cell mass and underscore the diabetogenic effects of ?-cell signaling. Furthermore, the results suggest that K cells are less involved in acute regulation of mouse glucose metabolism than L cells and ?-cells. PMID:23115082

Pedersen, J; Ugleholdt, R K; Jørgensen, S M; Windeløv, J A; Grunddal, K V; Schwartz, T W; Füchtbauer, E M; Poulsen, S S; Holst, P J; Holst, J J

2013-01-01

14

Glucose metabolism is altered after loss of L cells and ?-cells but not influenced by loss of K cells  

DEFF Research Database (Denmark)

The enteroendocrine K and L cells are responsible for secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon like-peptide 1 (GLP-1), whereas pancreatic ?-cells are responsible for secretion of glucagon. In rodents and humans, dysregulation of the secretion of GIP, GLP-1, and glucagon is associated with impaired regulation of metabolism. This study evaluates the consequences of acute removal of Gip- or Gcg-expressing cells on glucose metabolism. Generation of the two diphtheria toxin receptor cellular knockout mice, TgN(GIP.DTR) and TgN(GCG.DTR), allowed us to study effects of acute ablation of K and L cells and ?-cells. Diphtheria toxin administration reduced the expression of Gip and content of GIP in the proximal jejunum in TgN(GIP.DTR) and expression of Gcg and content of proglucagon-derived peptides in both proximal jejunum and terminal ileum as well as content of glucagon in pancreas in TgN(GCG.DTR) compared with wild-type mice. GIP response to oral glucose was attenuated following K cell loss, but oral and intraperitoneal glucose tolerances were unaffected. Intraperitoneal glucose tolerance was impaired following combined L cell and ?-cell loss and normal following ?-cell loss. Oral glucose tolerance was improved following L cell and ?-cell loss and supernormal following ?-cell loss. We present two mouse models that allow studies of the effects of K cell or L cell and ?-cell loss as well as isolated ?-cell loss. Our findings show that intraperitoneal glucose tolerance is dependent on an intact L cell mass and underscore the diabetogenic effects of ?-cell signaling. Furthermore, the results suggest that K cells are less involved in acute regulation of mouse glucose metabolism than L cells and ?-cells.

Pedersen, J; Ugleholdt, R K

2013-01-01

15

Honeybee retinal glial cells transform glucose and supply the neurons with metabolic substrate  

International Nuclear Information System (INIS)

The retina of the honeybee drone is a nervous tissue in which glial cells and photoreceptor cells (sensory neurons) constitute two distinct metabolic compartments. Retinal slices incubated with 2-deoxy[3H]glucose convert this glucose analogue to 2-deoxy[3H]glucose 6-phosphate, but this conversion is made only in the glial cells. Hence, glycolysis occurs only in glial cells. In contrast, the neurons consume O2 and this consumption is sustained by the hydrolysis of glycogen, which is contained in large amounts in the glia. During photostimulation the increased oxidative metabolism of the neurons is sustained by a higher supply of carbohydrates from the glia. This clear case of metabolic interaction between neurons and glial cells supports Golgi's original hypothesis, proposed nearly 100 years ago, about the nutritive function of glial cells in the nervous system

16

Altered glucose metabolism in Harvey-ras transformed MCF10A cells.  

Science.gov (United States)

Metabolic reprogramming that alters the utilization of glucose including the "Warburg effect" is critical in the development of a tumorigenic phenotype. However, the effects of the Harvey-ras (H-ras) oncogene on cellular energy metabolism during mammary carcinogenesis are not known. The purpose of this study was to determine the effect of H-ras transformation on glucose metabolism using the untransformed MCF10A and H-ras oncogene transfected (MCF10A-ras) human breast epithelial cells, a model for early breast cancer progression. We measured the metabolite fluxes at the cell membrane by a selective micro-biosensor, [(13) C6 ]glucose flux by (13) C-mass isotopomer distribution analysis of media metabolites, intracellular metabolite levels by NMR, and gene expression of glucose metabolism enzymes by quantitative PCR. Results from these studies indicated that MCF10A-ras cells exhibited enhanced glycolytic activity and lactate production, decreased glucose flux through the tricarboxylic acid (TCA) cycle, as well as an increase in the utilization of glucose in the pentose phosphate pathway (PPP). These results provide evidence for a role of H-ras oncogene in the metabolic reprogramming of MCF10A cells during early mammary carcinogenesis. © 2013 Wiley Periodicals, Inc. PMID:24000146

Zheng, Wei; Tayyari, Fariba; Gowda, G A Nagana; Raftery, Daniel; McLamore, Eric S; Porterfield, D Marshall; Donkin, Shawn S; Bequette, Brian; Teegarden, Dorothy

2015-02-01

17

Honeybee retinal glial cells transform glucose and supply the neurons with metabolic substrate.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The retina of the honeybee drone is a nervous tissue in which glial cells and photoreceptor cells (sensory neurons) constitute two distinct metabolic compartments. Retinal slices incubated with 2-deoxy[3H]glucose convert this glucose analogue to 2-deoxy[3H]glucose 6-phosphate, but this conversion is made only in the glial cells. Hence, glycolysis occurs only in glial cells. In contrast, the neurons consume O2 and this consumption is sustained by the hydrolysis of glycogen, which is contained ...

Tsacopoulos, M.; Eve?quoz-mercier, V.; Perrottet, P.; Buchner, E.

1988-01-01

18

Quantitative aspects of glucose and glutamine metabolism by intestinal cells.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Gut fuel utilisation has several unique features. Arterial and luminal fuels provide nutrition for the enterocyte, the former being of more importance. This factor, and the heterogeneity of cell types within the gut makes it difficult to define its fuel utilisation. Metabolic control logic suggests that modulation of the maximal activity of any pathway resides in those enzymes that operate in vivo at rates far below their maximal capacity and that catalyse non-equilibrium reactions. On this b...

Newsholme, E. A.; Carrie?, A. L.

1994-01-01

19

Non-Classical Gluconeogenesis-Dependent Glucose Metabolism in Rhipicephalus microplus Embryonic Cell Line BME26  

Directory of Open Access Journals (Sweden)

Full Text Available In this work we evaluated several genes involved in gluconeogenesis, glycolysis and glycogen metabolism, the major pathways for carbohydrate catabolism and anabolism, in the BME26 Rhipicephalus microplus embryonic cell line. Genetic and catalytic control of the genes and enzymes associated with these pathways are modulated by alterations in energy resource availability (primarily glucose. BME26 cells in media were investigated using three different glucose concentrations, and changes in the transcription levels of target genes in response to carbohydrate utilization were assessed. The results indicate that several genes, such as glycogen synthase (GS, glycogen synthase kinase 3 (GSK3, phosphoenolpyruvate carboxykinase (PEPCK, and glucose-6 phosphatase (GP displayed mutual regulation in response to glucose treatment. Surprisingly, the transcription of gluconeogenic enzymes was found to increase alongside that of glycolytic enzymes, especially pyruvate kinase, with high glucose treatment. In addition, RNAi data from this study revealed that the transcription of gluconeogenic genes in BME26 cells is controlled by GSK-3. Collectively, these results improve our understanding of how glucose metabolism is regulated at the genetic level in tick cells.

Renato Martins da Silva

2015-01-01

20

Non-Classical Gluconeogenesis-Dependent Glucose Metabolism in Rhipicephalus microplus Embryonic Cell Line BME26  

Science.gov (United States)

In this work we evaluated several genes involved in gluconeogenesis, glycolysis and glycogen metabolism, the major pathways for carbohydrate catabolism and anabolism, in the BME26 Rhipicephalus microplus embryonic cell line. Genetic and catalytic control of the genes and enzymes associated with these pathways are modulated by alterations in energy resource availability (primarily glucose). BME26 cells in media were investigated using three different glucose concentrations, and changes in the transcription levels of target genes in response to carbohydrate utilization were assessed. The results indicate that several genes, such as glycogen synthase (GS), glycogen synthase kinase 3 (GSK3), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6 phosphatase (GP) displayed mutual regulation in response to glucose treatment. Surprisingly, the transcription of gluconeogenic enzymes was found to increase alongside that of glycolytic enzymes, especially pyruvate kinase, with high glucose treatment. In addition, RNAi data from this study revealed that the transcription of gluconeogenic genes in BME26 cells is controlled by GSK-3. Collectively, these results improve our understanding of how glucose metabolism is regulated at the genetic level in tick cells. PMID:25594873

da Silva, Renato Martins; Della Noce, Bárbara; Waltero, Camila Fernanda; Costa, Evenilton Pessoa; de Abreu, Leonardo Araujo; Githaka, Naftaly Wang’ombe; Moraes, Jorge; Gomes, Helga Fernandes; Konnai, Satoru; da Silva Vaz, Itabajara; Ohashi, Kazuhiko; Logullo, Carlos

2015-01-01

 
 
 
 
21

Proliferation-dependent changes in amino acid transport and glucose metabolism in glioma cell lines  

International Nuclear Information System (INIS)

Amino acid imaging is increasingly being used for assessment of brain tumor malignancy, extent of disease, and prognosis. This study explores the relationship between proliferative activity, amino acid transport, and glucose metabolism in three glioma cell lines (U87, Hs683, C6) at different phases of growth in culture. Growth phase was characterized by direct cell counting, proliferation index determined by flow cytometry, and [3H]thymidine (TdR) accumulation, and was compared with the uptake of two non-metabolized amino acids ([14C]aminocyclopentane carboxylic acid (ACPC) and [14C]aminoisobutyric acid (AIB)), and [18F]fluorodeoxyglucose (FDG). Highly significant relationships between cell number (density), proliferation index, and TdR accumulation rate were observed in all cell lines (r>0.99). Influx (K1) of both ACPC and AIB was directly related to cell density, and inversely related to the proliferation index and TdR accumulation in all cell lines. The volume of distribution (Vd) for ACPC and AIB was lowest during rapid growth and highest during the near-plateau growth phase in all cell lines. FDG accumulation in Hs683 and C6 cells was unaffected by proliferation rate, growth phase, and cell density, whereas FDG accumulation was correlated with TdR accumulation, growth phase, and cell density in U87 cells. This study demonstrates that proliferation rate and glucose metabolism are not necessarily co-glucose metabolism are not necessarily co-related in all glioma cell lines. The values of K1 and Vd for ACPC and AIB under different growth conditions suggest that these tumor cell lines can up-regulate amino acid transporters in their cell membranes when their growth conditions become adverse and less than optimal. (orig.)

22

Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells.  

Science.gov (United States)

The metabolism of glutamine and glucose is recognized as a promising therapeutic target for the treatment of cancer; however, targeted molecule that mediate glutamine and glucose metabolism in cancer cells has not been addressed. Here, we show that restricting the supply of glutamine in hepatoma cells, including HepG2 and Hep3B cells, markedly increased the expression of retinoic acid-related orphan receptor (ROR) ?. Up-regulation of ROR? in glutamine-deficient hepatoma cells resulted from an increase in the level of cellular reactive oxygen species and in the NADP(+) /NADPH ratio, which was consistent with a reduction in the GSH/GSSG ratio. Adenovirus-mediated overexpression of ROR? (Ad-ROR?) or treatment with the ROR? activator, SR1078, reduced aerobic glycolysis and down-regulated biosynthetic pathways in hepatoma cells. Ad-ROR? and SR1078 reduced the expression of pyruvate dehydrogenase kinase 2 (PDK2) and inhibited the phosphorylation of PDHe1?, subsequently shifted pyruvate to complete oxidation. The ROR?-mediated decrease in PDK2 levels was caused by up-regulation of p21 rather than p53. Furthermore, ROR? inhibited hepatoma growth both in vitro and in a xenograft model in vivo. We also found that suppression of PDK2 inhibited hepatoma growth in a xenograft model. These findings mimic the altered glucose utilization and hepatoma growth caused by glutamine deprivation. Finally, tumor tissue from 187 hepatocellular carcinoma patients expressed lower levels of ROR? than adjacent non-tumor tissue, supporting a potential beneficial effect of ROR? activation in the treatment of liver cancer. Conclusion: The data reported herein show that ROR? mediates reprogramming of glucose metabolism in hepatoma cells in response to glutamine deficiency. The relationships established here between glutamine metabolism, ROR? expression and signaling, and aerobic glycolysis have implications for therapeutic targeting of liver cancer metabolism. (Hepatology 2014). PMID:25346526

Byun, Jun-Kyu; Choi, Yeon-Kyung; Kang, Yu Na; Jang, Byoung Kuk; Kang, Koo Jeong; Jeon, Yong Hyun; Lee, Ho-Won; Jeon, Jae-Han; Koo, Seung-Hoi; Jeong, Won-Il; Harris, Robert A; Lee, In-Kyu; Park, Keun-Gyu

2014-10-25

23

Pregnancy alters glucose-6-phosphate dehydrogenase trafficking, cell metabolism, and oxidant release of maternal neutrophils  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Pregnancy is associated with changes in host susceptibility to infections and inflammatory disease. We hypothesize that metabolic enzyme trafficking affects maternal neutrophil activation. Specifically, immunofluorescence microscopy has shown that glucose-6-phosphate dehydrogenase (G-6-PDase), the rate-controlling step of the hexose monophosphate shunt (HMS), is located near the cell periphery in control neutrophils but is found near the microtubule-organizing centers in cells from pregnant w...

Kindzelskii, Andrei L.; Huang, Ji-biao; Chaiworapongsa, Tinnakorn; Fahmy, Ryan M.; Kim, Yeon Mee; Romero, Roberto; Petty, Howard R.

2002-01-01

24

Glycated albumin suppresses glucose-induced insulin secretion by impairing glucose metabolism in rat pancreatic ?-cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Abstract Background Glycated albumin (GA) is an Amadori product used as a marker of hyperglycemia. In this study, we investigated the effect of GA on insulin secretion from pancreatic ? cells. Methods Islets were collected from male Wistar rats by collagenase digestion. Insulin secretion in the presence of non-glycated human albumin (HA) and GA was measured under three different glucose concentrations, 3 mM (G3), 7 mM (G7), and 15 mM (G15), with various stimula...

Muto Takashi; Sakuraoka Yuhki; Okada Toshie; Sawada Tokihiko; Miura Yoshikazu; Shiraki Takayuki; Kubota Keiichi

2011-01-01

25

Pancreatic beta-cell lipoprotein lipase independently regulates islet glucose metabolism and normal insulin secretion.  

Science.gov (United States)

Lipid and glucose metabolism are adversely affected by diabetes, a disease characterized by pancreatic beta-cell dysfunction. To clarify the role of lipids in insulin secretion, we generated mice with beta-cell-specific overexpression (betaLPL-TG) or inactivation (betaLPL-KO) of lipoprotein lipase (LPL), a physiologic provider of fatty acids. LPL enzyme activity and triglyceride content were increased in betaLPL-TG islets; decreased LPL enzyme activity in betaLPL-KO islets did not affect islet triglyceride content. Surprisingly, both betaLPL-TG and betaLPL-KO mice were strikingly hyperglycemic during glucose tolerance testing. Impaired glucose tolerance in betaLPL-KO mice was present at one month of age, whereas betaLPL-TG mice did not develop defective glucose homeostasis until approximately five months of age. Glucose-simulated insulin secretion was impaired in islets isolated from both mouse models. Glucose oxidation, critical for ATP production and triggering of insulin secretion mediated by the ATP-sensitive potassium (KATP) channel, was decreased in betaLPL-TG islets but increased in betaLPL-KO islets. Islet ATP content was not decreased in either model. Insulin secretion was defective in both betaLPL-TG and betaLPL-KO islets under conditions causing calcium-dependent insulin secretion independent of the KATP channel. These results show that beta-cell-derived LPL has two physiologically relevant effects in islets, the inverse regulation of glucose metabolism and the independent mediation of insulin secretion through effects distal to membrane depolarization. PMID:15637076

Pappan, Kirk L; Pan, Zhijun; Kwon, Guim; Marshall, Connie A; Coleman, Trey; Goldberg, Ira J; McDaniel, Michael L; Semenkovich, Clay F

2005-03-11

26

PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1.  

Science.gov (United States)

PTEN-induced kinase-1 (PINK1) is a Ser/Thr kinase implicated in familial early-onset Parkinson's disease, and was first reported as a growth suppressor. PINK1 loss-of-function compromises both mitochondrial autophagy and oxidative phosphorylation. Here we report that PINK1 deficiency triggers hypoxia-inducible factor-1? (HIF1?) stabilization in cultured Pink1(-/-) mouse embryonic fibroblasts and primary cortical neurons as well as in vivo. This effect, mediated by mitochondrial reactive oxygen species, led to the upregulation of the HIF1 target, pyruvate dehydrogenase kinase-1, which inhibits PDH activity. Furthermore, we show that HIF1? stimulates glycolysis in the absence of Pink1, and that the promotion of intracellular glucose metabolism by HIF1? stabilization is required for cell proliferation in Pink1(-/-) mice. We propose that loss of Pink1 reprograms glucose metabolism through HIF1?, sustaining increased cell proliferation. PMID:25058378

Requejo-Aguilar, Raquel; Lopez-Fabuel, Irene; Fernandez, Emilio; Martins, Luis M; Almeida, Angeles; Bolaños, Juan P

2014-01-01

27

New aspects of an old drug: Diclofenac targets MYC and glucose metabolism in tumor cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspir...

Kreutz, Marina; Gottfried, Eva; Lang, Sven A.; Renner, Kathrin; Bosserhoff, Anja-katrin; Gronwald, Wolfram; Rehli, Michael; Einhell, Sabine; Gedig, Isabell; Singer, Katrin; Seilbeck, Anton; Mackensen, Andreas; Grauer, Oliver; Hau, Peter; Dettmer, Katja

2013-01-01

28

Interactions between the metabolism of L-leucine and D-glucose in the pancreatic ?-cells  

International Nuclear Information System (INIS)

?-cell-rich pancreatic islets microdissected from obese-hyperglycemic mice were used to study interactions between the metabolism of L-leucine and D-glucose. L-leucine reduced the islet content of aspartic acid whereas D-glucose, when added to L-leucine-incubated islets, increased the contents of aspartic acid and ?-aminobutyric acid (GABA). D-glucose also increased the incorporation of L-leucine carbon into aspartic acid, GABA and glutamic acid, suggesting stimulation of a malate shuttle mechanism. When expressed per mole of the individual amino acids, the incorporation of L-leucine carbon into GABA was 2.5 - 4 times higher than into glutamic acid indicating intracellular compartmentation of the latter amino acid. Both L-leucine and D-leucine stimulated 14CO2 production from 14C-labelled D-glucose. L-leucine did not affect 3H2O production from tritiated D-glucose. The present data do not indicate a role of other amino acids or D-glucose in L-leucine-stimulated insulin release. (orig.)

29

Proliferation-dependent changes in amino acid transport and glucose metabolism in glioma cell lines  

Energy Technology Data Exchange (ETDEWEB)

Amino acid imaging is increasingly being used for assessment of brain tumor malignancy, extent of disease, and prognosis. This study explores the relationship between proliferative activity, amino acid transport, and glucose metabolism in three glioma cell lines (U87, Hs683, C6) at different phases of growth in culture. Growth phase was characterized by direct cell counting, proliferation index determined by flow cytometry, and [{sup 3}H]thymidine (TdR) accumulation, and was compared with the uptake of two non-metabolized amino acids ([{sup 14}C]aminocyclopentane carboxylic acid (ACPC) and [{sup 14}C]aminoisobutyric acid (AIB)), and [{sup 18}F]fluorodeoxyglucose (FDG). Highly significant relationships between cell number (density), proliferation index, and TdR accumulation rate were observed in all cell lines (r>0.99). Influx (K{sub 1}) of both ACPC and AIB was directly related to cell density, and inversely related to the proliferation index and TdR accumulation in all cell lines. The volume of distribution (V{sub d}) for ACPC and AIB was lowest during rapid growth and highest during the near-plateau growth phase in all cell lines. FDG accumulation in Hs683 and C6 cells was unaffected by proliferation rate, growth phase, and cell density, whereas FDG accumulation was correlated with TdR accumulation, growth phase, and cell density in U87 cells. This study demonstrates that proliferation rate and glucose metabolism are not necessarily co-related in all glioma cell lines. The values of K{sub 1} and V{sub d} for ACPC and AIB under different growth conditions suggest that these tumor cell lines can up-regulate amino acid transporters in their cell membranes when their growth conditions become adverse and less than optimal. (orig.)

Sasajima, Toshio [Department of Neurology, C799, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10021, New York (United States); Neurosurgical Service, Akita University Hospital, Akita (Japan); Miyagawa, Tadashi [Department of Neurology, C799, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10021, New York (United States); Department of Neurosurgery, Chiba University School of Medicine, Chuo-ku, Chiba (Japan); Oku, Takamitsu [Department of Neurology, C799, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10021, New York (United States); Department of Neurosurgery, Miyazaki Medical College, Miyazaki (Japan); Gelovani, Juri G. [Department of Neurology, C799, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10021, New York (United States); Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York (United States); Department of Experimental Diagnostic Imaging, The University of Texas, MD Anderson Cancer Center, TX 77030, Houston (United States); Finn, Ronald [Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York (United States); Blasberg, Ronald [Department of Neurology, C799, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10021, New York (United States); Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York (United States)

2004-09-01

30

Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression.  

Science.gov (United States)

Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1? (peroxisome-proliferator-activated receptor-? coactivator-1?) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1? and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1?. Although insulin is a mitogenic signal in proliferative cells, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1? acetylation. Insulin/GSK-3? (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1? activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division. PMID:24870244

Lee, Yoonjin; Dominy, John E; Choi, Yoon Jong; Jurczak, Michael; Tolliday, Nicola; Camporez, Joao Paulo; Chim, Helen; Lim, Ji-Hong; Ruan, Hai-Bin; Yang, Xiaoyong; Vazquez, Francisca; Sicinski, Piotr; Shulman, Gerald I; Puigserver, Pere

2014-06-26

31

Metabolic labeling with (14C)-glucose of bloodstream and cell culture trypanosoma cruzi trypomastigotes:  

International Nuclear Information System (INIS)

Trypomastigote forms of Trypanosoma cruzi from infected mouse blood and from cell culture were metabolically labeled by incubation with D-(14C)-glucose. Analysis by polyacrylamide gel electrophoresis of lysates from parasites of two strains (RA and CA1) showed a significantly different pattern. The difference was mainly quantitative when the blood and cell culture trypomastigotes of the RA strain were compared. Analysis of the culture medium by paper electrophoresis showed an anionic exometabolite only in the blood forms of both strains. (Author)

32

Flow cytometric quantification of glucose-stimulated beta-cell metabolic flux can reveal impaired islet functional potency.  

Science.gov (United States)

The objective of this study was to develop a multiparametric flow cytometry assay to simultaneously quantify isolated pancreatic islet cell viability, apoptosis, and glucose-induced metabolic flux. INS-1 and rat islet beta-cells were stained with fluorescent probes for cell viability (ToPro3), apoptosis (Annexin V and VADFMK), and intracellular calcium (Ca2+(i)) (Fura Red), stimulated with glucose, and analyzed on a FACS Vantage flow cytometer. Glucose-induced metabolic activity was indicated by changes in Fura Red fluorescence and the autofluorescence of the pyridine [NAD(P)H] and flavin (FAD/FMN) nucleotides. Rat islets cultured under conditions of proinflammatory cytokine-induced oxidative stress were evaluated by flow cytometry and transplantation into diabetic mice. INS-1 and rat islet beta-cell health and metabolic activity were quantified in response to elevated glucose dose and inhibitors of glycolysis and mitochondrial function. Changes in metabolite fluorescence were converted to an area under the curve (AUC) value. Rat islets cultured under oxidative stress conditions showed decreased viability, increased apoptosis, and decreased glucose-induced metabolic activity indicated by reduced AUC for pyridine and flavin nucleotides and Ca2+(i). Reduced metabolite AUC measured by flow cytometry correlated with the inability to reverse diabetes in mice. Single cell flow cytometry can simultaneously quantify both overall islet cell health and beta-cell glucose responsiveness as indicators of functional potency. PMID:19364071

Hanson, Matthew S; Steffen, Anja; Danobeitia, Juan S; Ludwig, Barbara; Fernandez, Luis A

2008-01-01

33

Yeast PAS kinase coordinates glucose partitioning in response to metabolic and cell integrity signaling.  

Science.gov (United States)

PAS kinase is an evolutionarily conserved serine/threonine protein kinase. Mammalian PAS kinase is activated under nutrient replete conditions and is important for controlling metabolic rate and energy homeostasis. In yeast, PAS kinase acts to increase the synthesis of structural carbohydrate at the expense of storage carbohydrates through phosphorylation of the enzyme UDP-glucose pyrophosphorylase. We have identified two pathways that activate yeast PAS kinase; one is responsive to nutrient conditions while the other is responsive to cell integrity stress. These pathways differentially activate the two PAS kinase proteins in Saccharomyces cerevisiae, Psk1 and Psk2, with Psk1 alone responding to activation by nonfermentative carbon sources. We demonstrate that, in addition to transcriptional effects, both of these pathways post-translationally activate PAS kinase via its regulatory N-terminus. As a whole, this system acts to coordinate glucose partitioning with alterations in demand due to changes in environmental and nutrient conditions. PMID:17989693

Grose, Julianne H; Smith, Tammy L; Sabic, Hana; Rutter, Jared

2007-11-28

34

Effects of lindane on the glucose metabolism in rat brain cortex cells  

International Nuclear Information System (INIS)

The influence of 0.5 mM ?-hexachlorocyclohexane (?-HCH, lindane) on glucose transport has been investigated using the analog 3-O-methyl-D(U-14C) glucose. The glucose uptake was lineal for at least 10 sec. Preincubation of dissociated brain cortex cells with lindane decreased the transport of glucose with respect to the controls. The treatment of brain cortex cells with other organochlorine compounds indicated that the ?-, ?-HCH isomers and dieldrin reproduced the same inhibitory pattern, while ?-HCH and endrin were inactive. The total radioactivity incorporated into CO2 from (U-14C) glucose in the cerebral cortex is also inhibited by lindane in a time dependent manner

35

Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.  

LENUS (Irish Health Repository)

Many anticancer drugs activate caspases via the mitochondrial apoptosis pathway. Activation of this pathway triggers a concomitant bioenergetic crisis caused by the release of cytochrome-c (cyt-c). Cancer cells are able to evade these processes by altering metabolic and caspase activation pathways. In this study, we provide the first integrated system study of mitochondrial bioenergetics and apoptosis signalling and examine the role of mitochondrial cyt-c release in these events. In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ??(m) from -142 to -88 mV, with active caspase-3 potentiating this decrease. ATP synthase was reversed under such conditions, consuming ATP and stabilising ??(m). However, the direction and level of ATP synthase activity showed significant heterogeneity in individual cancer cells, which the model explained by variations in (i) accessible cyt-c after release and (ii) the cell\\'s glycolytic capacity. Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.

Huber, Heinrich J

2011-03-01

36

Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism  

Energy Technology Data Exchange (ETDEWEB)

In this study we characterized {sup 3}H-2-deoxy-D-glucose ({sup 3}H -DG) uptake by the estrogen receptor (ER)-positive MCF7 and the ER-negative MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon {sup 3}H-DG uptake, glucose metabolism and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells {sup 3}H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (V{sub max}) and affinity (K{sub m}), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin-stimulated. This suggests that {sup 3}H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concentration-dependently inhibited {sup 3}H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compounds blocked lactate production by MCF7 cells. Additionally, a 4 h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-negative breast tumors. -- Highlights: • Glucose uptake by MCF7 and MDA-MB-231 cells is mainly mediated by GLUT1. • QUE and EGCG inhibit cellular glucose uptake thus abolishing the Warburg effect. • This process induces cytotoxicity and proliferation arrest in MCF7 cells. • The flavonoids’ effects are independent of estrogen receptor signalling.

Moreira, Liliana, E-mail: lilianam87@gmail.com [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Araújo, Isabel, E-mail: isa.araujo013@gmail.com [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Costa, Tito, E-mail: tito.fmup16@gmail.com [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Correia-Branco, Ana, E-mail: ana.clmc.branco@gmail.com [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Faria, Ana, E-mail: anafaria@med.up.pt [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Chemistry Investigation Centre (CIQ), Faculty of Sciences of University of Porto, Rua Campo Alegre, 4169-007 Porto (Portugal); Faculty of Nutrition and Food Sciences of University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto (Portugal); Martel, Fátima, E-mail: fmartel@med.up.pt [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal); Keating, Elisa, E-mail: keating@med.up.pt [Department of Biochemistry (U38-FCT), Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto (Portugal)

2013-07-15

37

Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism  

International Nuclear Information System (INIS)

In this study we characterized 3H-2-deoxy-D-glucose (3H -DG) uptake by the estrogen receptor (ER)-positive MCF7 and the ER-negative MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon 3H-DG uptake, glucose metabolism and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells 3H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (Vmax) and affinity (Km), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin-stimulated. This suggests that 3H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concentration-dependently inhibited 3H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compounds blocked lactate production by MCF7 cells. Additionally, a 4 h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-negative breast tumors. -- Highlights: • Glucose uptake by MCF7 and MDA-MB-231 cells is mainly mediated by GLUT1. • QUE and EGCG inhibit cellular glucose uptake thus abolishing the Warburg effect. • This process induces cytotoxicity and proliferation arrest in MCF7 cells. • The flavonoids’ effects are independent of estrogen receptor signalling

38

Formaldehyde Metabolism and Formaldehyde-induced Alterations in Glucose and Glutathione Metabolism of Cultured Brain Cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Formaldehyde is an environmental pollutant that is also generated in the body during normal metabolic processes. Interestingly, several pathological conditions are associated with an increase in formaldehyde-generating enzymes in the body. The level of formaldehyde in the brain is elevated with increasing age and in neurodegenerative conditions which may contribute to lowered cognitive functions. Although the neurotoxic potential of formaldehyde is well established, the molecular mechanisms i...

Tulpule, Ketki

2013-01-01

39

Targeting glucose metabolism in chondrosarcoma cells enhances the sensitivity to doxorubicin through the inhibition of lactate dehydrogenase-A.  

Science.gov (United States)

Chondrosarcoma is a malignant cartilage-forming cancer composed of cells derived from transformed cells that produce cartilage. Conventional chemotherapy and radiotherapy have very limited efficacy in patients with advanced chondrosarcoma. In the present study, we reported a novel therapeutic approach in the treatment of chondrosarcoma cells. We detected that lactate dehydrogenase-A (LDHA) is highly active in chondrosarcoma cells and chondrosarcoma patient samples compared with normal chondrocyte cell lines and primary human chondrocyte. Moreover, chondrosarcoma cells exhibited elevated levels of LDHA expression under doxorubicin treatment. To further explore the mechanisms, we generated doxorubicin-resistant cells from SW1353 chondrosarcoma cell line. Notably, the activity and expression of LDHA are upregulated in doxorubicin-resistant cells. Moreover, our data showed a strong correlation between glucose metabolism and doxorubicin resistance in chondrosarcoma cells; doxorubicin-resistant cells displayed highly activated glucose metabolism and depended more on glucose supply. Finally, we reported a synergistic effect produced by incorporating doxorubicin with glycolysis inhibitors-oxamate in the combined treatment of chondrosarcoma cells in vitro and in vivo. In summary, the present study may aid in the development of new approaches using the combination of chemotherapeutic agents for the treatment of chondrosarcoma patients. PMID:24789077

Hua, Guojun; Liu, Yunpeng; Li, Xiangyong; Xu, Peirong; Luo, Yuchun

2014-06-01

40

Estimation of liver glucose metabolism after refeeding  

International Nuclear Information System (INIS)

Refeeding or infusing glucose to rats fasted for 24 hr or more causes rapid liver glycogen synthesis, the carbon source now considered to be largely from gluconeogenesis. While substrate cycling between plasma glucose and liver glucose-6P is known to occur, this cycling has apparently been ignored when calculations are made of % contribution of direct and indirect pathways to liver glycogen synthesis, or when hepatic glucose output is calculated from glucose turnover minus the glucose infusion rate. They show that, isotopically, an estimate of the fluxes of liver glucokinase and glucose-6-phosphatase is required to quantitate sources of carbon for liver glycogen synthesis, and to measure hepatic glucose output (or uptake). They propose a method to estimate these fluxes, involving a short infusion of a 14C labelled gluconeogenic precursor plus (6T)glucose, with determination of isotopic yields in liver glycogen and total glucose. Given also the rate of liver glycogen synthesis, this procedure permits the estimation of net gluconeogenesis and hepatic glucose output or uptake. Also, in vitro evidence against the notion of a drastic zonation of liver carbohydrate metabolism is presented, e.g. raising the glucose concentration from 10 to 25 mM increases the 14C yield from H14CO3- in lactate, with the increased pyruvate kinase flux and decreased gluconeogenesis occurring in the same cell type, not opposing pathways in dsame cell type, not opposing pathways in different hepatocyte types (as has been postulated by some to occur in vivo after refeeding

 
 
 
 
41

Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication.  

Science.gov (United States)

Virus infections trigger metabolic changes in host cells that support the bioenergetic and biosynthetic demands of viral replication. Although recent studies have characterized virus-induced changes in host cell metabolism (Munger et al., 2008; Terry et al., 2012), the molecular mechanisms by which viruses reprogram cellular metabolism have remained elusive. Here, we show that the gene product of adenovirus E4ORF1 is necessary for adenovirus-induced upregulation of host cell glucose metabolism and sufficient to promote enhanced glycolysis in cultured epithelial cells by activation of MYC. E4ORF1 localizes to the nucleus, binds to MYC, and enhances MYC binding to glycolytic target genes, resulting in elevated expression of specific glycolytic enzymes. E4ORF1 activation of MYC promotes increased nucleotide biosynthesis from glucose intermediates and enables optimal adenovirus replication in primary lung epithelial cells. Our findings show how a viral protein exploits host cell machinery to reprogram cellular metabolism and promote optimal progeny virion generation. PMID:24703700

Thai, Minh; Graham, Nicholas A; Braas, Daniel; Nehil, Michael; Komisopoulou, Evangelia; Kurdistani, Siavash K; McCormick, Frank; Graeber, Thomas G; Christofk, Heather R

2014-04-01

42

Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release  

Digital Repository Infrastructure Vision for European Research (DRIVER)

How can cancer cells survive the consequences of cyt-c release? Huber et al provide a quantitative analysis of the protective role of enhanced glucose utilization in cancer cells and investigate the impact of cell-to-cell heterogeneity in mitochondrial bioenergetics.

Huber, Heinrich J.; Dussmann, Heiko; Kilbride, Sea?n M.; Rehm, Markus; Prehn, Jochen H. M.

2011-01-01

43

Estimation of liver glucose metabolism after refeeding  

Energy Technology Data Exchange (ETDEWEB)

Refeeding or infusing glucose to rats fasted for 24 hr or more causes rapid liver glycogen synthesis, the carbon source now considered to be largely from gluconeogenesis. While substrate cycling between plasma glucose and liver glucose-6P is known to occur, this cycling has apparently been ignored when calculations are made of % contribution of direct and indirect pathways to liver glycogen synthesis, or when hepatic glucose output is calculated from glucose turnover minus the glucose infusion rate. They show that, isotopically, an estimate of the fluxes of liver glucokinase and glucose-6-phosphatase is required to quantitate sources of carbon for liver glycogen synthesis, and to measure hepatic glucose output (or uptake). They propose a method to estimate these fluxes, involving a short infusion of a /sup 14/C labelled gluconeogenic precursor plus (6T)glucose, with determination of isotopic yields in liver glycogen and total glucose. Given also the rate of liver glycogen synthesis, this procedure permits the estimation of net gluconeogenesis and hepatic glucose output or uptake. Also, in vitro evidence against the notion of a drastic zonation of liver carbohydrate metabolism is presented, e.g. raising the glucose concentration from 10 to 25 mM increases the /sup 14/C yield from H/sup 14/CO/sub 3//sup -/ in lactate, with the increased pyruvate kinase flux and decreased gluconeogenesis occurring in the same cell type, not opposing pathways in different hepatocyte types (as has been postulated by some to occur in vivo after refeeding.

Rognstad, R.

1987-05-01

44

Study on the insulin resistance and ?-cell function in individuals with normal and those with abnormal glucose metabolism  

International Nuclear Information System (INIS)

Objective: To study the insulin resistance and ?-cell function in individuals with normal glucose tolerance (NGT) and those with glucose metabolism dysfunction. Methods: Insulin resistance and ?-cell function were studied with oral glucose tolerance test and the following parameters: 2h insulin/2h plasma glucose (2hIns/2hPG), insulin resistance index (IRI), insulin sensitivity index (ISI) and 30 min net increment of insulin/30min net increment of glucose (AI30/AG30) were examined in 44 individuals with NGT, 45 subjects with impaired glucose tolerance (IGT), 66 recently diagnosed diabetics and 175 well-established diabetics. Results: The insulin resistance index (IRI) increased progressively from that in NGT individuals to that in recently diabetics (20 ± 1. 5?3.1 ± 1.6?4.1 ± 1.8), while the 2hIns/2hPG, ?I30/?G30 and ISI decreased progressively with significant differences between those in successive groups (P30/?G30 and ISI kept decreasing (values in patients with disease history less than 3 yrs vs those in patients with disease over 3yrs: 2.9 ± 3.2 vs 2.4 + 2.3, 30.2 + 1.1 vs 23.4 ± 2.3, P30/?G30 were significantly correlated with ISI (F =96.3, 58.4 and 47.5 respectively). For principal component analysis display, the cumulative contriby, the cumulative contribution rate of four parameters (2hIns/2hPG, ISI, ?I30/?G30 and 2h C-peptide) exceeded 85% (86.5%). Conclusion: As the dysfunction of glucose metabolism proceeded from IGT to well established diabetes, the IR increased first with decrease of ?-cell secretion followed. The parameters 2hIns/2hPG, ISI, 2h C-peptide ?I30/?G30 were especially useful for the investigation . (authors)

45

Yeast PAS kinase coordinates glucose partitioning in response to metabolic and cell integrity signaling  

Digital Repository Infrastructure Vision for European Research (DRIVER)

PAS kinase is an evolutionarily conserved serine/threonine protein kinase. Mammalian PAS kinase is activated under nutrient replete conditions and is important for controlling metabolic rate and energy homeostasis. In yeast, PAS kinase acts to increase the synthesis of structural carbohydrate at the expense of storage carbohydrates through phosphorylation of the enzyme UDP-glucose pyrophosphorylase. We have identified two pathways that activate yeast PAS kinase; one is responsive to nutrient ...

Grose, Julianne H.; Smith, Tammy L.; Sabic, Hana; Rutter, Jared

2007-01-01

46

Energy metabolism in astrocytes and neurons treated with manganese: relation among cell-specific energy failure, glucose metabolism, and intercellular trafficking using multinuclear NMR-spectroscopic analysis.  

Science.gov (United States)

A central question in manganese neurotoxicity concerns mitochondrial dysfunction leading to cerebral energy failure. To obtain insight into the underlying mechanism(s), the authors investigated cell-specific pathways of [1-13C]glucose metabolism by high-resolution multinuclear NMR-spectroscopy. Five-day treatment of neurons with 100-micro mol/L MnCl(2) led to 50% and 70% decreases of ATP/ADP and phosphocreatine-creatine ratios, respectively. An impaired flux of [1-13C]glucose through pyruvate dehydrogenase, which was associated with Krebs cycle inhibition and hence depletion of [4-13C]glutamate, [2-13C]GABA, and [13C]glutathione, hindered the ability of neurons to compensate for mitochondrial dysfunction by oxidative glucose metabolism and further aggravated neuronal energy failure. Stimulated glycolysis and oxidative glucose metabolism protected astrocytes against energy failure and oxidative stress, leading to twofold increased de novo synthesis of [3-13C]lactate and fourfold elevated [4-13C]glutamate and [13C]glutathione levels. Manganese, however, inhibited the synthesis and release of glutamine. Comparative NMR data obtained from cocultures showed disturbed astrocytic function and a failure of astrocytes to provide neurons with substrates for energy and neurotransmitter metabolism, leading to deterioration of neuronal antioxidant capacity (decreased glutathione levels) and energy metabolism. The results suggest that, concomitant to impaired neuronal glucose oxidation, changes in astrocytic metabolism may cause a loss of intercellular homeostatic equilibrium, contributing to neuronal dysfunction in manganese neurotoxicity. PMID:12796724

Zwingmann, Claudia; Leibfritz, Dieter; Hazell, Alan S

2003-06-01

47

Paclitaxel Combined with Inhibitors of Glucose and Hydroperoxide Metabolism Enhances Breast Cancer Cell Killing Via H2O2-Mediated Oxidative Stress  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Cancer cells (relative to normal cells) demonstrate alterations in oxidative metabolism characterized by increased steady-state levels of reactive oxygen species [i.e. hydrogen peroxide, H2O2] that may be compensated for by increased glucose metabolism but the therapeutic significance of these observations is unknown. In the current study, inhibitors of glucose [i.e., 2-deoxy-D-glucose, 2DG] and hydroperoxide [i.e., L-buthionine-S, R-sulfoximine, BSO] metabolism were utilized in combination w...

Hadzic, Tanja; Aykin-burns, Nu?khet; Zhu, Yueming; Coleman, Mitchell C.; Leick, Katie; Jacobson, Geraldine M.; Spitz, Douglas R.

2010-01-01

48

Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Cancer cells feature altered glucose metabolism that allows their rapid growth. They consume large amounts of glucose to produce lactate, even in the presence of ample oxygen, which is known as the Warburg effect. Pyruvate kinase M2 (PKM2) contributes to the Warburg effect by previously unknown mechanisms. Hypoxia-inducible factor 1 (HIF-1) mediates PKM2 gene transcription and metabolic reprogramming in cancer cells. The recent discovery of novel physical and functional interactions between P...

Luo, Weibo; Semenza, Gregg L.

2011-01-01

49

Uptake and Metabolic Fate of Glucose, Arabinose, and Xylose by Zea mays Coleoptiles in Relation to Cell Wall Synthesis.  

Science.gov (United States)

According to the acid-growth hypothesis, auxin-induced secretion of hydrogen ions activate "wall loosening" enzymes that change the rheological properties of the cell wall. The wall loosening process may yield monosaccharides by the enzymic cleavage of load-bearing polysaccharides. Our study was initiated to determine the metabolic fate of such sugars when released from the major hemicellulosic polysaccharides of the cell walls of Zea mays coleoptiles.Excised coleoptile sections accumulated radioactive glucose, arabinose, and xylose supplied in an incubation medium, and the radioactivity from these sugars was incorporated into polysaccharides. At least 50% of the radioactivity from glucose accumulated in the soluble neutral sugar fraction regardless of external concentrations. The distribution of radioactivity from xylose into all subcellular fractions was similar to that from glucose, indicating that xylose was converted to glucose before being used by the coleoptile. IAA increased the incorporation of glucose into cell wall polysaccharide and neutral sugar pools when the exogenous concentration was higher than 1 millimolar.Over 80% of the radioactivity from arabinose accumulated by the coleoptile sections was incorporated into soluble and noncellulosic polymers; IAA induced an increase in the incorporation of arabinose into noncellulosic polymers by 22%. Accumulation of radioactivity from arabinose into polysaccharide was enhanced by IAA at concentrations of exogenous arabinose up to 33 millimolar.IAA promoted the incorporation of both arabinose and glucose into cell wall polysaccharides even when elongation was inhibited by CaCl(2), indicating that the influence of IAA was not a consequence of the growth response. PMID:16662366

Carpita, N C; Brown, R A; Weller, K M

1982-05-01

50

Dysregulation of Dicer1 in Beta Cells Impairs Islet Architecture and Glucose Metabolism  

Science.gov (United States)

microRNAs (miRNAs) play important roles in pancreas development and in regulation of insulin expression in the adult. Here we show that loss of miRNAs activity in beta-cells during embryonic development results in lower beta-cell mass and in impaired glucose tolerance. Dicer1-null cells initially constitute a significant portion of the total beta-cell population. However, during postnatal development, Dicer1-null cells are depleted. Furthermore, wild-type beta cells are repopulating the islets in complex compensatory dynamics. Because loss of Dicer1 is also associated with changes in the distribution of membranous E-cadherin, we hypothesized that E-cadherin activity may play a role in beta cell survival or islet architecture. However, genetic loss of E-cadherin function does not impair islet architecture, suggesting that miRNAs likely function through other or redundant effectors in the endocrine pancreas. PMID:22991506

Mandelbaum, Amitai D.; Melkman-Zehavi, Tal; Oren, Roni; Kredo-Russo, Sharon; Nir, Tomer; Dor, Yuval; Hornstein, Eran

2012-01-01

51

Intracellular Glucose Concentration in Derepressed Yeast Cells Consuming Glucose Is High Enough To Reduce the Glucose Transport Rate by 50%  

Digital Repository Infrastructure Vision for European Research (DRIVER)

In Saccharomyces cerevisiae cells exhibiting high-affinity glucose transport, the glucose consumption rate at extracellular concentrations above 10 mM was only half of the zero trans-influx rate. To determine if this regulation of glucose transport might be a consequence of intracellular free glucose we developed a new method to measure intracellular glucose concentrations in cells metabolizing glucose, which compares glucose stereoisomers to correct for adhering glucose. The intracellular gl...

Teusink, Bas; Diderich, Jasper A.; Westerhoff, Hans V.; Dam, Karel; Walsh, Michael C.

1998-01-01

52

Effect of endotoxin-induced monokines on glucose metabolism in the muscle cell line L6  

Energy Technology Data Exchange (ETDEWEB)

Exposure of fully differentiated L6 myotubes to a crude monokine preparation from endotoxin-stimulated RAW 264.7 cells resulted in a rapid and substantial (70%) increase in fructose 2,6-bisphosphate concentration coincident with a depletion of cellular glycogen and an increased lactate production. During the time required for glycogen depletion (3 hr), stimulation of 3-O-methyl-D-glucose and 2-deoxy-D-glucose uptake was initiated and observed to reach a maximum enhancement of 200% 12-15 hr later. The monokine had no effect on the K/sub m/ value for 2-deoxy-D-glucose uptake (1.1 mM), while V/sub max/ was increased from 912 to 2400 pmol/min per mg of protein. The increase was cytochalasin B inhibitable and was dependent on protein synthesis. Photoaffinity labeling and equilibrium binding studies with (/sup 3/H)cytochalasin B support the hypothesis that this increase in hexose transport was due to an increase in hexose transporters present in the plasma membrane. Purified recombinant interleukin-1..cap alpha.. had no effect on hexose transport, whereas purified recombinant cachectin/tumor necrosis factor did stimulate hexose uptake, with half-maximal stimulation occurring at 36 nM. Although cachectin accounts for most of the biological activity associated with the crude monokine preparation, it is not the only monokine capable of inducing glucose transport in L6 cells. Specific immunoabsorption of cachectin/tumor necrosis factor from the crude monokine preparation revealed a monokine that had a similar bioactivity at extremely low concentrations on L6 cells.

Lee, M.D.; Zentella, A.; Pekala, P.H.; Cerami, A.

1987-05-01

53

Glucosamine metabolism of herpes simplex virus infected cells. Inhibition of glycosylation by tunicamycin and 2-deoxy-D-glucose  

International Nuclear Information System (INIS)

The formation of glucosamine-containing cell surface glycoproteins of herpes simplex virus (HSV) infected BMK cells was studied. Tunicamycin (TM) and 2-deoxy-D-glucose (DG) were used as inhibitors. With both inhibitors the multiplication of HSV was inhibited. DG markedly reduced cellular uptake of radioactively labelled glucosamine while TM interfered with the processing of glucosamine into TCA-insoluble material. Gel filtration chromatography on Sephadex G50 gel of cell surface material released by trypsin and further prepared by digestion with pronase indicated that TM and DG reduced the apparent high molecular weights of virus induced surface glycoproteins. In presence of DG the accumulation of a class of glucosamine-containing heterosaccharides (MW less than 3000) not present on DG-free HSV infected cells was observed. IN TM treated cells virtually all surface heterosaccharides with molecular weights exceeding 3000 and containing glucosamine disappeared. Moreover, a component compatible with a lipid-linked oligosaccharide present in DG treated cells was not observed in HSV infected TM treated cells. The results exemplifies some different steps in glucosamine metabolism of virus-induced cell surface glycoproteins differently affected by tunicamycin and 2-deoxy-D-glucose. (author)

54

The Acute Effects of Low-Dose TNF- ? on Glucose Metabolism and ? -Cell Function in Humans  

DEFF Research Database (Denmark)

Type 2 diabetes is characterized by increased insulin resistance and impaired insulin secretion. Type 2 diabetes is also associated with low-grade inflammation and increased levels of proinflammatory cytokines such as TNF- ? . TNF- ? has been shown to impair peripheral insulin signaling in vitro and in vivo. However, it is unclear whether TNF- ? may also affect endogenous glucose production (EGP) during fasting and glucose-stimulated insulin secretion (GSIS) in vivo. We hypothesized that low-dose TNF- ? would increase EGP and attenuate GSIS. Recombinant human TNF- ? or placebo was infused in healthy, nondiabetic young men (n = 10) during a 4-hour basal period followed by an intravenous glucose tolerance test (IVGTT). TNF- ? lowered insulin levels by 12% during the basal period (P < 0.05). In response to the IVGTT, insulin levels increased markedly in both trials, but there was no difference between trials. Compared to placebo, TNF- ? did not affect EGP during the basal period. Our results indicate that TNF- ?acutely lowers basal plasma insulin levels but does not impair GSIS. The mechanisms behind this are unknown but we suggest that it may be due to TNF- ? increasing clearance of insulin from plasma without impairing beta-cell function or hepatic insulin sensitivity

Ibfeldt, T; Fischer, Christian Philip

2014-01-01

55

Effects of simvastatin on glucose metabolism in mouse MIN6 cells.  

Science.gov (United States)

The aim of this study was to investigate the effects of simvastatin on insulin secretion in mouse MIN6 cells and the possible mechanism. MIN6 cells were, respectively, treated with 0? ? M, 2? ? M, 5? ? M, and 10? ? M simvastatin for 48?h. Radio immunoassay was performed to measure the effect of simvastatin on insulin secretion in MIN6 cells. Luciferase method was used to examine the content of ATP in MIN6 cells. Real-time PCR and western blotting were performed to measure the mRNA and protein levels of inward rectifier potassium channel 6.2 (Kir6.2), voltage-dependent calcium channel 1.2 (Cav1.2), and glucose transporter-2 (GLUT2), respectively. ATP-sensitive potassium current and L-type calcium current were recorded by whole-cell patch-clamp technique. The results showed that high concentrations of simvastatin (5? ? M and 10? ? M) significantly reduced the synthesis and secretion of insulin compared to control groups in MIN6 cells (P MIN6 cells. PMID:24995341

Zhou, Jieqiong; Li, Weihua; Xie, Qiang; Hou, Yuxi; Zhan, Shaopeng; Yang, Xi; Xu, Xiaofeng; Cai, Jun; Huang, Zhengrong

2014-01-01

56

Glycolysis inhibitor 2-deoxy-D-glucose suppresses carcinogen-induced rat hepatocarcinogenesis by restricting cancer cell metabolism.  

Science.gov (United States)

The abnormal metabolism of cancer cells is a crucial feature of tumors and provides promising therapeutic targets for cancer treatments. Aerobic glycolysis in cancer cells, termed the Warburg effect, is a highlighted characteristic of cancer?specific metabolism. However, the effect of glycolysis inhibition on hepatocarcinogenesis remains to be elucidated. In the present study, the effects of the glycolysis inhibitor 2?deoxy?D?glucose (2?DG) on the N?diethylnitrosamine (DEN)?induced rat hepatocarcinoma model and its underlying mechanisms were investigated. It was observed that 2?DG significantly delayed hepatocarcinogenesis and effectively prolonged survival time in the DEN?treated rats. The glycolysis inhibitor, 2?DG prominently decreased cell proliferation and increased cell apoptosis in the DEN?induced rat hepatoma and had no evident impact on the pericarcinomatous liver tissues. Further investigation revealed that 2?DG resulted in a reduction of glycolysis products, the compensatory increase of hexokinase 2 expression and a decrease in 6?phosphofructo?2?kinase, pyruvate kinase M2 and lactate dehydrogenase A expression in the hepatoma tissues. The inhibition of glycolysis further suppressed the tricarboxylic acid cycle, fatty acid and cholesterol biosynthesis and ATP production, while it promoted autophagic activation. In addition, the in vitro study demonstrated that hypoxia, an important factor in the tumor microenvironment, may assist in increasing 2?DG?induced inhibition of cell viability, cell cycle retardation and the decrease of colony formation ability in hepatoma cells. Taken together, the present results suggested that 2?DG may inhibit hepatocarcinogenesis in the DEN?treated rats via restricting cancer cell metabolism. This finding provides a promising measure in the prevention and treatment of hepatoma. PMID:25394852

Wang, Zhaofa; Zhang, Liming; Zhang, Dong; Sun, Rongsheng; Wang, Qingyan; Liu, Xinyi

2015-03-01

57

Amino acid and glucose metabolism in fed-batch CHO cell culture affects antibody production and glycosylation.  

Science.gov (United States)

Fed-batch Chinese hamster ovary (CHO) cell culture is the most commonly used process for IgG production in the biopharmaceutical industry. Amino acid and glucose consumption, cell growth, metabolism, antibody titer, and N-glycosylation patterns are always the major concerns during upstream process optimization, especially media optimization. Gaining knowledge on their interrelations could provide insight for obtaining higher immunoglobulin G (IgG) titer and better controlling glycosylation-related product quality. In this work, different fed-batch processes with two chemically defined proprietary media and feeds were studied using two IgG-producing cell lines. Our results indicate that the balance of glucose and amino acid concentration in the culture is important for cell growth, IgG titer and N-glycosylation. Accordingly, the ideal fate of glucose and amino acids in the culture could be mainly towards energy and recombinant product, respectively. Accumulation of by-products such as NH4(+) and lactate as a consequence of unbalanced nutrient supply to cell activities inhibits cell growth. The levels of Leu and Arg in the culture, which relate to cell growth and IgG productivity, need to be well controlled. Amino acids with the highest consumption rates correlate with the most abundant amino acids present in the produced IgG, and thus require sufficient availability during culture. Case-by-case analysis is necessary for understanding the effect of media and process optimization on glycosylation. We found that in certain cases the presence of Man5 glycan can be linked to limitation of UDP-GlcNAc biosynthesis as a result of insufficient extracellular Gln. However, under different culture conditions, high Man5 levels can also result from low ?-1,3-mannosyl-glycoprotein 2-?-N-acetylglucosaminyltransferase (GnTI) and UDP-GlcNAc transporter activities, which may be attributed to high level of NH4+ in the cell culture. Furthermore, galactosylation of the mAb Fc glycans was found to be limited by UDP-Gal biosynthesis, which was observed to be both cell line and cultivation condition-dependent. Extracellular glucose and glutamine concentrations and uptake rates were positively correlated with intracellular UDP-Gal availability. All these findings are important for optimization of fed-batch culture for improving IgG production and directing glycosylation quality. Biotechnol. Bioeng. 2014;9999: 1-15. © 2014 Wiley Periodicals, Inc. PMID:25220616

Fan, Yuzhou; Jimenez Del Val, Ioscani; Müller, Christian; Wagtberg Sen, Jette; Rasmussen, Søren Kofoed; Kontoravdi, Cleo; Weilguny, Dietmar; Andersen, Mikael Rørdam

2014-09-12

58

Amino acid and glucose metabolism in fed-batch CHO cell culture affects antibody production and glycosylation  

DEFF Research Database (Denmark)

Fed-batch Chinese hamster ovary (CHO) cell culture is the most commonly used process for IgG production in the biopharmaceutical industry. Amino acid and glucose consumption, cell growth, metabolism, antibody titer, and N-glycosylation patterns are always the major concerns during upstream process optimization, especially media optimization. Gaining knowledge on their interrelations could provide insight for obtaining higher immunoglobulin G (IgG) titer and better controlling glycosylationrelated product quality. In this work, different fed-batch processes with two chemically defined proprietary media and feeds were studied using two IgG-producing cell lines. Our results indicate that the balance of glucose and amino acid concentration in the culture is important for cell growth, IgG titer and N-glycosylation. Accordingly, the ideal fate of glucose and amino acids in the culture could be mainly towards energy and recombinant product, respectively. Accumulation of by-products such as NH4+ and lactate as a consequence of unbalanced nutrient supply to cell activities inhibits cell growth. The levels of Leu and Arg in the culture, which relate to cell growth and IgG productivity, need to be well controlled. Amino acids with the highest consumption rates correlate with the most abundant amino acids present in the produced IgG, and thus require sufficient availability during culture. Case-by-case analysis is necessary for understanding the effect of media and process optimization on glycosylation. We found that in certain cases the presence of Man5 glycan can be linked to limitation of UDP-GlcNAc biosynthesis as a result of insufficient extracellular Gln. However, under different culture conditions, high Man5 levels can also result from low a-1,3-mannosyl-glycoprotein 2-ß-N-acetylglucosaminyltransferase (GnTI) and UDPGlcNAc transporter activities, which may be attributed to high level of NH4+ in the cell culture. Furthermore, galactosylation of the mAb Fc glycans was found to be limited by UDP-Gal biosynthesis, whichwas observed to be both cell line and cultivation condition-dependent. Extracellular glucose and glutamine concentrations and uptake rates were positively correlated with intracellular UDP-Gal availability. All these findings are important for optimization of fed-batch culture for improving IgG production and directing glycosylation quality.

Fan, Yuzhou; Jimenez Del Val, Ioscani

2014-01-01

59

Elevated White Blood Cell Count Is Associated with Higher Risk of Glucose Metabolism Disorders in Middle-Aged and Elderly Chinese People  

Directory of Open Access Journals (Sweden)

Full Text Available White blood cell (WBC count has been associated with diabetic risk, but whether the correlation is independent of other risk factors has hardly been studied. Moreover, very few such studies with large sample sizes have been conducted in Chinese. Therefore, we investigated the relationship between WBC count and glucose metabolism in china. We also examined the relevant variables of WBC count. A total of 9,697 subjects (mean age, 58.0 ± 9.1 years were recruited. The subjects were classified into four groups, including subjects with normal glucose tolerance, isolated impaired fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus (T2DM. We found that WBC count increased as glucose metabolism disorders exacerbated. WBC count was also positively correlated with waist hip ratio, body mass index, smoking, triglycerides, glycosylated haemoglobin A1c (HbA1c and 2-h postprandial glucose. In addition, high density lipoprotein and the female gender were inversely correlated with WBC count. In patients with previously diagnosed T2DM, the course of T2DM was not correlated with WBC count. Our findings indicate that elevated WBC count is independently associated with worsening of glucose metabolism in middle-aged and elderly Chinese. In addition, loss of weight, smoking cessation, lipid-modifying therapies, and control of postprandial plasma glucose and HbA1c may ameliorate the chronic low-grade inflammation.

Hua Jiang

2014-05-01

60

Effects of fluctuating glucose concentrations on oxidative metabolism of glucose in cultured neurons and astroglia  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The objective of the present study was to evaluate the effects of hyperglycemia on glucose metabolism of brain cells. Not only a sustained hyperglycemic state, but also a fluctuating plasma glucose concentration has been implicated in the pathogenesis of diabetic angiopathy. Acutely increasing plasma glucose levels have not been reported to alter glucose utilization of the brain as a whole. In the present study, we examined the effects of chronic (3 weeks) or short-term (24-hour) exposure to ...

Takato Abe; Shinichi Takahashi; Yoshikane Izawa; Norihiro Suzuki

2012-01-01

 
 
 
 
61

Visfatin, glucose metabolism and vascular disease: a review of evidence  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Abstract The adipose tissue is an endocrine organ producing substances called adipocytokines that have different effects on lipid metabolism, metabolic syndrome, and cardiovascular risk. Visfatin was recently described as an adipocytokine with potentially important effects on glucose metabolism and atherosclerosis. Visfatin has been linked to several inflammatory conditions, beta cell function, and cardiovascular disease. The growing number of publications on the subject shall bring...

Saddi-Rosa Pedro; Sv, Oliveira Carolina; Ma, Giuffrida Fernando; Reis André F.

2010-01-01

62

Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia  

DEFF Research Database (Denmark)

Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined.

Green, Charlotte J; Henriksen, Tora I

2012-01-01

63

Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice.  

Science.gov (United States)

Non-coding variation within TCF7L2 remains the strongest genetic determinant of type 2 diabetes risk in humans. A considerable effort has been placed in understanding the functional roles of TCF7L2 in pancreatic beta cells, despite evidence of TCF7L2 expression in various peripheral tissues important in glucose homeostasis. Here, we use a humanized mouse model overexpressing Tcf7l2, resulting in glucose intolerance, to infer the contribution of Tcf7l2 overexpression in beta cells and in other tissues to the metabolic phenotypes displayed by these mice. Restoring Tcf7l2 expression specifically in beta cells to endogenous levels, in face of its overexpression elsewhere, results in impaired insulin secretion, reduced beta cell number and islet area, corroborating data obtained in humans showing similar phenotypes as a result of manipulations leading to Tcf7l2 loss of function. Interestingly, the persistent overexpression of Tcf7l2 in non-pancreatic tissues results in a significant worsening in glucose tolerance in vivo, indicating that Tcf7l2 overexpression in beta cells does not account for the glucose intolerance in the Tcf7l2 overexpression mouse model. Collectively, these data posit that Tcf7l2 plays key roles in glucose metabolism through actions beyond pancreatic beta cells, and further points to functionally opposing cell-type specific effects for Tcf7l2 on the maintenance of balanced glucose metabolism, thereby urging a careful examination of its role in non-pancreatic tissues as well as its composite metabolic effects across distinct tissues. Uncovering these roles may lead to new therapeutic targets for type 2 diabetes. PMID:25398947

Bailey, Kathleen A; Savic, Daniel; Zielinski, Mark; Park, Soo-Young; Wang, Ling-Jia; Witkowski, Piotr; Brady, Matthew; Hara, Manami; Bell, Graeme I; Nobrega, Marcelo A

2014-11-14

64

Altered glucose metabolism and proteolysis in pancreatic cancer cell conditioned myoblasts: searching for a gene expression pattern with a microarray analysis of 5000 skeletal muscle genes  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Background and aims: We verified whether conditioned media (CM) from pancreatic cancer cell lines (MIAPaCa2, CAPAN-1, PANC-1, BxPC3) alter glucose metabolism and gene expression profiles (microarray experiment with a platform of 5000 skeletal muscle cDNA) in mice myoblasts.

Basso, D.; Millino, C.; Greco, E.; Romualdi, C.; Fogar, P.; Valerio, A.; Bellin, M.; Zambon, C-f; Navaglia, F.; Dussini, N.; Avogaro, A.; Pedrazzoli, S.; Lanfranchi, G.; Plebani, M.

2004-01-01

65

Effects of fluctuating glucose concentrations on oxidative metabolism of glucose in cultured neurons and astroglia  

Directory of Open Access Journals (Sweden)

Full Text Available The objective of the present study was to evaluate the effects of hyperglycemia on glucose metabolism of brain cells. Not only a sustained hyperglycemic state, but also a fluctuating plasma glucose concentration has been implicated in the pathogenesis of diabetic angiopathy. Acutely increasing plasma glucose levels have not been reported to alter glucose utilization of the brain as a whole. In the present study, we examined the effects of chronic (3 weeks or short-term (24-hour exposure to a high glucose concentration on the oxidative metabolism of neurons and astroglia. Cells were prepared from Sprague-Dawley rats and cultured in the presence of a high (22 mM or low (5 mM concentration of glucose. The high or low glucose media did not alter either the rates of [14C]deoxyglucose phosphorylation (an indicator of total glucose utilization or [14C]lactate and [14C]pyruvate oxidation (indicators of oxidative glucose metabolism in neurons. In contrast, chronic or short-term exposure to a high glucose concentration resulted in significant decreases in oxidation of [14C]acetate, an astrocyte-specific reporter molecule, or [14C]lactate and [14C]pyruvate oxidation in the astroglia. Thus, either chronic or short-term increases in the glucose concentration suppressed oxidative metabolism only in astroglia, indicating neuro-protective roles against hyperglycemic brain cell injury in diabetes mellitus. These different responses of neurons and astroglia may also shed new light on brain energy metabolism in diabetic patients with either chronic high or fluctuating plasma glucose concentrations.

Takato Abe

2012-02-01

66

Visfatin, glucose metabolism and vascular disease: a review of evidence  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract The adipose tissue is an endocrine organ producing substances called adipocytokines that have different effects on lipid metabolism, metabolic syndrome, and cardiovascular risk. Visfatin was recently described as an adipocytokine with potentially important effects on glucose metabolism and atherosclerosis. Visfatin has been linked to several inflammatory conditions, beta cell function, and cardiovascular disease. The growing number of publications on the subject shall bring further evidence about this adipocytokine. Its findings may contribute in the identification of higher risk individuals for diabetes and cardiovascular disease with a better comprehension about the complex intercorrelation between adiposity, glucose metabolism and vascular disease.

Saddi-Rosa Pedro

2010-03-01

67

Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling  

Energy Technology Data Exchange (ETDEWEB)

As differentiated cells, hepatocytes primarily metabolize glucose for ATP production through oxidative phosphorylation of glycolytic pyruvate, whereas proliferative hepatocellular carcinoma (HCC) cells undergo a metabolic shift to aerobic glycolysis despite oxygen availability. Keratins, the intermediate filament (IF) proteins of epithelial cells, are expressed as pairs in a lineage/differentiation manner. Hepatocyte and HCC (hepatoma) cell IFs are made solely of keratins 8/18 (K8/K18), thus providing models of choice to address K8/K18 IF functions in normal and cancerous epithelial cells. Here, we demonstrate distinctive increases in glucose uptake, glucose-6-phosphate formation, lactate release, and glycogen formation in K8/K18 IF-lacking hepatocytes and/or hepatoma cells versus their respective IF-containing counterparts. We also show that the K8/K18-dependent glucose uptake/G6P formation is linked to alterations in hexokinase I/II/IV content and localization at mitochondria, with little effect on GLUT1 status. In addition, we find that the insulin-stimulated glycogen formation in normal hepatocytes involves the main PI-3 kinase-dependent signaling pathway and that the K8/K18 IF loss makes them more efficient glycogen producers. In comparison, the higher insulin-dependent glycogen formation in K8/K18 IF-lacking hepatoma cells is associated with a signaling occurring through a mTOR-dependent pathway, along with an augmentation in cell proliferative activity. Together, the results uncover a key K8/K18 regulation of glucose metabolism in normal and cancerous hepatic cells through differential modulations of mitochondrial HK status and insulin-mediated signaling.

Mathew, Jasmin; Loranger, Anne; Gilbert, Stéphane [Centre de recherche en cancérologie de l' Université Laval and Centre de recherche du CHUQ (L' Hôtel-Dieu de Québec), 9 McMahon, Québec, Qc, Canada G1R 2J6 (Canada); Faure, Robert [Département de Pédiatrie, Université Laval and Centre de recherche du CHUQ (Centre Mère-Enfant), Québec, Qc, Canada G1V 4G2 (Canada); Marceau, Normand, E-mail: normand.marceau@crhdq.ulaval.ca [Centre de recherche en cancérologie de l' Université Laval and Centre de recherche du CHUQ (L' Hôtel-Dieu de Québec), 9 McMahon, Québec, Qc, Canada G1R 2J6 (Canada)

2013-02-15

68

Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling  

International Nuclear Information System (INIS)

As differentiated cells, hepatocytes primarily metabolize glucose for ATP production through oxidative phosphorylation of glycolytic pyruvate, whereas proliferative hepatocellular carcinoma (HCC) cells undergo a metabolic shift to aerobic glycolysis despite oxygen availability. Keratins, the intermediate filament (IF) proteins of epithelial cells, are expressed as pairs in a lineage/differentiation manner. Hepatocyte and HCC (hepatoma) cell IFs are made solely of keratins 8/18 (K8/K18), thus providing models of choice to address K8/K18 IF functions in normal and cancerous epithelial cells. Here, we demonstrate distinctive increases in glucose uptake, glucose-6-phosphate formation, lactate release, and glycogen formation in K8/K18 IF-lacking hepatocytes and/or hepatoma cells versus their respective IF-containing counterparts. We also show that the K8/K18-dependent glucose uptake/G6P formation is linked to alterations in hexokinase I/II/IV content and localization at mitochondria, with little effect on GLUT1 status. In addition, we find that the insulin-stimulated glycogen formation in normal hepatocytes involves the main PI-3 kinase-dependent signaling pathway and that the K8/K18 IF loss makes them more efficient glycogen producers. In comparison, the higher insulin-dependent glycogen formation in K8/K18 IF-lacking hepatoma cells is associated with a signaling occurring through a mTOR-dependent pathway, along with an augmentation in cell proliferative activity. Together, the results uncover a key K8/K18 regulation of glucose metabolism in normal and cancerous hepatic cells through differential modulations of mitochondrial HK status and insulin-mediated signaling

69

Glucose metabolism in diabetic blood vessels  

Energy Technology Data Exchange (ETDEWEB)

Since glycolysis appears to be coupled to active ion transport in vascular smooth muscle, alterations in glucose metabolism may contribute to cellular dysfunction and angiopathy in diabetes. Uptake and utilization of glucose were studied in perfused blood vessels in which pulsatile flow and perfusion pressure were similar to those measured directly in vivo. Thoracic aortae isolated from 8-wk alloxan diabetic (D) and nondiabetic control rabbits were cannulated, tethered, and perfused with oxygenated buffer containing 7 or 25 mM glucose and tracer amounts of glucose-U/sup -14/ C. Norepinephrine (NE) (10/sup -6/ M) and/or insulin (I) (150 ..mu..U/ml) and albumin (0.2%) were added. NE-induced tension development increased glucose uptake 39% and /sup 14/CO/sub 2/ and lactate production 2.3-fold. With 7 mM glucose, marked decreases in glucose uptake (74%), /sup 14/CO/sub 2/ (68%), lactate (30%), total tissue glycogen (75%), and tissue phospholipids (70%) were observed in D. Addition of I or elevation of exogenous glucose to 25 mM normalized glucose uptake, but had differential effects on the pattern of substrate utilization. Thus, in D, there was a marked depression of vascular glucose metabolism that was partially reversed by addition of low concentrations of insulin or D levels of glucose.

Brown, B.J.; Crass, M.F. III

1986-03-05

70

Glucose metabolism in diabetic blood vessels  

International Nuclear Information System (INIS)

Since glycolysis appears to be coupled to active ion transport in vascular smooth muscle, alterations in glucose metabolism may contribute to cellular dysfunction and angiopathy in diabetes. Uptake and utilization of glucose were studied in perfused blood vessels in which pulsatile flow and perfusion pressure were similar to those measured directly in vivo. Thoracic aortae isolated from 8-wk alloxan diabetic (D) and nondiabetic control rabbits were cannulated, tethered, and perfused with oxygenated buffer containing 7 or 25 mM glucose and tracer amounts of glucose-U-14 C. Norepinephrine (NE) (10-6 M) and/or insulin (I) (150 ?U/ml) and albumin (0.2%) were added. NE-induced tension development increased glucose uptake 39% and 14CO2 and lactate production 2.3-fold. With 7 mM glucose, marked decreases in glucose uptake (74%), 14CO2 (68%), lactate (30%), total tissue glycogen (75%), and tissue phospholipids (70%) were observed in D. Addition of I or elevation of exogenous glucose to 25 mM normalized glucose uptake, but had differential effects on the pattern of substrate utilization. Thus, in D, there was a marked depression of vascular glucose metabolism that was partially reversed by addition of low concentrations of insulin or D levels of glucose

71

Glucose deprivation-induced metabolic oxidative stress and cancer therapy  

Directory of Open Access Journals (Sweden)

Full Text Available Cancer cells (vs. normal cells demonstrate evidence of oxidative stress, increased glycolysis, and increased pentose cycle activity. The oxidative stress in cancer cells has been hypothesized to arise from mitochondrial dysfunction leading to increased levels of hydroperoxides, and cancer cells have been proposed to compensate for this defect by increasing glucose metabolism. Glucose metabolism has also been shown to play a role in hydroperoxide detoxification via the formation of pyruvate (from glycolysis and NADPH (from the pentose cycle. Furthermore, in cancer cells, glucose deprivation as well as treatment with 2-deoxyglucose (2?DG has been shown to induce oxidative stress and cytotoxicity. Additionally, transformed cells have been shown to be more susceptible to glucose deprivation (and 2DG--induced cytotoxicity and oxidative stress than untransformed cells. These results support the hypothesis that cancer cells have a defect in mitochondrial respiration leading to increased steady state levels of O 2· - and H 2 O2 , and glucose metabolism is increased to compensate for this defect. The application of these findings to developing cancer therapies using 2DG combined with inhibitors of hydroperoxide metabolism to induce radio/chemosensitization is discussed, as well as the possibility that FDG-PET imaging may predict tumor responses to these therapies.

Simons Andrean

2009-09-01

72

Glucose metabolism in cultured trophoblasts from human placenta  

International Nuclear Information System (INIS)

The development of appropriate placental trophoblast isolation and culture techniques enables the study of pathways of glucose utilization by this important cell layer in vitro. Trophoblasts from normal term placentas were isolated and cultured 24 hours and 72 hours in uncoated polystyrene culture tubes or tubes previously coated with a fibrin matrix. Trophoblasts cultured on fibrin are morphologically distinct from those cultured on plastic or other matrices and generally resemble in vivo syncytium. Cells were incubated up to 3 hours with 14C-labeled glucose and reactions were stopped by addition of perchloric acid. 14CO2 production by trophoblasts increased linearly with time however the largest accumulation of label was in organic acids. Trophoblasts cultured in absence of fibrin utilized more glucose and accumulated more 14C in metabolic products compared to cells cultured on fibrin. Glucose oxidation to CO2 by the phosphogluconate (PG) pathway was estimated from specific yields of 14CO2 from [1-14C]-D-glucose and [6-14C]-D-glucose. Approximately 6% of glucose oxidation was by the PG pathway when cells were cultured on fibrin compared to approximately 1% by cells cultured in the absence of fibrin. The presence of a fibrin growth matrix appears to modulate the metabolism of glucose by trophoblast from human placenta in vitro

73

Preferential transport and metabolism of glucose in Bergmann glia over Purkinje cells: a multiphoton study of cerebellar slices.  

Science.gov (United States)

Knowing how different cell types handle glucose should help to decipher how energy supply is adjusted to energy demand in the brain. Previously, the uptake of glucose by cultured brain cells was studied in real-time using fluorescent tracers and confocal microscopy. Here, we have adapted this technique to acute slices prepared from the rat cerebellum by means of multiphoton microscopy. The transport of the fluorescent glucose analogs 2NBDG and 6NBDG was several-fold faster in the molecular layer of the cerebellar cortex than in Purkinje cell somata and granule cells. After washout of free tracer, it became apparent that most phosphorylated tracer was located in Bergmann glia, which was confirmed by counterstaining with the glial marker sulforhodamine 101. The effective recovery of fluorescence after photobleaching showed that 2NBDG-P can diffuse horizontally across the molecular layer, presumably through gap junctions between Bergmann glial cells. Our main conclusion is that in acute cerebellar slices, the glucose transport capacity and glycolytic rate of Bergmann glia are several-fold higher than those of Purkinje cells. Given that the cerebellum is largely fueled by glucose and Purkinje neurons are estimated to spend more energy than Bergmann glial cells, these results suggest substantial shuttling of an energy-rich metabolite like lactate between glial cells and neurons. PMID:19062182

Barros, L F; Courjaret, R; Jakoby, P; Loaiza, A; Lohr, C; Deitmer, J W

2009-07-01

74

Glucose Metabolism in Mentally Retarded Children  

International Nuclear Information System (INIS)

Glucose metabolism has been studied in normal, mentally retarded and hypothyroid children who exhibited subnormal I.Q. in spite of an adequate thyroxine dose. Two parameters, the breath and the blood, were examined. Continuous breath analysis following intravenous glucose-U-14C was carried out to examine its end product 14CO2. Blood was analysed half-hourly for the specific activity of glucose in this pool. Data are presented in terms of stable carbon dioxide expiration rate, the maximum specific activity of carbon dioxide attained, the glucose pool of the body and its turnover rate. (author)

75

Glucose metabolism of lactobacillus divergens  

International Nuclear Information System (INIS)

The aim of this study was to compile an optimal growth and selective medium for Lactobacillus divergens and to determine the pathway by which it metabolised glucose. The optimum growth temperature is 25oC which is lower than that of most other lactobacilli. Citrate stimulates growth up to a concentration of 1% while acetate inhibits the organism at neutral pH, but it stimulates growth at pH 8.5 up to a concentration of 0.8%. MRS medium was therefore modified in order to obtain maximum growth of the organism. The acetate was omitted, sucrose was substituted for glucose and the pH was adjusted to 8.5. Sucrose was used, since a neutral pH is obtained after sterilisation of glucose in alkaline (pH ? 7.5) solution due to the degradation of glucose by the Maillard reaction. Various inhibitors and dyes were tested in order to formulate a selective medium. In the present study differently labelled glucose precursors were fermented by L. divergens and the fermentation products isolated by HPLC. The concentrations of acetate and formate were determined by comparison to a standard while the concentration of lactate and glucose was determined by enzymic assay. The radioactivity was determined by liquid scintillation counting and the positional labelling in lactate and acetate by chemical degradation. Fermentation of D-[U-14C]-glucose was included to correct for endogenous product dilution

76

Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: A role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation  

Energy Technology Data Exchange (ETDEWEB)

Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. - Highlights: • DCA modulates tumor progression and chemoresistance. • DCA alters molecules regulating cell survival, glucose metabolism and MDR. • DCA reconstitutes biophysical and cellular composition of tumor microenvironment. • DCA augments BMC cellularity, differentiation and repolarization of macrophages.

Kumar, Ajay; Kant, Shiva; Singh, Sukh Mahendra, E-mail: sukhmahendrasingh@yahoo.com

2013-11-15

77

Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: A role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation  

International Nuclear Information System (INIS)

Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. - Highlights: • DCA modulates tumor progression and chemoresistance. • DCA alters molecules regulating cell survival, glucose metabolism and MDR. • DCA reconstitutes biophysical and cellular composition of tumor microenvironment. • DCA augments BMC cellularity, differentiation and repolarization of macrophages

78

Warburg meets non-coding RNAs: the emerging role of ncRNA in regulating the glucose metabolism of cancer cells.  

Science.gov (United States)

Unlike normal differentiated cells, cancer cells primarily rely on glycolysis to generate energy needed for cellular processes even in normoxia conditions. This phenomenon is called aerobic glycolysis or "the Warburg effect." Aerobic glycolysis is inefficient to generate ATP, but the advantages it confers to cancer cells remain to be fully explained. Several oncogenic signaling pathways, interplaying with enzymes and kinases involved in glucose metabolism, participate in the switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Non-coding RNAs (ncRNAs) are a family of functional RNA molecules that are not further translated into proteins, which exert regulatatory roles in gene transcription and translation. ncRNAs, especially miRNAs and long non-coding RNAs (lncRNAs), may also have great effect on glucose metabolism by targeting not only glycolysis enzymes directly but also oncogenic signaling pathways indirectly. A better understanding of the Warburg effect and the regulatory role of ncRNAs in cancer glucose metabolism may contribute to the treatment of cancers. PMID:25431262

Yu, Chenxiao; Xue, Jiao; Zhu, Wei; Jiao, Yang; Zhang, Shuyu; Cao, Jianping

2014-11-28

79

Glucose metabolism and NADH recycling by Treponema hyodysenteriae, the agent of swine dysentery.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Glucose metabolism and the mechanisms of NADH oxidation by Treponema hyodysenteriae were studied. Under an N2 atmosphere, washed cell suspensions of the spirochete consumed glucose and produced acetate, butyrate, H2, and CO2. Approximately twice as much H2 as CO2 was produced. Determinations of radioactivity in products of [14C]glucose and [14C]pyruvate metabolism and analyses of enzyme activities in cell lysates revealed that glucose was catabolized to pyruvate via the Embden-Meyerhof-Parnas...

Stanton, T. B.

1989-01-01

80

Inhibitors of cannabinoid receptors and glucose metabolism.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

PURPOSE OF REVIEW: Abdominal obesity is closely related to type 2 diabetes and overactivity of the endocannabinoid system. The present review aims at evaluating the role of endocannabinoid system in glucose dysregulation and the effects of cannabinoid 1 receptor blockade on glucose metabolism in both animal models and overweight/obese humans, especially with type 2 diabetes. RECENT FINDINGS: Cannabinoid 1 receptors have been identified not only in the brain, but also in the adipose tissue, th...

Scheen, Andre?; Paquot, Nicolas

2008-01-01

 
 
 
 
81

Effects of gamma-rays and glucose analogs on the energy metabolism of a cell line derived from human cerebral glioma  

International Nuclear Information System (INIS)

Effects of gamma-rays and glucose analogs, 2-deoxy-D-glucose (2-DG), 5-thio-D-glucose (5-TG) and 3-O-methyl glucose (3-O-MG) on cellular energy metabolism have been studied in a cell line, derived from a human cerebral glioma, by analysing intermediates of glycolysis and some important nucleotides (ATP, NAD etc.) using the technique of isotachophoresis. Gamma-irradiation induced a transient decrease in the nucleotide levels accompanied by an accumulation of sugar phosphates, the nucleotide levels recovering in a few hours post-irradiation. 2-DG inhibited glycolysis and reduced the nucleotide levels of irradiated as well as unirradiated cells in a concentration-dependent manner both in presence and absence of respiration, whereas 5-TG and 3-OMG did not show significant effects in the presence of respiration. Reduced energy status observed with 2-DG under respiratory proficient conditions was completely reversed in 2 hr following its removal, whereas such a recovery was not observed in the absence of respiration. These results have important implications in the energy-linked modifications of tumor radiation response using glucose analogs. (author). 36 refs., 6 figs., 4 tabs

82

Glucose metabolism in a rat mammary adenocarcinoma  

International Nuclear Information System (INIS)

Full text: Tumor hypoxia, which decreases therapy response is common in tumors. Glucose metabolism is closely tied to tumor oxygenation and alteration of its metabolism could improve tumor oxygenation. The objective of the study was to compare tissue pharmacokinetics of 14C-2-deoxyglucose (14C2DG) and 14C-glucose in an adenocarcinoma (R3230Ac) and normal control tissue (subcutis:SQ) using a novel fiberoptic scintillation detector. Fischer 344 rats with R3230Ac tumors were anesthetized with Isoflurane and detectors were inserted. Baseline data was acquired for 45 minutes, then 14C2DG or 14C-glucose (i.v.) was injected and data was acquired for 3 hours. After 100mCi of 14C2DG both tissues reached peaks (R3230Ac, 0.4mCi/g; SQ, 0.75mCi/g) 20 minutes post-injection that remained stable for 3 hours. With 200mCi 14C2DG R3230Ac peaked and plateaued at 1.75mCi/g by 50 minutes. SQ peaked (2.25mCi/g) at 20 minutes and decreased to a stable plateau (0.75mCi/g) at 50 minutes. Kinetics of 14C-glucose were different from 14C2DG. R3230Ac and SQ increased over 20 minutes, reaching peaks of 2.4mCi/g and 1.5mCi/g, respectively. A slow decrease followed, but tumor signal (1.25mCi/g) remained higher than SQ (0.5mCi/g). Kinetics of 14C2DG and 14C-glucose were distinctly different. In SQ a wash-in/wash-out effect was observed at 200mCi of 14C2DG. In tumor 00mCi of 14C2DG. In tumor 14C2DG accumulated to a plateau (1.75mCi/g) that persisted out to 3 hours. 14C-glucose signal declined below 14C2DG signal in both tissues, suggesting they both metabolize 14C-glucose and excrete 14C-containing metabolites. PET can assess flouride-deoxyglucose uptake in tumors, which is analogous to our 14C2DG studies. However, PET cannot provide data on glucose metabolism and excretion because there is not a metabolizable fluorinated-glucose analogue that is imageable by PET. In summary, this novel detector has the unique capability to evaluate real-time accumulation, metabolism, and excretion of radiolabeled glucose in tissues before and after metabolic manipulation

83

Effect of 2-deoxy-D-glucose on DNA double strand break repair, cell survival and energy metabolism in euoxic Ehrlich ascites tumour cells  

Energy Technology Data Exchange (ETDEWEB)

Effects of 2-deoxy-D-glucose (2-DG) on DNA double strand break (dsb) repair, cell survival and on the energy metabolism were investigated in exponentially growing Ehrlich ascites tumour (EAT) cells. Cells in suspension were exposed to 40 Gy of X-rays and allowed to repair (up to 4h) with or without 2-DG at 37[sup o]C. DNA dsb rejoining was measured by means of clamped homogeneous electric field (CHEF), a pulsed field gel electrophoresis technique. The fraction of activity released (FAR) during electrophoresis (DNA associated [sup 14]C-thymidine) was used as a parameter to determine the number of dsb present in the DNA. Biphasic kinetics for dsb repair were observed. The presence of 2-DG significantly inhibited the slow component of dsb repair. The presence of 2-DG also enhanced radiation-induced cell killing. ATP content of cells was measured by a bioluminescence method. ATP content in exponentially growing cells was about 4 pg per cell. The level of ATP was reduced by 50% in presence of 2-DG (C[sub 2-DG]/C[sub G] = 1.0). (author).

Jha, B.; Pohlit, W. (L.N. Mithila Univ., Darbhanga (India). Botany Dept.)

1992-10-01

84

Sirtuin 1 stabilization by HuR represses TNF-?- and glucose-induced E-selectin release and endothelial cell adhesiveness in vitro: relevance to human metabolic syndrome.  

Science.gov (United States)

Chronic inflammation and hyperglycaemia, typical features of metabolic diseases, trigger endothelial damage and release of E-selectin, a marker of endothelial activation. In the present study, we investigated molecular pathways involved in the regulation of endothelial cell activation induced by tumour necrosis factor-? (TNF-?) and high glucose. In cultured human umbilical vein endothelial cells (HUVECs), we studied the role of HuR, an ELAV (embryonic lethal, abnormal vision, Drosophila) family RNA-binding protein, and Sirtuin 1 (SIRT1) on E-selectin release and cell adhesion at different glucose concentrations. HuR expression and binding to SIRT1 were also analysed ex vivo in peripheral blood mononuclear cells (PBMCs) of subjects with and without the metabolic syndrome (MS), by immunoprecipitation (IP) of the ribonucleoprotein (RNP) complex. We found that SIRT1 overexpression prevented TNF-?- and high-glucose-dependent nuclear factor-?B (NF-?B)-p65 acetylation, E-selectin promoter activity, E-selectin release and adhesion of THP-1 cells to HUVECs. The same was mimicked by HuR overexpression, which binds and stabilizes SIRT1 mRNA. Importantly, in PBMCs of individuals with MS compared with those without, SIRT1 expression was lower, and the ability of HuR to bind SIRT1 mRNA was significantly reduced, while plasma E-selectin was increased. We conclude that post-transcriptional stabilization of SIRT1 by HuR represses inflammation- and hyperglycaemia-induced E-selectin release and endothelial cell activation. Therefore, increasing SIRT1 expression represents a strategy to counter the accelerated vascular disease in metabolic disorders. PMID:24702436

Ceolotto, Giulio; De Kreutzenberg, Saula Vigili; Cattelan, Arianna; Fabricio, Aline S C; Squarcina, Elisa; Gion, Massimo; Semplicini, Andrea; Fadini, Gian Paolo; Avogaro, Angelo

2014-10-01

85

Alteration of hepatic cells glucose metabolism as a non-cholinergic detoxication mechanism in counteracting diazinon-induced oxidative stress.  

Science.gov (United States)

The aim of this study was to evaluate effects of acute exposure to various doses of diazinon, a widely used synthetic organophosphorus (OP) insecticide on plasma glucose, hepatic cells key enzymes of glycogenolysis and gluconeogenesis, and oxidative stress in rats. Diazinon was administered by gavage at doses of 15, 30 and 60 mg/ kg. The liver was perfused and removed under anaesthesia. The activities of glycogen phosphorylase (GP), phosphoenolpyruvate carboxykinase (PEPCK), thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) were analysed in liver homogenate. Administration of diazinon (15, 30 and 60 mg/kg) increased plasma glucose concentrations by 101.43% (P = 0.001), 103.68% (P = 0.000) and 160.65% (P = 0.000) of control, respectively. Diazinon (15, 30 and 60 mg/kg) increased hepatic GP activity by 43.5% (P = 0.05), 70.3% (P = 0.00) and 117.2% (P = 0.02) of control, respectively. In addition, diazinon (30 and 60 mg/kg) increased hepatic PEPCK by 77.3% (P = 0.000) and 93.5% (P = 0.000) of control, respectively. Diazinon (30 and 60 mg/kg) decreased liver TAC by 38% (P = 0.046) and 48% (P = 0.000) of control, respectively. Also diazinon (30 and 60 mg/kg) increased hepatic cell liver lipid peroxidation by 77% (P = 0.05) and 280% (P = 0.000) of control. The correlations between plasma glucose and hepatic cells TBARS (r2 = 0.537, P = 0.02), between plasma glucose and ChE activity (r2 = 0.81, P = 0.049) and between plasma glucose and hepatic cells GP activity (r2 = 0.833, P = 0.04) were significant. It is concluded that the liver cells are a site of toxic action of diazinon. Diazinon increases glucose release from liver into blood through activation of glycogenolysis and gluconeogenesis as a detoxication non-cholinergic mechanism to overwhelm diazinon-induced toxic stress. The results are in accordance with the hypothesis that OPs are a predisposing factor of diabetes. PMID:17286147

Teimouri, Fatemeh; Amirkabirian, Nasim; Esmaily, Hadi; Mohammadirad, Azadeh; Aliahmadi, Atousa; Abdollahi, Mohammad

2006-12-01

86

Determination of regional glucose metabolism in the brain  

International Nuclear Information System (INIS)

Since the energy requirement of the brain is supplied almost exclusively by glucose, the functional state of the tissue can be estimated and quantitatively demonstrated by reference to the glucose metabolism. The investigation method in most widespread use employs 18F-fluoro-2-deoxy-D-glucose (18FDG) for quantitative imaging of the glucose metabolism by means of PET

87

Cerebral glucose metabolism in childhood onset schizophrenia.  

Science.gov (United States)

Decreased frontal cortical glucose metabolism has been demonstrated in adult schizophrenics both at rest and while engaging in tasks that normally increase frontal metabolism, such as the Continuous Performance Test (CPT). The authors tested the hypothesis that adolescents with childhood onset schizophrenia would also demonstrate hypofrontality while performing the CPT. Cerebral glucose metabolism was examined in 16 adolescents (mean age 14.1 +/- 1.7) with onset of schizophrenia by age 12 (mean age at onset 9.9 +/- 1.8) and 26 healthy adolescents selected to be similar in age, sex and handedness using positron emission tomography and 18F-fluorodeoxyglucose. Patients with childhood onset schizophrenia made fewer correct and more incorrect identifications on the CPT. Region of interest analysis revealed no significant group differences in global cerebral glucose metabolism, but increased metabolic rate in supramarginal gyrus (F = 6.74, P < 0.05) and inferior frontal gyrus/insula (F = 7.09, P < 0.05) and decreased metabolic rate in middle frontal gyrus (F = 6.72, P < 0.05) and superior frontal gyrus (t = 2.04, P < 0.05) in schizophrenics. Comparison of effect sizes with an identically designed study of adult schizophrenics did not indicate more severe hypofrontality in childhood onset schizophrenia. Pixel-based analyses indicated a more complex pattern of group differences in cerebral metabolism with bilaterally increased cerebellar metabolic rate in childhood onset schizophrenics. These findings suggest that childhood onset schizophrenia may be associated with a similar, but not more severe, degree of hypofrontality relative to that seen in adult onset schizophrenia. PMID:9437771

Jacobsen, L K; Hamburger, S D; Van Horn, J D; Vaituzis, A C; McKenna, K; Frazier, J A; Gordon, C T; Lenane, M C; Rapoport, J L; Zametkin, A J

1997-10-31

88

Targeting glucose metabolism in patients with cancer.  

Science.gov (United States)

Nearly a century ago, Otto Warburg made the astute observation that the metabolic properties of cancer cells differ markedly from those of normal cells. Several decades passed before the concept of exploiting cancer cell metabolism came into clinical practice with the advent of chemotherapy, the underlying principle of which is to target rapidly dividing cells by interfering with critical processes that are all, on some level, driven by cell metabolism. Although chemotherapy can be quite effective, success rates are highly variable and the adverse effects associated with treatment often outweigh the benefits due to the fact that chemotherapy is indiscriminately cytotoxic against all rapidly dividing cells, cancerous or healthy. During the past several years, a more intricate understanding of cancer cell metabolism has permitted the development of targeted therapies that aim to specifically target cancer cells and spare healthy tissue by exploiting the altered metabolism of cancer cells. The identification of new metabolic targets and the subsequent development of small-molecule inhibitors of metabolic enzymes have demonstrated the utility and promise of targeting cancer cell metabolism as an anticancer strategy. This review summarizes recent advances in the identification and characterization of several metabolic enzymes as emerging anticancer targets. PMID:24374503

Elf, Shannon E; Chen, Jing

2014-03-15

89

Glucose availability and glycolytic metabolism dictate glycosphingolipid levels.  

Science.gov (United States)

Cancer therapeutics has seen an emergence and re-emergence of two metabolic fields in recent years, those of bioactive sphingolipids and glycolytic metabolism. Anaerobic glycolysis and its implications in cancer have been at the forefront of cancer research for over 90 years. More recently, the role of sphingolipids in cancer cell metabolism has gained recognition, notably ceramide's essential role in programmed cell death and the role of the glucosylceramide synthase (GCS) in chemotherapeutic resistance. Despite this knowledge, a direct link between these two fields has yet to be definitively drawn. Herein, we show that in a model of highly glycolytic cells, generation of the glycosphingolipid (GSL) glucosylceramide (GlcCer) by GCS was elevated in response to increased glucose availability, while glucose deprivation diminished GSL levels. This effect was likely substrate dependent, independent of both GCS levels and activity. Conversely, leukemia cells with elevated GSLs showed a significant change in GCS activity, but no change in glucose uptake or GCS expression. In a leukemia cell line with elevated GlcCer, treatment with inhibitors of glycolysis or the pentose phosphate pathway (PPP) significantly decreased GlcCer levels. When combined with pre-clinical inhibitor ABT-263, this effect was augmented and production of pro-apoptotic sphingolipid ceramide increased. Taken together, we have shown that there exists a definitive link between glucose metabolism and GSL production, laying the groundwork for connecting two distinct yet essential metabolic fields in cancer research. Furthermore, we have proposed a novel combination therapeutic option targeting two metabolic vulnerabilities for the treatment of leukemia. PMID:25145677

Stathem, Morgan; Marimuthu, Subathra; O'Neal, Julie; Rathmell, Jeffrey C; Chesney, Jason A; Beverly, Levi J; Siskind, Leah J

2015-01-01

90

Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: a role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation.  

Science.gov (United States)

Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. PMID:24051182

Kumar, Ajay; Kant, Shiva; Singh, Sukh Mahendra

2013-11-15

91

Correlation of hypoxic cell fraction with glucose metabolic rate in gliomas with {sup 18}F-Fluoromisonidazole (FMISO) and {sup 18}F- Fluorodeoxyglucose (FDG) positron emission tomography (PET)  

Energy Technology Data Exchange (ETDEWEB)

Full text: FDG-PET studies of brain tumours to measure tumour activity are well established, with regions of higher grade tumour utilising more glucose compared to lower grade tumour tissue and normal tissue. FDG uptake in tumour cells may reflect anaerobic glycolysis, but this has not been proven in- vivo. FMISO is a novel positron-emitting compound that has been shown to selectively identify hypoxic but viable tissue, which may contribute to chemoradiotherapy resistance in tumour cells. Studies correlating measurements of regional hypoxia and glucose activity within brain tumours prior to therapy may help gain further insight into the relationship between hypoxic tumour tissue and resistance to chemoradiotherapy. Three patients with newly diagnosed primary brain tumours have been prospectively studied with FMISO-PET, FDG-PET and MRI, prior to surgery. Each patient presented with a suspected primary brain glioma on MRI, which were all confirmed to be high grade glioma on subsequent histology at surgery FMISO-PET, FDG-PET and MRI images of all patients were co-registered to precisely identify the areas of metabolic activity within tumour and surrounding cortical tissue. All gliomas demonstrated areas of FMISO uptake, which corresponded to areas of maximal FDG uptake, indicating a correlation between hypoxic areas within tumour with areas of increased glucose metabolic activity. This supports the hypothesis that hypoxic areas within tumour tissue may be associated with increased FDG uptake, although whether hypoxia itself increases FDG uptake remains controversial. These correlative studies characterising areas of hypoxia and glucose activity should hopefully assist in future therapeutic manipulations to improve the outcome from treatment of primary brain tumours

Tauro, A.J.; Scott, A.M.; Hannah, A.; Pathmaraj, K.; Tochon-Danguy, H.; Sachinidis, J.I.; Chan, J.D.; Berlangieri, S.U.; Egan, G.F.; Fabinyi, G.; McKay, W.J.; Cher, L.M. [Ludwig Institute for Cancer Research, Vic, (Australia). Department of Nuclear Medicine and Centre for PET]|[Austin and Repatriation Medical Centre, Heidelberg, VIC (Australia). Department of Neurosurgery

1998-06-01

92

Correlation of hypoxic cell fraction with glucose metabolic rate in gliomas with 18F-Fluoromisonidazole (FMISO) and 18F- Fluorodeoxyglucose (FDG) positron emission tomography (PET)  

International Nuclear Information System (INIS)

Full text: FDG-PET studies of brain tumours to measure tumour activity are well established, with regions of higher grade tumour utilising more glucose compared to lower grade tumour tissue and normal tissue. FDG uptake in tumour cells may reflect anaerobic glycolysis, but this has not been proven in- vivo. FMISO is a novel positron-emitting compound that has been shown to selectively identify hypoxic but viable tissue, which may contribute to chemoradiotherapy resistance in tumour cells. Studies correlating measurements of regional hypoxia and glucose activity within brain tumours prior to therapy may help gain further insight into the relationship between hypoxic tumour tissue and resistance to chemoradiotherapy. Three patients with newly diagnosed primary brain tumours have been prospectively studied with FMISO-PET, FDG-PET and MRI, prior to surgery. Each patient presented with a suspected primary brain glioma on MRI, which were all confirmed to be high grade glioma on subsequent histology at surgery FMISO-PET, FDG-PET and MRI images of all patients were co-registered to precisely identify the areas of metabolic activity within tumour and surrounding cortical tissue. All gliomas demonstrated areas of FMISO uptake, which corresponded to areas of maximal FDG uptake, indicating a correlation between hypoxic areas within tumour with areas of increased glucose metabolic activity. This supports the hypothesis that hypoxic areas within tumour tissue may be associated withithin tumour tissue may be associated with increased FDG uptake, although whether hypoxia itself increases FDG uptake remains controversial. These correlative studies characterising areas of hypoxia and glucose activity should hopefully assist in future therapeutic manipulations to improve the outcome from treatment of primary brain tumours

93

Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism  

Science.gov (United States)

The brain keenly depends on glucose for energy, and mammalians have redundant systems to control glucose production. An increase in circulating glucose inhibits glucose production in the liver, but this negative feedback is impaired in type 2 diabetes. Here we report that a primary increase in hypothalamic glucose levels lowers blood glucose through inhibition of glucose production in rats. The effect of glucose requires its conversion to lactate followed by stimulation of pyruvate metabolism, which leads to activation of adenosine triphosphate (ATP)-sensitive potassium channels. Thus, interventions designed to enhance the hypothalamic sensing of glucose may improve glucose homeostasis in diabetes.

Lam, Tony K. T.; Gutierrez-Juarez, Roger; Pocai, Alessandro; Rossetti, Luciano

2005-08-01

94

D-Lactate production as a function of glucose metabolism in Saccharomyces cerevisiae.  

Science.gov (United States)

Methylglyoxal, a reactive, toxic dicarbonyl, is generated by the spontaneous degradation of glycolytic intermediates. Methylglyoxal can form covalent adducts with cellular macromolecules, potentially disrupting cellular function. We performed experiments using the model organism Saccharomyces cerevisiae, grown in media containing low, moderate and high glucose concentrations, to determine the relationship between glucose consumption and methylglyoxal metabolism. Normal growth experiments and glutathione depletion experiments showed that metabolism of methylglyoxal by log-phase yeast cultured aerobically occurred primarily through the glyoxalase pathway. Growth in high-glucose media resulted in increased generation of the methylglyoxal metabolite D-lactate and overall lower efficiency of glucose utilization as measured by growth rates. Cells grown in high-glucose media maintained higher glucose uptake flux than cells grown in moderate-glucose or low-glucose media. Computational modelling showed that increased glucose consumption may impair catabolism of triose phosphates as a result of an altered NAD?:NADH ratio. PMID:23361949

Stewart, Benjamin J; Navid, Ali; Kulp, Kristen S; Knaack, Jennifer L S; Bench, Graham

2013-02-01

95

Brain glucose metabolism in thalamic syndrome.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Regional brain glucose metabolism was studied in a case of postischaemic thalamic syndrome. Despite a normal density of the thalamus on MRI and CT images, a 17% relative hypometabolism was found in the posterior thalamus on the affected side. This observation of functional anomalies in the posterior thalamic complex in case of thalamic syndrome is compatible with a deregulated processing of pain-related information at this level.

Laterre, Emile-christian; Volder, Anne; Goffinet, Andre?

1988-01-01

96

High Passage MIN6 Cells Have Impaired Insulin Secretion with Impaired Glucose and Lipid Oxidation  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Type 2 diabetes is a metabolic disorder characterized by the inability of beta-cells to secrete enough insulin to maintain glucose homeostasis. MIN6 cells secrete insulin in response to glucose and other secretagogues, but high passage (HP) MIN6 cells lose their ability to secrete insulin in response to glucose. We hypothesized that metabolism of glucose and lipids were defective in HP MIN6 cells causing impaired glucose stimulated insulin secretion (GSIS). HP MIN6 cells had no first phase an...

Cheng, Kim; Delghingaro-augusto, Viviane; Nolan, Christopher J.; Turner, Nigel; Hallahan, Nicole; Andrikopoulos, Sofianos; Gunton, Jenny E.

2012-01-01

97

Glucose transporters and ATP-gated K+ (KATP) metabolic sensors are present in type 1 taste receptor 3 (T1r3)-expressing taste cells.  

Science.gov (United States)

Although the heteromeric combination of type 1 taste receptors 2 and 3 (T1r2 + T1r3) is well established as the major receptor for sugars and noncaloric sweeteners, there is also evidence of T1r-independent sweet taste in mice, particularly so for sugars. Before the molecular cloning of the T1rs, it had been proposed that sweet taste detection depended on (a) activation of sugar-gated cation channels and/or (b) sugar binding to G protein-coupled receptors to initiate second-messenger cascades. By either mechanism, sugars would elicit depolarization of sweet-responsive taste cells, which would transmit their signal to gustatory afferents. We examined the nature of T1r-independent sweet taste; our starting point was to determine if taste cells express glucose transporters (GLUTs) and metabolic sensors that serve as sugar sensors in other tissues. Using RT-PCR, quantitative PCR, in situ hybridization, and immunohistochemistry, we determined that several GLUTs (GLUT2, GLUT4, GLUT8, and GLUT9), a sodium-glucose cotransporter (SGLT1), and two components of the ATP-gated K(+) (K(ATP)) metabolic sensor [sulfonylurea receptor (SUR) 1 and potassium inwardly rectifying channel (Kir) 6.1] were expressed selectively in taste cells. Consistent with a role in sweet taste, GLUT4, SGLT1, and SUR1 were expressed preferentially in T1r3-positive taste cells. Electrophysiological recording determined that nearly 20% of the total outward current of mouse fungiform taste cells was composed of K(ATP) channels. Because the overwhelming majority of T1r3-expressing taste cells also express SUR1, and vice versa, it is likely that K(ATP) channels constitute a major portion of K(+) channels in the T1r3 subset of taste cells. Taste cell-expressed glucose sensors and K(ATP) may serve as mediators of the T1r-independent sweet taste of sugars. PMID:21383163

Yee, Karen K; Sukumaran, Sunil K; Kotha, Ramana; Gilbertson, Timothy A; Margolskee, Robert F

2011-03-29

98

The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells.  

Science.gov (United States)

The H19 lncRNA has been implicated in development and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly decreased in muscle of human subjects with type-2 diabetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is recapitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia downregulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogenesis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells. PMID:25399420

Gao, Yuan; Wu, Fuju; Zhou, Jichun; Yan, Lei; Jurczak, Michael J; Lee, Hui-Young; Yang, Lihua; Mueller, Martin; Zhou, Xiao-Bo; Dandolo, Luisa; Szendroedi, Julia; Roden, Michael; Flannery, Clare; Taylor, Hugh; Carmichael, Gordon G; Shulman, Gerald I; Huang, Yingqun

2014-12-16

99

Glucose metabolism by lymphocytes, macrophages, and tumor cells from Walker 256 tumor-bearing rats supplemented with fish oil for one generation.  

Science.gov (United States)

Here we investigated the effect of lifelong supplementation of the diet with coconut fat (CO, rich in saturated fatty acids) or fish oil (FO, rich in n-3 polyunsaturated fatty acids) on tumor growth and lactate production from glucose in Walker 256 tumor cells, peritoneal macrophages, spleen, and gut-associated lymphocytes. Female Wistar rats were supplemented with CO or FO prior to mating and then throughout pregnancy and gestation and then the male offspring were supplemented from weaning until 90 days of age. Then they were inoculated subcutaneously with Walker 256 tumor cells. Tumor weight at 14 days in control rats (those fed standard chow) and CO supplemented was approximately 30 g. Supplementation of the diet with FO significantly reduced tumor growth by 76%. Lactate production (nmol h(-1) mg(-1) protein) from glucose by Walker 256 cells in the group fed regular chow (W) was 381.8 +/- 14.9. Supplementation with coconut fat (WCO) caused a significant reduction in lactate production by 1.6-fold and with fish oil (WFO) by 3.8-fold. Spleen lymphocytes obtained from W and WCO groups had markedly increased lactate production (553 +/- 70 and 635 +/- 150) when compared to non-tumor-bearing rats ( approximately 260 +/- 30). FO supplementation reduced significantly the lactate production (297 +/- 50). Gut-associated lymphocytes obtained from W and WCO groups increased lactate production markedly (280 +/- 31 and 276 +/- 25) when compared to non-tumor-bearing rats ( approximately 90 +/- 18). FO supplementation reduced significantly the lactate production (168 +/- 14). Lactate production by peritoneal macrophages was increased by tumor burden but there was no difference between the groups fed the various diets. Lifelong consumption of FO protects against tumor growth and modifies glucose metabolism in Walker tumor cells and lymphocytes but not in macrophages. PMID:18946876

Aikawa, Júlia; Moretto, Karla D; Denes, Francilene; Yamazaki, Ricardo K; Freitas, Fábio A P; Hirabara, Sandro M; Tchaikovski, Osvaldo; Kaelher, Marcos de A; Brito, Gleysson A P; Curi, Rui; Fernandes, Luiz C

2008-12-01

100

Brain Glucose Metabolism Controls Hepatic Glucose and Lipid Production  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Brain glucose-sensing mechanisms are implicated in the regulation of feeding behavior and hypoglycemic-induced hormonal counter-regulation. This commentary discusses recent findings indicating that the brain senses glucose to regulate both hepatic glucose and lipid production.

Lam, Tony K. T.

2007-01-01

 
 
 
 
101

Simvastatin inhibits glucose metabolism and legumain activity in human myotubes.  

Science.gov (United States)

Simvastatin, a HMG-CoA reductase inhibitor, is prescribed worldwide to patients with hypercholesterolemia. Although simvastatin is well tolerated, side effects like myotoxicity are reported. The mechanism for statin-induced myotoxicity is still poorly understood. Reports have suggested impaired mitochondrial dysfunction as a contributor to the observed myotoxicity. In this regard, we wanted to study the effects of simvastatin on glucose metabolism and the activity of legumain, a cysteine protease. Legumain, being the only known asparaginyl endopeptidase, has caspase-like properties and is described to be involved in apoptosis. Recent evidences indicate a regulatory role of both glucose and statins on cysteine proteases in monocytes. Satellite cells were isolated from the Musculus obliquus internus abdominis of healthy human donors, proliferated and differentiated into polynuclear myotubes. Simvastatin with or without mevalonolactone, farnesyl pyrophosphate or geranylgeranyl pyrophosphate were introduced on day 5 of differentiation. After 48 h, cells were either harvested for immunoblotting, ELISA, cell viability assay, confocal imaging or enzyme activity analysis, or placed in a fuel handling system with [¹?C]glucose or [³H]deoxyglucose for uptake and oxidation studies. A dose-dependent decrease in both glucose uptake and oxidation were observed in mature myotubes after exposure to simvastatin in concentrations not influencing cell viability. In addition, simvastatin caused a decrease in maturation and activity of legumain. Dysregulation of glucose metabolism and decreased legumain activity by simvastatin points out new knowledge about the effects of statins on skeletal muscle, and may contribute to the understanding of the myotoxicity observed by statins. PMID:24416446

Smith, Robert; Solberg, Rigmor; Jacobsen, Linn Løkken; Voreland, Anette Larsen; Rustan, Arild Christian; Thoresen, G Hege; Johansen, Harald Thidemann

2014-01-01

102

Effects of Glucose on Differentiation and Fat Metabolism of Chicken Preadipocytes  

Directory of Open Access Journals (Sweden)

Full Text Available The present study was carried out to illustrate the effect of glucose on chicken (Gallus gallus preadipocyte differentiation and fat metabolism. Adipocyte differentiation was initiated by maintaining confluent cells in a glucose-free medium supplemented with different concentrations of glucose. Upon exposure to high concentrations of glucose (25 mmol L-1, Peroxisome Proliferator-Activated Receptor ? (PPAR? and CCAAT/Enhancer-Binding Protein ? (C/EBP? as adipocyte differentiation markers were significantly increased compared with control cells. The morphology of the glucose-treated cells changed from fibroblast-like to polygonal and cells treated with moderate concentrations of glucose (15 mmol L-1 accumulated the most number of cytoplasmic lipid droplets as estimated by Oil red O staining. Compared with control cells varying concentrations of glucose affected the mRNA expression and protein levels for Fatty Acid Synthesis (FAS and Adipose Triglyceride Lipase (ATGL, the master regulators of fat metabolism. Moreover, the mRNA expression levels and protein contents of fatty acid transporters in glucose-treated cells were higher than in untreated cells. These results indicated that glucose is essential material for chick adipocytes differentiation. Moreover, overhigh concentrations of glucose maybe stimulate lipolysis in the cells.

Zhao Taotao

2012-01-01

103

D-Glucose and D-mannose-based metabolic probes. Part 3: Synthesis of specifically deuterated D-glucose, D-mannose, and 2-deoxy-D-glucose.  

Science.gov (United States)

Altered carbohydrate metabolism in cancer cells was first noted by Otto Warburg more than 80 years ago. Upregulation of genes controlling the glycolytic pathway under normoxia, known as the Warburg effect, clearly differentiates malignant from non-malignant cells. The resurgence of interest in cancer metabolism aims at a better understanding of the metabolic differences between malignant and non-malignant cells and the creation of novel therapeutic and diagnostic agents exploiting these differences. Modified d-glucose and d-mannose analogs were shown to interfere with the metabolism of their respective monosaccharide parent molecules and are potentially clinically useful anticancer and diagnostic agents. One such agent, 2-deoxy-d-glucose (2-DG), has been extensively studied in vitro and in vivo and also clinically evaluated. Studies clearly indicate that 2-DG has a pleiotropic mechanism of action. In addition to effectively inhibiting glycolysis, 2-DG has also been shown to affect protein glycosylation. In order to better understand its molecular mechanism of action, we have designed and synthesized deuterated molecular probes to study 2-DG interference with d-glucose and d-mannose metabolism using mass spectrometry. We present here the synthesis of all desired probes: 2-deutero-d-glucose, 2-deutero-d-mannose, 6-deutero-d-glucose, 6-deutero-d-mannose, and 2-deutero-2-deoxy-d-glucose as well as their complete chemical characterization. PMID:23376241

Fokt, Izabela; Skora, Stanislaw; Conrad, Charles; Madden, Timothy; Emmett, Mark; Priebe, Waldemar

2013-03-01

104

Cilostazol Enhances Oxidative Glucose Metabolism in Both Neurons and Astroglia without Increasing Ros Production  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Cilostazol, a potent inhibitor of type 3 phosphodiesterase (PDE3), has recently been reported to exert neuroprotective effects during acute cerebral ischemic injury. These effects are, at least in part, mediated by the inhibition of oxidative cell death. However, the effects of cilostazol on glucose metabolism in brain cells have not been determined. In the present study, we examined the effects of cilostazol on the oxidative metabolism of glucose and the resultant formation of reactive oxyge...

Shinichi Takahashi; Yoshikane Izawa; Norihiro Suzuki

2011-01-01

105

Glucose-dependent glucose transporter 1 expression and its impact on viability of thyroid cancer cells.  

Science.gov (United States)

Cancer cells exhibit an altered metabolism characterized by enhanced glycolysis and glucose consumption. In glucose?addicted cancer cells upregulation of glucose transport across the plasma membrane is mediated by a family of facilitated glucose transporter proteins, particularly glucose transporter 1 (GLUT1). The aim of the present study was to investigate the impact of GLUT1 expression on glucose uptake and viability of FTC-133 and 8305c thyroid cancer cells growing in hypoglycemic, normoglycemic and hyperglycemic conditions. The results showed that the total expression of GLUT1 was higher in the two cell types growing in low glucose compared to cells growing in normoglycemia or hyperglycemia and this was correlated with AKT Ser473 phosphorylation but not with the expression of hypoxia inducible factor ? (HIF1?). However, the membrane expression of GLUT1 was correlated with HIF1? expression. HIF1? expression was positively correlated with the glucose concentration in FTC-133 cells, whereas this expression was inversely correlated in 8305c cells. Glucose uptake was dependent on the membrane level of GLUT1 but not total GLUT1 expression. Downregulation of GLUT1 expression by RNAi in FTC-133 cells caused a reduction in glucose uptake but did not significantly affect cell viability. In the case of 8305c cells showing low endogenous GLUT1 expression and lack of HIF1? expression in normoxic conditions GLUT1 RNAi impacted cell viability. These data suggested that GLUT1 may be part of an AKT1-dependent mechanism allowing cells to survive in low levels of glucose. Glucose concentration inversely affected HIF1? expression and the level of GLUT1 in membrane as well as glucose uptake in FTC-133 and 8305c cells. The extent of GLUT1 impact on cell viability was also cell-type-dependent. PMID:25502934

Jó?wiak, Pawe?; Krze?lak, Anna; Bry?, Magdalena; Lipi?ska, Anna

2015-02-01

106

Glucose Metabolism in Breast Cancer and its Implication in Cancer Therapy  

Directory of Open Access Journals (Sweden)

Full Text Available It is well known that malignant cells have accelerated glucose uptake and metabolism in order to maintain their fast proliferation rates. With the increased influx of glucose into cancer cells, glycolysis is facilitated through a coordinated regulation of metabolic enzymes and pyruvate consumption. Shiftting from mitochondrial oxidative phosphorylation to glycolysis and other pathways such as pentose phosphate pathway (PPP and de novo fatty acid synthesis in the breast tumor provides not only energy but also the materials needed for cell proliferation. Glucose augmentation in tumor cells can be due to the elevated level of glucose transporter (GLUT proteins, such as the over-expression of GLUT1 and expression of GLUT5 in breast cancers. Moreover, other factors such as hypoxia-inducible factor-1 (HIF-1, estrogen and growth factors are important modulators of glucose metabolism in the progression of breast carcinomas. Therapies targeting at the glycolytic pathway, fatty acid synthesis and GLUTs expression are currently being investigated. Restoring tumor cells to its normal glucose metabolic state would endow tumor specific and accessible treatment that targets glucose metabolism.

Yuewen Gong

2011-05-01

107

Energetics of Glucose Metabolism: A Phenomenological Approach to Metabolic Network Modeling  

Directory of Open Access Journals (Sweden)

Full Text Available A new formalism to describe metabolic fluxes as well as membrane transport processes was developed. The new flux equations are comparable to other phenomenological laws. Michaelis-Menten like expressions, as well as flux equations of nonequilibrium thermodynamics, can be regarded as special cases of these new equations. For metabolic network modeling, variable conductances and driving forces are required to enable pathway control and to allow a rapid response to perturbations. When applied to oxidative phosphorylation, results of simulations show that whole oxidative phosphorylation cannot be described as a two-flux-system according to nonequilibrium thermodynamics, although all coupled reactions per se fulfill the equations of this theory. Simulations show that activation of ATP-coupled load reactions plus glucose oxidation is brought about by an increase of only two different conductances: a [Ca2+] dependent increase of cytosolic load conductances, and an increase of phosphofructokinase conductance by [AMP], which in turn becomes increased through [ADP] generation by those load reactions. In ventricular myocytes, this feedback mechanism is sufficient to increase cellular power output and O2 consumption several fold, without any appreciable impairment of energetic parameters. Glucose oxidation proceeds near maximal power output, since transformed input and output conductances are nearly equal, yielding an efficiency of about 0.5. This conductance matching is fulfilled also by glucose oxidation of ?-cells. But, as a price for the metabolic mechanism of glucose recognition, ?-cells have only a limited capability to increase their power output.

Frank Diederichs

2010-08-01

108

Features of regional cerebral glucose metabolism abnormality in corticobasal degeneration.  

Science.gov (United States)

We studied regional cerebral glucose metabolism in 15 patients with a clinical diagnosis of corticobasal degeneration (CBD), 15 patients with probable Alzheimer's disease (AD), and 15 healthy controls for 19 brain regions. Asymmetry in regional glucose metabolism was found in the central and frontal cortices in patients with CBD as compared with either the normal controls or the patients with AD. Regional glucose metabolism in CBD patients was significantly lower in the paracentral and superior parietal areas and thalamus than in patients with AD. Relative glucose metabolism in patients with CBD was significantly higher in the posterior cingulate, medial temporal and basal frontal areas, and significantly lower in the paracentral and superior parietal areas than in those with AD. These features of regional glucose metabolic abnormality in CBD may correspond to neurological and cognitive disturbances peculiar to CBD. PMID:10765044

Hirono, N; Ishii, K; Sasaki, M; Kitagaki, H; Hashimoto, M; Imamura, T; Tanimukai, S; Hanihara, T; Kazui, H; Mori, E

2000-01-01

109

PTEN deficiency and mutant p53 confer glucose-addiction to thyroid cancer cells: impact of glucose depletion on cell proliferation, cell survival, autophagy and cell migration  

Science.gov (United States)

Proliferating cancer cells oxidize glucose through the glycolytic pathway. Since this metabolism is less profitable in terms of ATP production, cancer cells consume large quantity of glucose, and those that experience insufficient blood supply become glucose-addicted. We have analyzed the response to glucose depletion in WRO and FTC133 follicular thyroid cancer cells, which differ in the expression of two key regulators of the glucose metabolism. WRO cells, which express wild type p53 and PTEN, showed a higher rate of cell proliferation and were much less sensitive to glucose-depletion than FTC133 cells, which are PTEN null and express mutant p53. Glucose depletion slowed-down the autophagy flux in FTC133 cells, not in WRO cells. In a wound-healing assay, WRO cells were shown to migrate faster than FTC133 cells. Glucose depletion slowed down the cell migration rate, and these effects were more evident in FTC133 cells. Genetic silencing of either wild-type PTEN or p53 in WRO cells resulted in increased uptake of glucose, whereas the ectopic expression of PTEN in FTC133 cells resulted in diminished glucose uptake. In conclusion, compared to WRO, FTC133 cells were higher glucose up-taker and consumer. These data do not support the general contention that cancer cells lacking PTEN or expressing the mutant p53R273H are more aggressive and prone to better face glucose depletion. We propose that concurrent PTEN deficiency and mutant p53 leads to a glucose-addiction state that renders the cancer cell more sensitive to glucose restriction. The present observation substantiates the view that glucose-restriction may be an adjuvant strategy to combat these tumours. PMID:25221641

Morani, Federica; Phadngam, Suratchanee; Follo, Carlo; Titone, Rossella; Thongrakard, Visa; Galetto, Alessandra; Alabiso, Oscar; Isidoro, Ciro

2014-01-01

110

Berberine Moderates Glucose and Lipid Metabolism through Multipathway Mechanism  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Berberine is known to improve glucose and lipid metabolism disorders, but the mechanism is still under investigation. In this paper, we explored the effects of berberine on the weight, glucose levels, lipid metabolism, and serum insulin of KKAy mice and investigated its possible glucose and lipid-regulating mechanism. We randomly divided KKAy mice into two groups: berberine group (treated with 250?mg/kg/...

Hongding Xiang; Qi Sun; Xiaofang Sun; Tao Yuan; Wenhui Li; Tong Wang; Kai Feng; Xinhua Xiao; Qian Zhang; Heng Wang

2011-01-01

111

A distinct metabolic signature predicts development of fasting plasma glucose  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Abstract Background High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers...

Hische Manuela; Larhlimi Abdelhalim; Schwarz Franziska; Fischer-Rosinský Antje; Bobbert Thomas; Assmann Anke; Catchpole Gareth S; Fh, Pfeiffer Andreas; Willmitzer Lothar; Selbig Joachim; Spranger Joachim

2012-01-01

112

Utilization of dietary glucose in the metabolic syndrome  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Abstract This review is focused on the fate of dietary glucose under conditions of chronically high energy (largely fat) intake, evolving into the metabolic syndrome. We are adapted to carbohydrate-rich diets similar to those of our ancestors. Glucose is the main energy staple, but fats are our main energy reserves. Starvation drastically reduces glucose availability, forcing the body to shift to fatty acids as main energy substrate, sparing glucose and amino acids. We are not prepa...

Alemany Marià

2011-01-01

113

A review of metabolism of labeled glucoses for use in measuring glucose recycling  

Energy Technology Data Exchange (ETDEWEB)

The fate of tritium from each carbon of D-glucose and the metabolism of L-glucose and 2-deoxy-D-glucose are known. Differences in metabolism of labeled glucoses can be used to quantify physical and chemical recycling of glucose. Only physical recycling is measured by (1-{sup 3}H)-L-glucose, whereas (U-{sup 14}C)-D-glucose measures total recycling. The difference between (1-{sup 3}H)-L-glucose and (U-{sup 14}C)-D-glucose, therefore, is chemical recycling. Recycling from extracellular binding sites and hepatic glucose 6-phosphate can be measured by difference between (1,2-{sup 3}H)-2-deoxy-D-glucose and (1-{sup 3}H)-L-glucose, and the difference in irreversible loss of the two will measure extrahepatic uptake of D-glucose. Recycling via Cori-alanine cycle plus CO{sub 2} is the difference in irreversible loss measured by using (6-{sup 3}H)-glucose and (U-{sup 14}C)-D-glucose. Recycling via the hexose monophosphate pathway can be determined by difference in irreversible loss between (1-{sup 3}H)-D-glucose and (6-{sup 3}H)-D-glucose. Recycling via CO{sub 2} and glycerol must be measured directly with (U-{sup 14}C)glucose, bicarbonate, and glycerol. Recycling via hepatic glycogen can be estimated by subtracting all other measured chemical recycling from total chemical recycling. This review describes means to quantify glucose recycling in vivo, enabling studies of mechanisms for conservation and utilization of glucose. 54 references.

Russell, R.W.; Young, J.W. (Iowa State Univ., Ames (USA))

1990-04-01

114

276 PHOSPHOINOSITIDE 3-KINASE REGULATES EXPRESSION OF KEY ENZYMES AND CELLULAR TRANSPORTERS OF GLUCOSE METABOLISM IN CUMULUS CELLS OF BOVINE COCs CULTURED IN VITRO.  

Science.gov (United States)

The aim was to analyse the function of the PI3K pathway during oocyte maturation in bovine by use of the specific inhibitor, LY294002. Genes studied in cumulus cells (CC) were PDH, G6PDH, GLUT1, and GLUT4. PDH is an important enzyme for oxidative metabolism, G6PDH is related to resumption and progression of oocyte meiosis, and GLUT1 and GLUT4 are glucose transporters. This study was performed in defined medium (MIV B) in absence or presence of 10ngmL(-1) of FSH. Polar body extrusion was analysed after culture and correlated with gene expression. Experimental methods were bovine COC (n=35-40/well, n=3 replicates) collected from ovaries obtained from abattoirs (DF, Brazil) and cultivated in either 400µL of medium MIV B, or MIV B+100µM of LY294002, or MIV B+10ngmL(-1) of FSH; or MIV B+10ngmL(-1) of FSH+100µM of LY294002 during 22 to 24h. After culture, COC were mechanically denuded and CC from 20 COC/group were isolated. Gene expression of GLUT1, GLUT4, G6PDH, and PDH were measured by real time PCR. The CC of immature COC were also collected and analysed as the calibrator group. Student-Newman-Keuls was performed as a statistical test. The percentage of oocytes that extruded the polar body was determined. Two-way ANOVA, followed by Bonferroni test, and t-test were performed to determine statistical significance. In MIV B, the polar body extrusion rate was 25.48±7.64%, while FSH increased it up to 74.52±10.58% (P<0.05). The extrusion of polar body was inhibited by LY294002 in the absence or presence of FSH (67.51±6.13 and 31.02±16.97%, respectively, P<0.05). Gene expression of PDH was not altered by any culture medium in contrast to GLUT1, GLUT4, and G6PDH expression (Table 1). Only G6PDH expression showed the same pattern as the polar body extrusion, in absence or presence of FSH. In conclusion, PI3-K inhibition affects polar body extrusion and expression of genes related to glucose metabolism in CC. Lower G6PDH expression in CC may be related to low rates of polar body extrusion in treated oocytes. PMID:25472324

Kaiser de Souza, D; Salles, L P; Camargo, R; Dolabela de Lima, B; Torres, F A G; Rosa E Silva, A A M

2014-12-01

115

The effect of ascorbate, 2-deoxy-D-glucose and dichloroacetate on the growth and the glucose metabolism of neuroblastoma cells with or without N-myc-amplification  

Digital Repository Infrastructure Vision for European Research (DRIVER)

For decades there has been a controversy on the benefit of using ascorbate (AA) in cancer therapy. Lately, three articles in PNAS by Marc Levine et al. (NIH) generated new interest in the use of high dose ascorbate: First, high doses of ascorbate were shown to be cytotoxic to human lymphoma and mamma carcinoma cell lines in vitro. Cytotoxicity was mediated by H2O2 (Chen et al. 2005). Secondly, ascorbyl radical and H2O2 could be detected in the extracellular fluid of rats after intravenous app...

Deubzer, Beate Johanna Eleonore

2010-01-01

116

Regional glucose metabolism using PETT in normal and psychiatric populations  

International Nuclear Information System (INIS)

The metabolism of 18F-2-deoxy-2-fluoro-D-glucose (18FDG) in 150 subjects including normals, schizophrenics, senile dementias, and primary affective disorders was studied. Some of the data analyzed to date are discussed

117

Regional glucose metabolism using PETT in normal and psychiatric populations  

Energy Technology Data Exchange (ETDEWEB)

The metabolism of /sup 18/F-2-deoxy-2-fluoro-D-glucose (/sup 18/FDG) in 150 subjects including normals, schizophrenics, senile dementias, and primary affective disorders was studied. Some of the data analyzed to date are discussed.

Brodie, J.D.; Wolf, A.P.; Volkow, N.

1982-01-01

118

Postprandial gut hormone responses and glucose metabolism in cholecystectomized patients  

DEFF Research Database (Denmark)

Preclinical studies suggest that gallbladder emptying, via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells, may play a significant role in the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and, hence, postprandial glucose homeostasis. We examined the secretion of gut hormones in cholecystectomized subjects to test the hypothesis that gallbladder emptying potentiates postprandial release of GLP-1. Ten cholecystectomized subjects and 10 healthy, age-, gender-, and body mass index-matched control subjects received a standardized fat-rich liquid meal (2,200 kJ). Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), cholecystokinin (CCK), and gastrin were measured. Furthermore, gastric emptying and duodenal and serum bile acids were measured. We found similar basal glucose concentrations in the two groups, whereas cholecystectomized subjects had elevated postprandial glucose excursions. Cholecystectomized subjects had reduced postprandial concentrations of duodenal bile acids, but preserved postprandial plasma GLP-1 responses, compared with control subjects. Also, cholecystectomized patients exhibited augmented fasting glucagon. Basal plasma CCK concentrations were lower and peak concentrations were higher in cholecystectomized patients. The concentrations of GIP, GLP-2, and gastrin were similar in the two groups. In conclusion, cholecystectomized subjects had preserved postprandial GLP-1 responses in spite of decreased duodenal bile delivery, suggesting that gallbladder emptying is not a prerequisite for GLP-1 release. Cholecystectomized patients demonstrated a slight deterioration of postprandial glycemic control, probably because of metabolic changes unrelated to incretin secretion.

Sonne, David P; Hare, Kristine J

2013-01-01

119

Effects of MDMA on blood glucose levels and brain glucose metabolism  

Energy Technology Data Exchange (ETDEWEB)

This study was designed to assess changes in glucose metabolism in rats administered single or repeated doses of MDMA. Two different experiments were performed: (1) A single-dose study with four groups receiving 20 mg/kg, 40 mg/kg, saline or heat, and (2) a repeated-dose study with two groups receiving three doses, at intervals of 2 h, of 5 mg/kg or saline. Rats were imaged using a dedicated small-animal PET scanner 1 h after single-dose administration or 7 days after repeated doses. Glucose metabolism was measured in 12 cerebral regions of interest. Rectal temperature and blood glucose were monitored. Peak body temperature was reached 1 h after MDMA administration. Blood glucose levels decreased significantly after MDMA administration. In the single-dose experiment, brain glucose metabolism showed hyperactivation in cerebellum and hypo-activation in the hippocampus, amygdala and auditory cortex. In the repeated-dose experiment, brain glucose metabolism did not show any significant change at day 7. These results are the first to indicate that MDMA has the potential to produce significant hypoglycaemia. In addition, they show that MDMA alters glucose metabolism in components of the motor, limbic and somatosensory systems acutely but not on a long-term basis. (orig.)

Soto-Montenegro, M.L.; Vaquero, J.J.; Garcia-Barreno, P.; Desco, M. [Hospital General Universitario Gregorio Maranon, Laboratorio de Imagen, Medicina Experimental, Madrid (Spain); Arango, C. [Hospital General Gregorio Maranon, Departamento de Psiquiatria, Madrid (Spain); Ricaurte, G. [Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD (United States)

2007-06-15

120

Effects of MDMA on blood glucose levels and brain glucose metabolism  

International Nuclear Information System (INIS)

This study was designed to assess changes in glucose metabolism in rats administered single or repeated doses of MDMA. Two different experiments were performed: (1) A single-dose study with four groups receiving 20 mg/kg, 40 mg/kg, saline or heat, and (2) a repeated-dose study with two groups receiving three doses, at intervals of 2 h, of 5 mg/kg or saline. Rats were imaged using a dedicated small-animal PET scanner 1 h after single-dose administration or 7 days after repeated doses. Glucose metabolism was measured in 12 cerebral regions of interest. Rectal temperature and blood glucose were monitored. Peak body temperature was reached 1 h after MDMA administration. Blood glucose levels decreased significantly after MDMA administration. In the single-dose experiment, brain glucose metabolism showed hyperactivation in cerebellum and hypo-activation in the hippocampus, amygdala and auditory cortex. In the repeated-dose experiment, brain glucose metabolism did not show any significant change at day 7. These results are the first to indicate that MDMA has the potential to produce significant hypoglycaemia. In addition, they show that MDMA alters glucose metabolism in components of the motor, limbic and somatosensory systems acutely but not on a long-term basis. (orig.)

 
 
 
 
121

Degranulation effect of ferric nitrilotriacetate (Fe3+-NTA on the pancreatic islet beta-cells: its acute toxic effect on glucose metabolism.  

Directory of Open Access Journals (Sweden)

Full Text Available A single injection of ferric nitrilotriacetate (Fe3+-NTA caused a transitory increase in plasma immunoreactive insulin (IRI and plasma immunoreactive glucagon (IRG in rats. They reached maximum levels at 2 days after injection and returned to the normal range at 10 days. At 2 days after Fe3+-NTA injection, blood glucose level was normal but the glucose tolerance test (GTT was impaired. There was a further increase in plasma IRI level and IRG level was suppressed after glucose loading. At 10 days after Fe3+-NTA injection, glucose tolerance was normal and IRI also returned to the normal range. No degenerative changes were found on H.E.-stained rat pancreatic tissue sections after Fe3+-NTA injection. Histochemical staining, however, showed a reduction in beta-granules and heavy metals (Timm's granules from islet cells in the central area of the rat pancreatic islet 1 to 3 days after injection of Fe3+-NTA. The fading remained in some islets even at 10 days after injection, but by then the beta-granule distribution was restored in most islet cells. The results indicate a single Fe3+-NTA injection induced transitory instability of the pancreatic islet beta-cell granules and the glucose intolerance with a hyperresponse of IRI.

Yamanoi,Yasuhiro

1984-10-01

122

Glucose metabolism in anaerobic rice seedlings  

International Nuclear Information System (INIS)

More than 80% of the radioactivity from (U-14C)glucose metabolised by anaerobic rice seedlings or by excised roots or coleoptiles was recovered as ethanol plus CO2; less than 5% was recovered as water-soluble acidic components. Rates of 14CO2 formation from (U-14C)glucose were similar in roots and coleoptiles in both N2 and air atmospheres. More 14C02 was formed from (U-14C)glucose than could be accounted for by ethanolic fermentation, and the specific yields of 14CO2 from (6-14C)glucose and (1-14C)glucose gave unusually high C-6/C-1 ratios (1.7) in the anaerobic coleoptile. The results may indicate that appreciable pentan synthesis occurs in the anaerobic coleoptile. (author)

123

High glucose stimulates glutamate uptakes in pancreatic ?-cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Pancreatic ?-cells are major cells responsible for glucose metabolism in the body. Hyperglycemia is known to be a primary factor in the induction of diabetes mellitus. Glutamate is also an excitatory neurotransmitter in diverse organs. Oxidative stress also plays a pivotal role in the development of diabetes mellitus. However, the effect of hyperglycemia in glutamate uptake in the pancreas is not clear. Furthermore, the relationship between high glucose-induced glutamate uptake and oxidative...

Han, Ho Jae; Park, Soo Hyun

2011-01-01

124

Cerebral glucose metabolism in Wernicke's, Broca's, and conduction aphasia  

International Nuclear Information System (INIS)

Cerebral glucose metabolism was evaluated in patients with either Wernicke's (N = 7), Broca's (N = 11), or conduction (N = 10) aphasia using 18F-2-fluoro-2-deoxy-D-glucose with positron emission tomography. The three aphasic syndromes differed in the degree of left-to-right frontal metabolic asymmetry, with Broca's aphasia showing severe asymmetry and Wernicke's aphasia mild-to-moderate metabolic asymmetry, while patients with conduction aphasia were metabolically symmetric. On the other hand, the three syndromes showed the same degree of metabolic decline in the left temporal region. The parietal region appeared to separate conduction aphasia from both Broca's and Wernicke's aphasias. Common aphasic features in the three syndromes appear to be due to common changes in the temporal region, while unique features were associated with frontal and parietal metabolic differences

125

Non-invasive in-cell determination of free cytosolic [NAD+]/[NADH] ratios using hyperpolarized glucose show large variations in metabolic phenotypes  

DEFF Research Database (Denmark)

Accumulating evidence suggest that the pyridine nucleotide NAD has far wider biological functions than its classical role in energy metabolism. NAD is used by hundreds of enzymes that catalyse substrate oxidation and as such it plays a key role in various biological processes such as aging, cell death and oxidative stress. It has been suggested that changes in the ratio of free cytosolic [NAD+]/[NADH] reflects metabolic alterations leading to, or correlating with, pathological states. We have designed an isotopically labelled metabolic bioprobe of free cytosolic [NAD+]/[NADH] by combining a magnetic enhancement technique (hyperpolarization) with cellular glycolytic activity. The bioprobe reports free cytosolic [NAD+]/[NADH] ratios based on dynamically measured in-cell [pyruvate]/ [lactate] ratios. We demonstrate its utility in breast and prostate cancer cells. The free cytosolic [NAD+]/[NADH] ratio determined in prostate cancer cells was 4 times higher than in breast cancer cells. This higher ratio reflects adistinct metabolic phenotype of prostate cancer cells consistent with previously reported alterations in the energy metabolism of these cells. As a reporter on free cytosolic [NAD+]/[NADH] ratio, the bioprobe will enable better understanding of the origin of diverse pathological states of the cell as well as monitor cellular consequences of diseases and/or treatments.

Christensen, Caspar Elo; Karlsson, Magnus

2014-01-01

126

A link between sleep loss, glucose metabolism and adipokines  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english The present review evaluates the role of sleep and its alteration in triggering problems of glucose metabolism and the possible involvement of adipokines in this process. A reduction in the amount of time spent sleeping has become an endemic condition in modern society, and a search of the current l [...] iterature has found important associations between sleep loss and alterations of nutritional and metabolic contexts. Studies suggest that sleep loss is associated with problems in glucose metabolism and a higher risk for the development of insulin resistance and type 2 diabetes mellitus. The mechanism involved may be associated with the decreased efficacy of regulation of the hypothalamus-pituitary-adrenal axis by negative feedback mechanisms in sleep-deprivation conditions. In addition, changes in the circadian pattern of growth hormone (GH) secretion might also contribute to the alterations in glucose regulation observed during sleep loss. On the other hand, sleep deprivation stress affects adipokines - increasing tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6) and decreasing leptin and adiponectin -, thus establishing a possible association between sleep-debt, adipokines and glucose metabolism. Thus, a modified release of adipokines resulting from sleep deprivation could lead to a chronic sub-inflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes mellitus. Further studies are necessary to investigate the role of sleep loss in adipokine release and its relationship with glucose metabolism.

H.G., Padilha; C.A., Crispim; I.Z., Zimberg; D.A., De-Souza; J., Waterhouse; S., Tufik; M.T, de-Mello.

2011-10-01

127

Metabolism of tritiated D-glucose in rat erythrocytes  

International Nuclear Information System (INIS)

The metabolism of D-[U-14C]glucose, D-[1-14C]glucose, D-[6-14C]glucose, D-[1-3H]glucose, D-[2-3H]glucose, D-[3-3H]glucose, D-[3,4-3H]glucose, D-[5-3H]glucose, and D-[6-3H]glucose was examined in rat erythrocytes. There was a fair agreement between the rate of 3HOH production from either D-[3-3H]glucose and D-[5-3H]glucose, the decrease in the 2,3-diphosphoglycerate pool, its fractional turnover rate, the production of 14C-labeled lactate from D-[U-14C]glucose, and the total lactate output. The generation of both 3HOH and tritiated acidic metabolites from D-[3,4-3H]glucose indicated incomplete detritiation of the C4 during interconversion of fructose-1,6-bisphosphate and triose phosphates. Erythrocytes unexpectedly generated 3HOH from D-[6-3H]glucose, a phenomenon possibly attributable to the detritiation of [3-3H]pyruvate in the reaction catalyzed by glutamate pyruvate transaminase. The production of 3HOH from D-[2-3H]glucose was lower than that from D-[5-3H]glucose, suggesting enzyme-to-enzyme tunneling of glycolytic intermediates in the hexokinase/phosphoglucoisomerase/phosphofructokinase sequence. The production of 3HOH from D-[1-3H]glucose largely exceeded that of 14CO2 from D-[1-14C]glucose, a situation tentatively ascribed to the generation of 3HOH in the phosphomannoisomerase reaction. It is further speculated that the adjustment in specific radioactivity of D-[1-3H]glucose-6-phosphate cannot simultaneously match the vastly different degrees of isotopic discrimstly different degrees of isotopic discrimination in velocity at the levels of the reactions catalyzed by either glucose-6-phosphate dehydrogenase or phosphoglucoisomerase. The interpretation of the present findings thus raises a number of questions, which are proposed as a scope for further investigations

128

Oxygen- and Glucose-Dependent Regulation of Central Carbon Metabolism in Pichia anomala  

Digital Repository Infrastructure Vision for European Research (DRIVER)

We investigated the regulation of the central aerobic and hypoxic metabolism of the biocontrol and non-Saccharomyces wine yeast Pichia anomala. In aerobic batch culture, P. anomala grows in the respiratory mode with a high biomass yield (0.59 g [dry weight] of cells g of glucose?1) and marginal ethanol, glycerol, acetate, and ethyl acetate production. Oxygen limitation, but not glucose pulse, induced fermentation with substantial ethanol production and 10-fold-increased ethyl acetate produc...

Fredlund, Elisabeth; Blank, Lars M.; Schnu?rer, Johan; Sauer, Uwe; Passoth, Volkmar

2004-01-01

129

Tumor suppressor WWOX regulates glucose metabolism via HIF1? modulation.  

Science.gov (United States)

The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor with emerging role in regulation of aerobic glycolysis. WWOX controls glycolytic genes' expression through hypoxia-inducible transcription factor 1? (HIF1?) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1? and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1? levels and activity and displayed increased glucose uptake. Remarkably, WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, conditions resembling the 'Warburg effect'. Furthermore, Wwox-deficient cells are more tumorigenic and display increased levels of GLUT1 in vivo. Finally, WWOX expression is inversely correlated with GLUT1 levels in breast cancer samples highlighting WWOX as a modulator of cancer metabolism. Our studies uncover an unforeseen role for the tumor-suppressor WWOX in cancer metabolism. PMID:25012504

Abu-Remaileh, M; Aqeilan, R I

2014-11-01

130

Glucose, pyruvate, and acetate metabolism by developing soybean seeds  

International Nuclear Information System (INIS)

Developing soybean cotyledons were incubated with glucose-14C, pyruvate-14C, and acetate-14C. Glucose was metabolized by both the Embden-Meyerhof-parnas pathway and the pentose phosphate pathway. Developing soybean cotyledons also have the capacity to synthesize sucrose since 14C was found in fructose and sucrose from glucose incubations. Complete analysis showed that the carbons from glucose were directed into CO2, lipid, and solids. Pyruvate was metabolised to a C-2 unit which is presumably acetyl CoA. After conversion to the C-2 unit, the carbons of pyruvate were metabolized in the same manner as acetate. Both pyruvate and acetate carbons were directed predominately into lipids. (auth.)

131

Genome-Based Metabolic Modelling of CHO Cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Model-based analysis of cellular metabolism can facilitate our understanding of intracellular kinetics and aid the improvement of cell growth and biological product manufacturing. In this thesis, a model-based kinetic study of cytosolic glucose metabolism is presented. Based on the Kyoto Encyclopedia of Genes and Genomes and the Braunschweig Enzyme Database, a metabolic map of cytosolic glucose metabolism including 30 metabolites and 36 reactions, which consists of glycol...

Chen, Ning

2013-01-01

132

Dementia with impaired glucose metabolism in late onset metachromatic leukodystrophy  

DEFF Research Database (Denmark)

An unusual case of very-late-onset metachromatic leukodystrophy (MLD) with dementia was studied. The patient was a 41-year-old male who presented with mild dementia and a single generalized tonic clonic seizure. Neuropsychological assessment demonstrated mild amnesia, visuospatial dysfunction and attention deficits with a slow psychomotor speed. MR brain imaging displayed confluent hyperintensities of periventricular and subcortical white matter. Low levels of arylsulfatase A confirmed the diagnosis. Impaired cortical glucose metabolism especially of the medial temporal and frontal cortices was observed using positron emission tomography and fluor-18-labeled fluorodesoxyglucose. The neuropsychological deficits are related to the location of deficits in glucose metabolism.

Johannsen, P.; Ehlers, L.

2001-01-01

133

Estrogen receptor expression and glucose metabolism of uterine tumors  

International Nuclear Information System (INIS)

We aimed to clarify the relationship between estrogen receptor (ER) expression and glucose metabolism using 16 ?-[18F]fluoro-17?-estradiol (FES) and fluorodeoxyglucose positron emission tomography (FDG PET) in patients with benign and malignant uterine tumors. Endometrial carcinoma and sarcoma showed greater standardized uptake value (SUV) for FDG than for FES. In contrast, hyperplasia and leiomyoma showed opposite patterns for tracer accumulation. ER expression and glucose metabolism measured by PET showed opposite tendencies. PET studies with both FES and FDG could provide pathophysiologic information for the differential diagnosis of uterine tumors. (author)

134

The Role of Glucose Metabolism and Glucose-Associated Signalling in Cancer  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Aggressive carcinomas ferment glucose to lactate even in the presence of oxygen. This particular metabolism, termed aerobic glycolysis, the glycolytic phenotype, or the Warburg effect, was discovered by Nobel laureate Otto Warburg in the 1920s. Since these times, controversial discussions about the relevance of the fermentation of glucose by tumours took place; however, a majority of cancer researchers considered the Warburg effect as a non-causative epiphenomenon. Recent research demonstrate...

Wittig, Rainer; Coy, Johannes F.

2008-01-01

135

The pivotal role of glucose metabolism in determining oocyte developmental competence.  

Science.gov (United States)

The environment that the cumulus oocyte complex (COC) is exposed to during either in vivo or in vitro maturation (IVM) can have profound effects on the success of fertilisation and subsequent embryo development. Glucose is a pivotal metabolite for the COC and is metabolised by glycolysis, the pentose phosphate pathway (PPP), the hexosamine biosynthesis pathway (HBP) and the polyol pathway. Over the course of oocyte maturation, a large proportion of total glucose is metabolised via the glycolytic pathway to provide substrates such as pyruvate for energy production. Glucose is also the substrate for many cellular functions during oocyte maturation, including regulation of nuclear maturation and redox state via the PPP and for the synthesis of substrates of extracellular matrices (cumulus expansion) and O-linked glycosylation (cell signalling) via the HBP. However, the oocyte is susceptible to glucose concentration-dependent perturbations in nuclear and cytoplasmic maturation, leading to poor embryonic development post-fertilisation. For example, glucose concentrations either too high or too low result in precocious resumption of nuclear maturation. This review will discuss the relevant pathways of glucose metabolism by COCs during in vivo maturation and IVM, including the relative contribution of the somatic and gamete compartments of the COC to glucose metabolism. The consequences of exposing COCs to abnormal glucose concentrations will also be examined, either during IVM or by altered maternal environments, such as during hyperglycaemia induced by diabetes and obesity. PMID:20089664

Sutton-McDowall, Melanie L; Gilchrist, Robert B; Thompson, Jeremy G

2010-04-01

136

An in vitro assessment of the effect of Athrixia phylicoides DC. aqueous extract on glucose metabolism.  

Science.gov (United States)

Athrixia phylicoides DC. is an aromatic shrub indigenous to the eastern parts of Southern Africa. Indigenous communities brew "bush tea" from dried twigs and leaves of A. phylicoides, which is consumed as a beverage and used for its medicinal properties. Plant polyphenols have been shown to be beneficial to Type 2 diabetes mellitus (T2D) and obesity. Aqueous extracts of the plant have been shown to be rich in polyphenols, in particular phenolic acids, which may enhance glucose uptake and metabolism. The aim of this study was to determine the phenolic composition of a hot water A. phylicoides extract and assess its in vitro effect on cellular glucose utilisation. The most abundant phenolic compounds in the extract were 6-hydroxyluteolin-7-O-glucoside, chlorogenic acid, protocatechuic acid, a di-caffeoylquinic acid and a methoxy-flavonol derivative. The extract increased glucose uptake in C2C12, Chang and 3T3-L1 cells, respectively. Intracellular glucose was utilised by both oxidation (C2C12 myocytes and Chang cells; p < 0.01 and p < 0.05, respectively) and by increased glycogen storage (Chang cells; p < 0.05). No cytotoxicity was observed in Chang cells at the concentrations tested. The effects of the extract were not dose-dependent. A. phylicoides aqueous extract stimulated in vitro glucose uptake and metabolism, suggesting that consumption of this phenolic-rich extract could potentially ameliorate metabolic disorders related to obesity and T2D. PMID:22516895

Chellan, N; Muller, C J F; de Beer, D; Joubert, E; Page, B J; Louw, J

2012-06-15

137

Miniaturised glucose-oxygen biofuel cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Miniaturized glucose-oxygen biofuel cells are useful to power implantable medical devices such as biosensors. They are small, more biocompatible and run continuously on glucose and oxygen, providing cleaner energy at neutral environment. A typical glucose-oxygen biofuel cell consists of an anode with glucose oxidase (GOx) and a cathode with various oxygen reducing catalysts. This thesis describes experimental investigations of the major issues of such systems, viz.: complex ele...

Kikuchi, Yoko

2010-01-01

138

Snail modulates cell metabolism in MDCK cells  

International Nuclear Information System (INIS)

Highlights: ? MDCK/snail cells were more sensitive to glucose deprivation than MDCK/neo cells. ? MDCK/snail cells had decreased oxidative phosphorylation, O2 consumption and ATP content. ? TCA cycle enzyme activity, but not expression, was lower in MDCK/snail cells. ? MDCK/snail cells showed reduced PDH activity and increased PDK1 expression. ? MDCK/snail cells showed reduced expression of GLS2 and ACLY. -- Abstract: Snail, a repressor of E-cadherin gene transcription, induces epithelial-to-mesenchymal transition and is involved in tumor progression. Snail also mediates resistance to cell death induced by serum depletion. By contrast, we observed that snail-expressing MDCK (MDCK/snail) cells undergo cell death at a higher rate than control (MDCK/neo) cells in low-glucose medium. Therefore, we investigated whether snail expression influences cell metabolism in MDCK cells. Although gylcolysis was not affected in MDCK/snail cells, they did exhibit reduced pyruvate dehydrogenase (PDH) activity, which controls pyruvate entry into the tricarboxylic acid (TCA) cycle. Indeed, the activity of multiple enzymes involved in the TCA cycle was decreased in MDCK/snail cells, including that of mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2), succinate dehydrogenase (SDH), and electron transport Complex II and Complex IV. Consequently, lower ATP content, lower oxygen consumption and increased survival under hypoxic conditions was also observed in MDCK/snail cells compared to MDCK/neo cells. In addition, the expression and promoter activity of pyruvate dehydrogenase kinase 1 (PDK1), which phosphorylates and inhibits the activity of PDH, was increased in MDCK/snail cells, while expression levels of glutaminase 2 (GLS2) and ATP-citrate lyase (ACLY), which are involved in glutaminolysis and fatty acid synthesis, were decreased in MDCK/snail cells. These results suggest that snail modulates cell metabolism by altering the expression and activity of key enzymes. This results in enhanced glucose dependency and leads to cell death under low-glucose conditions. On the other hand, the reduced requirements for oxygen and nutrients from the surrounding environment, might confer the resistance to cell death induced by hypoxia and malnutrition

139

Snail modulates cell metabolism in MDCK cells  

Energy Technology Data Exchange (ETDEWEB)

Highlights: ? MDCK/snail cells were more sensitive to glucose deprivation than MDCK/neo cells. ? MDCK/snail cells had decreased oxidative phosphorylation, O{sub 2} consumption and ATP content. ? TCA cycle enzyme activity, but not expression, was lower in MDCK/snail cells. ? MDCK/snail cells showed reduced PDH activity and increased PDK1 expression. ? MDCK/snail cells showed reduced expression of GLS2 and ACLY. -- Abstract: Snail, a repressor of E-cadherin gene transcription, induces epithelial-to-mesenchymal transition and is involved in tumor progression. Snail also mediates resistance to cell death induced by serum depletion. By contrast, we observed that snail-expressing MDCK (MDCK/snail) cells undergo cell death at a higher rate than control (MDCK/neo) cells in low-glucose medium. Therefore, we investigated whether snail expression influences cell metabolism in MDCK cells. Although gylcolysis was not affected in MDCK/snail cells, they did exhibit reduced pyruvate dehydrogenase (PDH) activity, which controls pyruvate entry into the tricarboxylic acid (TCA) cycle. Indeed, the activity of multiple enzymes involved in the TCA cycle was decreased in MDCK/snail cells, including that of mitochondrial NADP{sup +}-dependent isocitrate dehydrogenase (IDH2), succinate dehydrogenase (SDH), and electron transport Complex II and Complex IV. Consequently, lower ATP content, lower oxygen consumption and increased survival under hypoxic conditions was also observed in MDCK/snail cells compared to MDCK/neo cells. In addition, the expression and promoter activity of pyruvate dehydrogenase kinase 1 (PDK1), which phosphorylates and inhibits the activity of PDH, was increased in MDCK/snail cells, while expression levels of glutaminase 2 (GLS2) and ATP-citrate lyase (ACLY), which are involved in glutaminolysis and fatty acid synthesis, were decreased in MDCK/snail cells. These results suggest that snail modulates cell metabolism by altering the expression and activity of key enzymes. This results in enhanced glucose dependency and leads to cell death under low-glucose conditions. On the other hand, the reduced requirements for oxygen and nutrients from the surrounding environment, might confer the resistance to cell death induced by hypoxia and malnutrition.

Haraguchi, Misako, E-mail: haraguci@m3.kufm.kagoshima-u.ac.jp [Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan); Indo, Hiroko P. [Department of Maxillofacial Radiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan); Iwasaki, Yasumasa [Health Care Center, Kochi University, Kochi 780-8520 (Japan); Iwashita, Yoichiro [Department of Maxillofacial Radiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan); Fukushige, Tomoko [Department of Dermatology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan); Majima, Hideyuki J. [Department of Maxillofacial Radiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan); Izumo, Kimiko; Horiuchi, Masahisa [Department of Environmental Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan); Kanekura, Takuro [Department of Dermatology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan); Furukawa, Tatsuhiko [Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan); Ozawa, Masayuki [Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544 (Japan)

2013-03-22

140

Chemosensitizing and cytotoxic effects of 2-deoxy-D-glucose on breast cancer cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Background: Accelerated glucose uptake for anerobic glycolysis is one of the major metabolic changes found in malignant cells. This property has been exploited for imaging malignancies and as a possible anticancer therapy. The nonmetabolizable glucose analog 2-deoxyglucose (2?DG) interferes with glucose metabolism leading to breast cancer cell death. Aims: To determine whether 2DG can synergize with chemotherapeutic agents commonly used in breast cancer treatment and id...

Zhang Fanjie; Aft Rebecca

2009-01-01

 
 
 
 
141

A distinct metabolic signature predicts development of fasting plasma glucose  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods. Methods We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up. We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS, and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort. Results We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis. Conclusions We demonstrate that metabolites identified using a high-throughput method (GC-MS perform well in predicting the development of fasting plasma glucose over several years. Notably, not single, but a complex pattern of metabolites propels the prediction and therefore reflects the complexity of the underlying molecular mechanisms. This result could only be captured by application of multivariate statistical approaches. Therefore, we highly recommend the usage of statistical methods that seize the complexity of the information given by high-throughput methods.

Hische Manuela

2012-02-01

142

Glycolysis-induced discordance between glucose metabolic rates measured with radiolabeled fluorodeoxyglucose and glucose  

International Nuclear Information System (INIS)

We have developed an autoradiographic method for estimating the oxidative and glycolytic components of local CMRglc (LCMRglc), using sequentially administered [18F]fluorodeoxyglucose (FDG) and [14C]-6-glucose (GLC). FDG-6-phosphate accumulation is proportional to the rate of glucose phosphorylation, which occurs before the divergence of glycolytic (GMg) and oxidative (GMo) glucose metabolism and is therefore related to total cerebral glucose metabolism GMt: GMg + GMo = GMt. With oxidative metabolism, the 14C label of GLC is temporarily retained in Krebs cycle-related substrate pools. We hypothesize that with glycolytic metabolism, however, a significant fraction of the 14C label is lost from the brain via lactate production and efflux from the brain. Thus, cerebral GLC metabolite concentration may be more closely related to GMo than to GMt. If true, the glycolytic metabolic rate will be related to the difference between FDG- and GLC-derived LCMRglc. Thus far, we have studied normal awake rats, rats with limbic activation induced by kainic acid (KA), and rats visually stimulated with 16-Hz flashes. In KA-treated rats, significant discordance between FDG and GLC accumulation, which we attribute to glycolysis, occurred only in activated limbic structures. In visually stimulated rats, significant discordance occurred only in the optic tectum

143

Radiorespirometric study of glucose metabolism in liver-damaged rats  

International Nuclear Information System (INIS)

Changes in glucose metabolism in rats during feeding with 3'-methyl-4-(dimethylamino)azobenzene(3'-Me-DAB) were investigated by radiorespirometry with 14C-labelled carbohydrates as substrates, in relation to the levels of liver glycolytic enzyme activities. Rats were fed on 0.06% 3'-Me-DAB for 7 weeks. Radiorespirometry was carried out by the IP administration of [U-14C]glucose 2.5 ?Ci or [1-14C]acetate 2.0 ?Ci weekly during the experimental period. In the analysis of the radiorespirometric pattern obtained with [U-14C]glucose, the peak time (PT) was markedly shortened at week 4. At week 6 of 3'-Me-DAB feeding, the peak height (PH) and yield value (YV) both increased significantly with concomitant shortening of PT. The duration of the activation in radiorespirometric parameters was paralleled reasonably well by that of glycolytic enzyme activity; the activation of liver glucose-6-phosphate dehydrogenase (G-6-PDH) shortens PT, while the activation of the tricarboxylic acid (TCA) cycle increases YV. This study showed that the radiorespirometric pattern reflected glucose metabolism in the liver well. In conclusion, radiorespirometric analysis with 14C-labelled glucose as a substrate may be useful for the clinical diagnosis of liver diseases. (orig.)

144

Altered glucose metabolism in mouse and humans conceived by IVF.  

Science.gov (United States)

In vitro fertilization (IVF) may influence the metabolic health of children. However, in humans, it is difficult to separate out the relative contributions of genetics, environment, or the process of IVF, which includes ovarian stimulation (OS) and embryo culture. Therefore, we examined glucose metabolism in young adult humans and in adult male C57BL/6J mice conceived by IVF versus natural birth under energy-balanced and high-fat-overfeeding conditions. In humans, peripheral insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (80 mU/m(2)/min), was lower in IVF patients (n = 14) versus control subjects (n = 20) after 3 days of an energy-balanced diet (30% fat). In response to 3 days of overfeeding (+1,250 kcal/day, 45% fat), there was a greater increase in systolic blood pressure in IVF versus controls (P = 0.02). Mice conceived after either OS alone or IVF weighed significantly less at birth versus controls (P < 0.01). However, only mice conceived by IVF displayed increased fasting glucose levels, impaired glucose tolerance, and reduced insulin-stimulated Akt phosphorylation in the liver after 8 weeks of consuming either a chow or high-fat diet (60% fat). Thus, OS impaired fetal growth in the mouse, but only embryo culture resulted in changes in glucose metabolism that may increase the risk of the development of metabolic diseases later in life, in both mice and humans. PMID:24760136

Chen, Miaoxin; Wu, Linda; Zhao, Junli; Wu, Fang; Davies, Michael J; Wittert, Gary A; Norman, Robert J; Robker, Rebecca L; Heilbronn, Leonie K

2014-10-01

145

Serum Visfatin Levels, Adiposity and Glucose Metabolism in Obese Adolescents  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Objective: Visfatin, an adipokine, has insulin-mimetic effects. The main determinants of both the production and the physiologic role of visfatin are still unclear. The aim of this study is to determine the relation of serum visfatin to adiposity and glucose metabolism.

Tas?kesen, Derya; Kirel, Birgu?l; Us, Tercan

2012-01-01

146

Transcriptional Regulation of Glucose Sensors in Pancreatic ?-Cells and Liver: An Update  

Directory of Open Access Journals (Sweden)

Full Text Available Pancreatic ?-cells and the liver play a key role in glucose homeostasis. After a meal or in a state of hyperglycemia, glucose is transported into the ?-cells or hepatocytes where it is metabolized. In the ?-cells, glucose is metabolized to increase the ATP:ADP ratio, resulting in the secretion of insulin stored in the vesicle. In the hepatocytes, glucose is metabolized to CO2, fatty acids or stored as glycogen. In these cells, solute carrier family 2 (SLC2A2 and glucokinase play a key role in sensing and uptaking glucose. Dysfunction of these proteins results in the hyperglycemia which is one of the characteristics of type 2 diabetes mellitus (T2DM. Thus, studies on the molecular mechanisms of their transcriptional regulations are important in understanding pathogenesis and combating T2DM. In this paper, we will review a recent update on the progress of gene regulation of glucose sensors in the liver and ?-cells.

Jin-Sik Bae

2010-05-01

147

Paricalcitol does not improve glucose metabolism in patients with stage 3-4 chronic kidney disease.  

Science.gov (United States)

Patients with chronic kidney disease are often insulin resistant and glucose intolerant--abnormalities that promote cardiovascular disease. Administration of 1,25-dihydroxyvitamin D (calcitriol) has improved glucose metabolism in patients with end-stage renal disease. We conducted a randomized, placebo-controlled clinical trial to test whether paricalcitol, a 1,25-dihydroxyvitamin D analog, changes glucose tolerance in earlier stages of chronic kidney disease. In a crossover design, 22 nondiabetic patients with estimated glomerular filtration rates of stage 3-4 chronic kidney disease and fasting plasma glucose of 100-125 mg/dl were given daily oral paricalcitol for 8 weeks and matching placebo for 8 weeks, separated by an 8-week washout period. The order of interventions was random and blinded to both participants and investigators. Paricalcitol significantly reduced serum concentrations of parathyroid hormone, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D while significantly increasing serum concentrations of fibroblast growth factor-23 and 24,25-dihydroxyvitamin D. Paricalcitol, however, had no significant effect on glucose tolerance (the primary outcome measure), insulin sensitivity, beta-cell insulin response, plasma free fatty acid suppression, or urinary F2-isoprostane excretion. Thus, despite substantial effects on vitamin D metabolism, paricalcitol did not improve glucose metabolism in nondiabetic patients with stage 3-4 chronic kidney disease. PMID:22913981

de Boer, Ian H; Sachs, Michael; Hoofnagle, Andrew N; Utzschneider, Kristina M; Kahn, Steven E; Kestenbaum, Bryan; Himmelfarb, Jonathan

2013-02-01

148

UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets.  

Science.gov (United States)

Uncoupling Protein 2 (UCP2) is expressed in the pancreatic ?-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/- islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2-/- and GK+/- islets compared with GK+/- islets and UCP2 deficiency improved glucose tolerance of GK+/- mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/- mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients. PMID:22177951

Dalgaard, Louise T

2012-01-01

149

UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets  

DEFF Research Database (Denmark)

Uncoupling Protein 2 (UCP2) is expressed in the pancreatic ?-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/? islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2?/? and GK+/? islets compared with GK+/? islets and UCP2 deficiency improved glucose tolerance of GK+/? mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/? mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients.

Dalgaard, Louise Torp

2012-01-01

150

Metabolic engineering of Acinetobacter baylyi ADP1 for improved growth on gluconate and glucose.  

Science.gov (United States)

A high growth rate in bacterial cultures is usually achieved by optimizing growth conditions, but metabolism of the bacterium limits the maximal growth rate attainable on the carbon source used. This limitation can be circumvented by engineering the metabolism of the bacterium. Acinetobacter baylyi has become a model organism for studies of bacterial metabolism and metabolic engineering due to its wide substrate spectrum and easy-to-engineer genome. It produces naturally storage lipids, such as wax esters, and has a unique gluconate catabolism as it lacks a gene for pyruvate kinase. We engineered the central metabolism of A. baylyi ADP1 more favorable for gluconate catabolism by expressing the pyruvate kinase gene (pykF) of Escherichia coli. This modification increased growth rate when cultivated on gluconate or glucose as a sole carbon source in a batch cultivation. The engineered cells reached stationary phase on these carbon sources approximately twice as fast as control cells carrying an empty plasmid and produced similar amount of biomass. Furthermore, when grown on either gluconate or glucose, pykF expression did not lead to significant accumulation of overflow metabolites and consumption of the substrate remained unaltered. Increased growth rate on glucose was not accompanied with decreased wax ester production, and the pykF-expressing cells accumulated significantly more of these storage lipids with respect to cultivation time. PMID:25192990

Kannisto, Matti; Aho, Tommi; Karp, Matti; Santala, Ville

2014-11-01

151

Placental glucose transporter gene expression and metabolism in the rat.  

Science.gov (United States)

In situ hybridization was used to evaluate patterns of gene expression for glucose transporters 1-4 (GT1-4) in the rat uteroplacenta from the time of implantation through term, and in vivo regional placental glucose metabolism was measured by 14C-labeled 2-deoxyglucose uptake. GT1 mRNA was highly abundant and GT3 was barely detected in the postimplantation decidual reaction. GT1 and 3 mRNAs were colocalized in the labyrinthine syncitiotrophoblast layer of the chorioallantoic placenta, which forms the membranous barrier between maternal and fetal circulations. The level of labyrinthine GT3 mRNA showed no change from midgestation through term; however, the volume of the labyrinth and hence total GT 3 gene expression increased greatly during this period. Labyrinthine GT1 mRNA levels, in contrast, showed significant diminution near term. GT1 mRNA was also localized in the placental growth plate, or junctional zone, where it was most abundant during the period of rapid placental growth and was decreased at term. Placental glucose metabolism, as reflected by steady-state 2-deoxyglucose uptake, was highest in the junctional zone during the rapid growth phase during midgestation, and decreased significantly at term, in parallel with GT1 gene expression. These findings suggest that GT1 is responsible for supplying glucose for use as a placental fuel and that GT3 is important for glucose transfer to the embryo. Images PMID:8450065

Zhou, J; Bondy, C A

1993-01-01

152

The effect of vagal nerve blockade using electrical impulses on glucose metabolism in nondiabetic subjects  

Directory of Open Access Journals (Sweden)

Full Text Available Matheni Sathananthan,1 Sayeed Ikramuddin,2 James M Swain,3,6 Meera Shah,1 Francesca Piccinini,4 Chiara Dalla Man,4 Claudio Cobelli,4 Robert A Rizza,1 Michael Camilleri,5 Adrian Vella1 1Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA; 2Division of General Surgery, University of Minnesota, Minneapolis, MN, USA; 3Division of General Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA; 4Department of Information Engineering, University of Padua, Padua, Italy; 5Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA; 6Scottsdale Healthcare Bariatric Center, Scottsdale, AZ, USA Purpose: Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans. Patients and methods: We utilized a randomized, cross-over study design where participants were studied after 2 weeks of activation or inactivation of vagal nerve blockade (VNB. Seven obese subjects with impaired fasting glucose previously enrolled in a long-term study to examine the effect of VNB on weight took part. We used a standardized triple-tracer mixed meal to enable measurement of the rate of meal appearance, endogenous glucose production, and glucose disappearance. The 550 kcal meal was also labeled with 111In-diethylene triamine pentaacetic acid (DTPA to measure gastrointestinal transit. Insulin action and ß-cell responsivity indices were estimated using the minimal model. Results: Integrated glucose, insulin, and glucagon concentrations did not differ between study days. This was also reflected in a lack of effect on ?-cell responsivity and insulin action. Furthermore, fasting and postprandial endogenous glucose production, integrated meal appearance, and glucose disposal did not differ in the presence or absence of VNB. Similarly, gastric emptying and colonic transit were unchanged by VNB. Conclusion: In this pilot study in nondiabetic humans, electrical vagal blockade had no acute effects on glucose metabolism, insulin secretion and action, or gastric emptying. It remains to be determined if more pronounced effects would be observed in diabetic subjects. Keywords: vagotomy, insulin secretion, insulin action, endogenous glucose production

Sathananthan M

2014-07-01

153

Cytotoxicity,radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose In vitro  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolytic ATP production, is the most widely investigated metabolic inhibitor for targeting glucose metabolism. Besides depleting energy in cells, 2-DG has also been found to alter N-linked glycosylation leading to unfolded protein responses and induce changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and apoptosis. Inhibiti...

Dwarakanath B

2009-01-01

154

Cerebral glucose metabolic differences in patients with panic disorder  

Energy Technology Data Exchange (ETDEWEB)

Regional glucose metabolic rates were measured in patients with panic disorder during the performance of auditory discrimination. Those regions examined by Reiman and colleagues in their blood flow study of panic disorder were examined with a higher resolution positron emission tomography (PET) scanner and with the tracer (F-18)-2-fluoro-2-deoxyglucose (FDG). In contrast to the blood flow findings of Reiman et al., we did not find global gray metabolic differences between patients with panic disorder and normal controls. Consistent with the findings of Reiman et al., we found hippocampal region asymmetry. We also found metabolic decreases in the left inferior parietal lobule and in the anterior cingulate (trend), as well as an increase in the metabolic rate of the medial orbital frontal cortex (trend) of panic disorder patients. It is unclear whether the continuous performance task (CPT) enhanced or diminished findings that would have been noted in a study performed without task.

Nordahl, T.E.; Semple, W.E.; Gross, M.; Mellman, T.A.; Stein, M.B.; Goyer, P.; King, A.C.; Uhde, T.W.; Cohen, R.M. (NIMH, Bethesda, MD (USA))

1990-08-01

155

Cerebral glucose metabolic differences in patients with panic disorder  

International Nuclear Information System (INIS)

Regional glucose metabolic rates were measured in patients with panic disorder during the performance of auditory discrimination. Those regions examined by Reiman and colleagues in their blood flow study of panic disorder were examined with a higher resolution positron emission tomography (PET) scanner and with the tracer [F-18]-2-fluoro-2-deoxyglucose (FDG). In contrast to the blood flow findings of Reiman et al., we did not find global gray metabolic differences between patients with panic disorder and normal controls. Consistent with the findings of Reiman et al., we found hippocampal region asymmetry. We also found metabolic decreases in the left inferior parietal lobule and in the anterior cingulate (trend), as well as an increase in the metabolic rate of the medial orbital frontal cortex (trend) of panic disorder patients. It is unclear whether the continuous performance task (CPT) enhanced or diminished findings that would have been noted in a study performed without task

156

Gut microbiota may have influence on glucose and lipid metabolism.  

DEFF Research Database (Denmark)

New gene sequencing-based techniques and the large worldwide sequencing capacity have introduced a new era within the field of gut microbiota. Animal and human studies have shown that obesity and type 2 diabetes are associated with changes in the composition of the gut microbiota and that prebiotics, antibiotics or faecal transplantation can alter glucose and lipid metabolism. This paper summarizes the latest research regarding the association between gut microbiota, diabetes and obesity and some of the mechanisms by which gut bacteria may influence host metabolism.

Mikkelsen, Kristian Hallundbæk; Nielsen, Morten Frost

2013-01-01

157

Further studies of the influence of apolipoprotein B alleles on glucose and lipid metabolism  

DEFF Research Database (Denmark)

The effect of five genetic polymorphisms in the apolipoprotein B gene on parameters of lipid and glucose metabolism was assessed in 564 Danish mono- and dizygotic twins. Genotypes in apolipoprotein B T71I (ApaLI RFLP), A591V (AluI RFLP), L2712P (MvaI RFLP), R3611Q (MspI RFLP), and E4154K (EcoRI RFLP) were established using polymerase chain reaction and restriction enzyme digests. The effect of genotypes on lipid levels and on glucose, insulin, and HOMA (i.e., calculated parameters of beta-cell function and insulin resistance) was assessed by multivariate analyses of variance correcting for the effect of gender, age, glucose tolerance status, and body mass index. The effect of genotype on the risk of having impaired glucose metabolism was calculated by logistic regression analysis. Finally, linkage between allele sharing and physiological parameters was calculated by the new Haseman-Elston method. The allele frequencies of all five polymorphisms were similar to those previously reported for Caucasian populations. The L2711P (MvaI RFLP) polymorphism influenced LDL-cholesterol and LDL-to-HDL measures (p = 0.04 and 0.03, respectively), while the R3611Q (MspI RFLP) polymorphism had an effect on the insulin-to-glucose ratio (p = 0.04), and E4154K (EcoRI RFLP) influenced HOMAbeta (p = 0.04). Significant interactions were observed between genotype in T71I (ApaLI RFLP), A591V (AluI RFLP), R3611Q (MspI RFLP), and E4154K (EcoRI RFLP) and glucose tolerance on lipid-related parameters (0.03 < p < 0.004), and between genotype in L2712P (MvaI RFLP) and E4154K (EcoRI RFLP) and gender on lipid and glucose-related parameters (0.02 < p < 0.003). No genotypes were significantly associated with impaired glucose tolerance measured by logistic regression. Likewise, no effect of allele sharing in the five polymorphisms was seen in the dizygotic twins. The effect of the polymorphisms on lipid and glucose parameters could be mediated through linkage to genes with known effect on glucose metabolism or through free fatty acids exerting their effect on glucose metabolism.

Bentzen, Joan; Poulsen, Pernille

2003-01-01

158

Testing the Role of Myeloid Cell Glucose Flux in Inflammation and Atherosclerosis  

Directory of Open Access Journals (Sweden)

Full Text Available Inflammatory activation of myeloid cells is accompanied by increased glycolysis, which is required for the surge in cytokine production. Although in vitro studies suggest that increased macrophage glucose metabolism is sufficient for cytokine induction, the proinflammatory effects of increased myeloid cell glucose flux in vivo and the impact on atherosclerosis, a major complication of diabetes, are unknown. We therefore tested the hypothesis that increased glucose uptake in myeloid cells stimulates cytokine production and atherosclerosis. Overexpression of the glucose transporter GLUT1 in myeloid cells caused increased glycolysis and flux through the pentose phosphate pathway but did not induce cytokines. Moreover, myeloid-cell-specific overexpression of GLUT1 in LDL receptor-deficient mice was ineffective in promoting atherosclerosis. Thus, increased glucose flux is insufficient for inflammatory myeloid cell activation and atherogenesis. If glucose promotes atherosclerosis by increasing cellular glucose flux, myeloid cells do not appear to be the key targets.

Tomohiro Nishizawa

2014-04-01

159

Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The control of lipid and glucose metabolism is closely linked. The nuclear receptors liver X receptor (LXR)? and LXR? have been implicated in gene expression linked to lipid homeostasis; however, their role in glucose metabolism is not clear. We demonstrate here that the synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance. Analysis of gene expression in LXR agonist-treated mice reveals coordinate regulation of genes involv...

Laffitte, Bryan A.; Chao, Lily C.; Li, Jing; Walczak, Robert; Hummasti, Sarah; Joseph, Sean B.; Castrillo, Antonio; Wilpitz, Damien C.; Mangelsdorf, David J.; Collins, Jon L.; Saez, Enrique; Tontonoz, Peter

2003-01-01

160

Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease  

Science.gov (United States)

Objective To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ?4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease. Design Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxy-glucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ?4 homozygotes, ?4 heterozygotes, and noncarriers. Setting Academic medical center. Participants A total of 31 ?4 homozygotes, 42 ?4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. Main Outcome Measures The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. Results Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P=.60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P=.001). The APOE ?4 gene dose was significantly associated with posterior cingulate glucose metabolism (r=0.29, P=.0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (PAlzheimer disease. PMID:23599929

Protas, Hillary D.; Chen, Kewei; Langbaum, Jessica B. S.; Fleisher, Adam S.; Alexander, Gene E.; Lee, Wendy; Bandy, Daniel; de Leon, Mony J.; Mosconi, Lisa; Buckley, Shannon; Truran-Sacrey, Diana; Schuff, Norbert; Weiner, Michael W.; Caselli, Richard J.; Reiman, Eric M.

2013-01-01

 
 
 
 
161

Heterogeneous cerebral glucose metabolism in normal pressure hydrocephalus.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The regional cerebral metabolic rate for glucose (rCMRglu) has never been investigated in large consecutive groups of patients with normal pressure hydrocephalus (NPH), a potentially treatable form of dementia with an unpredictable outcome after shunt surgery. Using PET and 18F-2-fluorodeoxyglucose, rCMRglu was studied in 18 patients who fulfilled hydrodynamic criteria for NPH and in whom a biopsy of the frontal cortex was obtained. When compared with an age matched group of 11 healthy subjec...

Tedeschi, E.; Hasselbalch, S. G.; Waldemar, G.; Juhler, M.; Høgh, P.; Holm, S.; Garde, L.; Knudsen, L. L.; Klinken, L.; Gjerris, F.

1995-01-01

162

The G-Protein-Coupled Long-Chain Fatty Acid Receptor GPR40 and Glucose Metabolism.  

Science.gov (United States)

Free fatty acids (FFAs) play a pivotal role in metabolic control and cell signaling processes in various tissues. In particular, FFAs are known to augment glucose-stimulated insulin secretion by pancreatic beta cells, where fatty acid-derived metabolites, such as long-chain fatty acyl-CoAs, are believed to act as crucial effectors. Recently, G-protein-coupled receptor 40 (GPR40), a receptor for long-chain fatty acids, was reported to be highly expressed in pancreatic beta cells and involved in the regulation of insulin secretion. Hence, GPR40 is considered to be a potential therapeutic target for the treatment of diabetes. In this review, we summarize the identification and gene expression patterns of GPR40 and its role in glucose metabolism. We also discuss the potential application of GPR40 as a therapeutic target. PMID:25309513

Tomita, Tsutomu; Hosoda, Kiminori; Fujikura, Junji; Inagaki, Nobuya; Nakao, Kazuwa

2014-01-01

163

Alleviation of glucose repression of maltose metabolism by MIG1 disruption in Saccharomyces cerevisiae.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The MIG1 gene was disrupted in a haploid laboratory strain (B224) and in an industrial polyploid strain (DGI 342) of Saccharomyces cerevisiae. The alleviation of glucose repression of the expression of MAL genes and alleviation of glucose control of maltose metabolism were investigated in batch cultivations on glucose-maltose mixtures. In the MIG1-disrupted haploid strain, glucose repression was partly alleviated; i.e., maltose metabolism was initiated at higher glucose concentrations than in...

Klein, C. J.; Olsson, L.; Rønnow, B.; Mikkelsen, J. D.; Nielsen, J.

1996-01-01

164

Therapeutic targeting of cancer cell metabolism.  

Science.gov (United States)

In 1927, Otto Warburg and coworkers reported the increased uptake of glucose and production of lactate by tumors in vivo as compared with normal tissues. This phenomenon, now known as the Warburg effect, was recapitulated in vitro with cancer tissue slices exhibiting excessive lactate production even with adequate oxygen. Warburg's in vivo studies of tumors further suggest that the dependency of tumors in vivo on glucose could be exploited for therapy, because reduction of arterial glucose by half resulted in a four-fold reduction in tumor fermentation. Recent work in cancer metabolism indicates that the Warburg effect or aerobic glycolysis contributes to redox balance and lipid synthesis, but glycolysis is insufficient to sustain a growing and dividing cancer cell. In this regard, glutamine, which contributes its carbons to the tricarboxylic acid (TCA) cycle, has been re-discovered as an essential bioenergetic and anabolic substrate for many cancer cell types. Could alterations in cancer metabolism be exploited for therapy? Here, we address this question by reviewing current concepts of normal metabolism and altered metabolism in cancer cells with specific emphasis on molecular targets involved directly in glycolysis or glutamine metabolism. PMID:21301795

Dang, Chi V; Hamaker, Max; Sun, Peng; Le, Anne; Gao, Ping

2011-03-01

165

Glucose transporters are expressed in taste receptor cells.  

Science.gov (United States)

In the intestine, changes of sugar concentration generated in the lumen during digestion induce adaptive responses of glucose transporters in the epithelium. A close matching between the intestinal expression of glucose transporters and the composition and amount of the diet has been provided by several experiments. Functional evidence has demonstrated that the regulation of glucose transporters into enterocytes is induced by the sensing of sugar of the enteroendocrine cells through activation of sweet taste receptors (T1R2 and T1R3) and their associated elements of G-protein-linked signaling pathways (e.g. ?-gustducin, phospholipase C ? type 2 and transient receptor potential channel M5), which are signaling molecules also involved in the perception of sweet substances in the taste receptor cells (TRCs) of the tongue. Considering this phenotypical similarity between the intestinal cells and TRCs, we evaluated whether the TRCs themselves possess proteins of the glucose transport mechanism. Therefore, we investigated the expression of the typical intestinal glucose transporters (i.e. GLUT2, GLUT5 and SGLT1) in rat circumvallate papillae, using immunohistochemistry, double-labeling immunofluorescence, immunoelectron microscopy and reverse transcriptase-polymerase chain reaction analysis. The results showed that GLUT2, GLUT5 and SGLT1 are expressed in TRCs; their immunoreactivity was also observed in cells that displayed staining for ?-gustducin and T1R3 receptor. The immunoelectron microscopic results confirmed that GLUT2, GLUT5 and SGLT1 were predominantly expressed in cells with ultrastructural characteristics of chemoreceptor cells. The presence of glucose transporters in TRCs adds a further link between chemosensory information and cellular responses to sweet stimuli that may have important roles in glucose homeostasis, contributing to a better understanding of the pathways implicated in glucose metabolism. PMID:21592100

Merigo, Flavia; Benati, Donatella; Cristofoletti, Mirko; Osculati, Francesco; Sbarbati, Andrea

2011-08-01

166

Regional cerebral glucose metabolism in patients with Parkinson's disease with or without dementia  

International Nuclear Information System (INIS)

By means of positron emission tomography, the cerebral glucose metabolism in 5 patients with Parkinson's disease with dementia was compared with that in 9 patients without dementia, and that in 5 normal volunteers. The metabolic rates for glucose were measured by placing one hundred regions of interest. In the demented patients, cerebral glucose metabolism was diffusely decreased compared with that of the non-demented patients and the normal controls. The most significant decrease in glucose metabolism was observed in the angular gyrus (49.7% of the normal controls). The glucose metabolism in the cingulate, pre- and postcentral, occipital and subcortical regions was relatively spared (62.1 to 85.5% of the normal controls). In the patients without dementia, the glucose metabolism in each region was not significantly different from that in the normal controls. These results suggest that diffuse glucose hypometabolism in the cerebral cortex may correlate with that of patients with Parkinson's disease with dementia. (author)

167

Human myotubes from myoblast cultures undergoing senescence exhibit defects in glucose and lipid metabolism  

DEFF Research Database (Denmark)

Adult stem cells are known to have a finite replication potential. Muscle biopsy-derived human satellite cells (SCs) were grown at different passages and differentiated to human myotubes in culture to analyze the functional state of various carbohydrate and lipid metabolic pathways. As the proliferative potential of myoblasts decreased dramatically with passage number, a number of cellular functions were altered: the capacity of myoblasts to fuse and differentiate into myotubes was reduced, and metabolic processes in myotubes such as glucose uptake, glycogen synthesis, glucose oxidation and fatty acid ?-oxidation became gradually impaired. Upon insulin stimulation, glucose uptake and glycogen synthesis increased but as the cellular proliferative capacity became gradually exhausted, the response dropped concomitantly. Palmitic acid incorporation into lipids in myotubes decreased with passage number and could be explained by reduced incorporation into diacyl- and triacylglycerols. The levels of long-chain acyl-CoA esters decreased with increased passage number. Late-passage, non-proliferating, myoblast cultures showed strong senescence-associated ?-galactosidase activity indicating that the observed metabolic defects accompany the induction of a senescent state. The main function of SCs is regeneration and skeletal muscle-build up. Thus, the metabolic defects observed during aging of SC-derived myotubes could have a role in sarcopenia, the gradual age-related loss of muscle mass and strength.

Nehlin, Jan O; Just, Marlene

2011-01-01

168

UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets  

International Nuclear Information System (INIS)

Highlights: ? UCP2 mRNA levels are decreased in islets of Langerhans from glucokinase deficient mice. ? UCP2 mRNA up-regulation by glucose is dependent on glucokinase. ? Absence of UCP2 increases GSIS of glucokinase heterozygous pancreatic islets. ? This may protect glucokinase deficient mice from hyperglycemic damages. -- Abstract: Uncoupling Protein 2 (UCP2) is expressed in the pancreatic ?-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/? islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2?/? and GK+/? islets compared with GK+/? islets and UCP2 deficiency improved glucose tolerance of GK+/? mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/? mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients.

169

UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets  

Energy Technology Data Exchange (ETDEWEB)

Highlights: Black-Right-Pointing-Pointer UCP2 mRNA levels are decreased in islets of Langerhans from glucokinase deficient mice. Black-Right-Pointing-Pointer UCP2 mRNA up-regulation by glucose is dependent on glucokinase. Black-Right-Pointing-Pointer Absence of UCP2 increases GSIS of glucokinase heterozygous pancreatic islets. Black-Right-Pointing-Pointer This may protect glucokinase deficient mice from hyperglycemic damages. -- Abstract: Uncoupling Protein 2 (UCP2) is expressed in the pancreatic {beta}-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/- islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2-/- and GK+/- islets compared with GK+/- islets and UCP2 deficiency improved glucose tolerance of GK+/- mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/- mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients.

Dalgaard, Louise T., E-mail: ltd@ruc.dk [Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (United States); Department of Science, Systems and Models, Roskilde University (Denmark)

2012-01-06

170

Effect of interferon therapy on glucose metabolism in children with chronic hepatitis B.  

Science.gov (United States)

The aim of this study was to investigate the effect of interferon (IFN)-alpha treatment on glucose metabolism in children with chronic hepatitis B (CHB). Forty children with CHB received IFN 10 MU/m2 for six months. Oral glucose tolerance test, anti-insulin and anti-glutamic acid decarboxylase (GAD) antibody, fasting plasma C-peptide and insulin (FPI), postprandial insulin, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA-cell, and glucose/insulin ratio (G/I) were measured before and after treatment. The last four parameters were also evaluated in healthy controls (n=42). In patients, fasting plasma glucose (FPG) and HOMA-IR levels were significantly lower than in controls (p = 0.001 and p = 0.020, respectively). There was a strong correlation between degree of liver disease and FPG. Two patients had hyperinsulinemia. HOMA-IR was suppressed in 7 patients enough to indicate increased sensitivity. FPI of 13 patients and HOMA-cell of 9 patients were lower than the minimum level of controls, features compatible with beta-cell hypofunction. Frequency of glucose metabolism abnormalities was not different before and after therapy. After therapy, only 1 patient developed anti-GAD antibody, and FPI of 8 children and HOMA-cell level of 9 children were lower than the minimum level of controls. Hyperinsulinemia was persistent in the same patients. We demonstrated that HBV-infected children had insulin sensitivity; however, no adverse effects of IFN on glucose homeostasis were seen. PMID:21428191

Kulo?lu, Zarife; Berbero?lu, Merih; Kansu, Aydan; Demirçeken, Fulya; Do?anci, Tümay; Ocal, Gönül; Girgin, Nurten

2010-01-01

171

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The glucose analogue 2-deoxy-d-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C. elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG. This finding indicates that 2-DG does not block cell growth solely by preventing glucose cataboli...

Ralser, Markus; Wamelink, Mirjam M.; Struys, Eduard A.; Joppich, Christian; Krobitsch, Sylvia; Jakobs, Cornelis; Lehrach, Hans

2008-01-01

172

PPAR? links maternal malnutrition and abnormal glucose and lipid metabolism in the offspring of mice.  

Science.gov (United States)

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that regulate gene transcription. PPARs play essential roles in modulating cell differentiation, development, and metabolism (carbohydrate, lipid, protein). Here, we investigated whether PPAR? plays a role in linking maternal malnutrition and aberrant metabolism in the offspring of mice. After feeding dams with high fat (HF) and low protein (LP) diet during pregnancy and lactation, we examined the effects on the offspring at weaning (age of 3-week). The results showed that the LP offspring had lower body weight and length than the control. The HF offspring had heavier body weight and longer body length than LP. The blood glucose levels in HF group were significantly higher at 30 min and 60 min after intraperitoneal glucose administration and the area under curve was also significantly larger than the control. The blood glucose levels in HF group were significantly higher at 30 min than LP. HF group had elevated total cholesterol levels and LP group had decreased total cholesterol levels compared with the control. All results were statistically significant as examined by t-test. More importantly, PPAR? expression levels detected by qRT-PCR were significantly increased in HF and LP groups compared with the control. In conclusion, maternal HF and LP diet during pregnancy and lactation can induce impaired glucose and lipid metabolism in the early life of mouse offspring, where PPAR? may play an important role. PMID:25608816

Jia, Zheng; Xinhua, Xiao; Qian, Zhang; Miao, Yu; Jianping, Xu; Zhixin, Wang; Yijing, Liu; Mingmin, Li

2015-01-20

173

Re-sensitization of 5-FU resistance by SPARC through negative regulation of glucose metabolism in hepatocellular carcinoma.  

Science.gov (United States)

Secreted protein, acidic and rich in cysteine (SPARC), a calcium-binding matricellular glycoprotein, is implicated in the progression of many cancers. Currently, there is growing evidence for important functions of SPARC in a variety of cancers and its role in cancer depends on tumor types. In this study, we reported SPARC negatively regulated glucose metabolism in hepatocellular carcinoma (HCC). Overexpression of SPARC inhibited glucose uptake and lactate product through downregulation of key enzymes of glucose metabolism. On the other hand, knock down of SPARC reversed the phenotypes. Meanwhile, exogenous expression of SPARC in HepG2 cells resulted in tolerance to low glucose and was correlated with AMPK pathway. Interestingly, the 5-fluorouracil (5-FU)-resistant HepG2 cells showed increased glucose metabolism and downregulated SPARC levels. Finally, we reported the overexpression of SPARC re-sensitize 5-FU-resistant cells to 5-FU through inhibition of glycolysis both in vitro and in vivo. Our study proposed a novel function of SPARC in the regulation of glucose metabolism in hepatocellular carcinoma and will facilitate the development of therapeutic strategies for the treatments of liver tumor patients. PMID:25252848

Hua, Hong-Wei; Jiang, Feng; Huang, Qian; Liao, Zhi-Jun; Ding, Gang

2015-01-01

174

Glucose metabolism in brain tumor as studied by positron-emission tomography  

International Nuclear Information System (INIS)

Although high rates of glycolysis have been correlated with malignancy in glioma on the basis of PET findings using 18-F-deoxyglucose, these results indicate only the activity of hexokinase in the tumor cells; they do not demonstrate what kinds of systems of glycolysis increase. In this report, the differences in the activities of systems of glycolysis on both benign and malignant tumors were studied by means of PET using 11C-glucose and 11C-pyruvate administration, along with PET studies of r-CBF, r-OEF and r-CMRO2. At a benign glioma, the uptake of 11C-glucose was lower than in normal brain tissue, with lower r-CBF, r-OEF, and r-CMRO2 values. Many malignant tumors and cases of meningioma showed increases in glucose uptake with lower oxygen metabolism. On the other hand, the activities of 11C-pyruvate in both benign and malignant tumors were increased 34 - 131 % relative to normal brain tissue, and there was no difference between benign and malignant tumors. According to these findings, it might be concluded that benign and malignant tumors have mainly an anerobic glycolytic pathway. However, the findings of the alternation of 11C-glucose uptake suggest that, in addition to the anerobic glycolytic pathway, an alternative metabolic pathway of glucose, such as a pentose-phosphate pathway or an amino-acid-utilizing pathway, may also be present. (author)

175

Cilostazol Enhances Oxidative Glucose Metabolism in Both Neurons and Astroglia without Increasing Ros Production  

Directory of Open Access Journals (Sweden)

Full Text Available Cilostazol, a potent inhibitor of type 3 phosphodiesterase (PDE3, has recently been reported to exert neuroprotective effects during acute cerebral ischemic injury. These effects are, at least in part, mediated by the inhibition of oxidative cell death. However, the effects of cilostazol on glucose metabolism in brain cells have not been determined. In the present study, we examined the effects of cilostazol on the oxidative metabolism of glucose and the resultant formation of reactive oxygen species (ROS in cultured neurons and astroglia. Cultures of neurons or astroglia were prepared from Sprague-Dawley rats. The cells were treated with cilostazol (0 – 30 ?M for 48 hours prior to the assay. L-[U-14C]lactate ([14C]lactate or [1-14C]pyruvate ([14C]pyruvate oxidation was measured. ROS production was determined using an H2DCFDA assay with a microplate reader. Forty-eight hours of exposure to cilostazol resulted in dose-dependent increases in [14C]lactate and [14C]pyruvate oxidation in both the neurons and astroglia. Dibutyryl cyclic AMP (0 – 0.5 mM also increased [14C]lactate oxidation, indicating cAMP-mediated PDH activation. In contrast, free radical formation was not affected by cilostazol in either the neurons or astroglia. Cilostazol enhanced the oxidative metabolism of glucose in both neurons and astroglia, while it did not augment ROS production.

Shinichi Takahashi

2011-10-01

176

Cerebral glucose metabolic abnormality in patients with congenital scoliosis  

International Nuclear Information System (INIS)

A possible association between congenital scoliosis and low mental status has been recognized, but there are no reports describing the mental status or cerebral metabolism in patients with congenital scoliosis in detail. We investigated the mental status using a mini-mental status exam as well as the cerebral glucose metabolism using F-18 fluorodeoxyglucose brain positron emission tomography in 12 patients with congenital scoliosis and compared them with those of 14 age-matched patients with adolescent idiopathic scoliosis. The mean mini-mental status exam score in the congenital scoliosis group was significantly lower than that in the adolescent idiopathic scoliosis group. Group analysis found that various brain areas of patients with congenital scoliosis showed glucose hypometabolisms in the left prefrontal cortex (Brodmann area 10), right orbitofrontal cortex (Brodmann area 11), left dorsolateral prefrontal cortex (Brodmann area 9), left anterior cingulate gyrus (Brodmann area 24) and pulvinar of the left thalamus. From this study, we could find the metabolic abnormalities of brain in patients with congenital scoliosis and suggest the possible role of voxel-based analysis of brain fluorodeoxyglucose positron emission tomography

177

Cerebral glucose metabolic abnormality in patients with congenital scoliosis  

Energy Technology Data Exchange (ETDEWEB)

A possible association between congenital scoliosis and low mental status has been recognized, but there are no reports describing the mental status or cerebral metabolism in patients with congenital scoliosis in detail. We investigated the mental status using a mini-mental status exam as well as the cerebral glucose metabolism using F-18 fluorodeoxyglucose brain positron emission tomography in 12 patients with congenital scoliosis and compared them with those of 14 age-matched patients with adolescent idiopathic scoliosis. The mean mini-mental status exam score in the congenital scoliosis group was significantly lower than that in the adolescent idiopathic scoliosis group. Group analysis found that various brain areas of patients with congenital scoliosis showed glucose hypometabolisms in the left prefrontal cortex (Brodmann area 10), right orbitofrontal cortex (Brodmann area 11), left dorsolateral prefrontal cortex (Brodmann area 9), left anterior cingulate gyrus (Brodmann area 24) and pulvinar of the left thalamus. From this study, we could find the metabolic abnormalities of brain in patients with congenital scoliosis and suggest the possible role of voxel-based analysis of brain fluorodeoxyglucose positron emission tomography.

Nam, H. Y.; Seo, G. T.; Lee, J. S.; Kim, S. C.; Kim, I. J.; Kim, Y. K.; Jeon, S. M. [Pusan National University Hospital, Pusan (Korea, Republic of)

2007-07-01

178

Regional cerebral glucose metabolism in frontotemporal lobar degeneration  

International Nuclear Information System (INIS)

Purpose: Frontotemporal lobar degeneration (FTLD) is the third most common cause of dementia, following Alzheimer's disease and Lewy body disease. Four prototypic neuro behavioral syndromes can be produced by FTLD: frontotemporal dementia (FTD), frontotemporal dementia with motor neuron disease (MND), semantic dementia (SD), and progressive aphasia (PA). We investigated patterns of metabolic impairment in patients with FTLD presented with four different clinical syndromes. Methods: We analyzed glucose metabolic patterns on FDG PET images obtained from 34 patients with a clinical diagnosis of FTLD (19 FTD, 6 MND, 6 SD, and 3 PA, according to a consensus criteria for clinical syndromes associated with FTLD) and 7 age-matched healthy controls using SPM99. Results: Patients with FTD had metabolic deficit in the left frontal cortex and bilateral anterior temporal cortex. Hypometabolism in the bilateral pre-motor area was shown in patients with MND. Patients with SD had metabolic deficit in the left posterior temporal cortex including Wernicke's area, while hypometabolism in the bilateral inferior frontal gyrus including Broca's area and left angular gyrus was seen in patients with PA. These metabolic patterns were well correlated with clinical and neuropsychological features of FTLD syndromes. Conclusion: These data provide a biochemical basis of clinical classification of FTLD. FDG PET may help evaluate and classify patients with FTLDFTLD

179

Metabolic engineering of Escherichia coli for (2S)-pinocembrin production from glucose by a modular metabolic strategy.  

Science.gov (United States)

Flavonoids are valuable natural products widely used in human health and nutrition. Recent advances in synthetic biology and metabolic engineering have yielded improved strain titers and yields. However, current fermentation strategies often require supplementation of expensive phenylpropanoic precursors in the media and separate evaluation of each strategy in turn as part of the flavonoid pathway, implicitly assuming the modifications are additive. In this study, an Escherichia coli fermentation system was developed to bypass both of these problems. An eight-step pathway, consisting of 3-deoxy-D-arabinoheptulosonate-7-phosphate synthase (DAHPS), chorismate mutase/prephenate dehydratase (CM/PDT), phenylalanine ammonia lyase (PAL), 4-coumarate:CoA ligase (4CL), chalcone synthase (CHS), chalcone isomerase (CHI), malonate synthetase, and malonate carrier protein, was assembled on four vectors in order to produce the flavonoid precursor (2S)-pinocembrin directly from glucose. Furthermore, a modular metabolic strategy was employed to identify conditions that optimally balance the four pathway modules. Once this metabolic balance was achieved, such strains were capable of producing 40.02mg/L (2S)-pinocembrin directly from glucose. These results were attained by culturing engineered cells in minimal medium without additional precursor supplementation. The fermentation platform described here paves the way for the development of an economical process for microbial production of flavonoids directly from glucose. PMID:23246524

Wu, Junjun; Du, Guocheng; Zhou, Jingwen; Chen, Jian

2013-03-01

180

Response gene to complement 32 (RGC-32) in endothelial cells is induced by glucose and helpful to maintain glucose homeostasis.  

Science.gov (United States)

Endothelium dysfunction has been understood primarily in terms of abnormal vasomotor function, which plays an important role in the pathogenesis of diabetes and chronic diabetic complications. However, it has not been fully studied that the endothelium may regulate metabolism itself. The response gene to complement 32 (RGC-32) has be considered as an angiogenic inhibitor in the context of endothelial cells. We found that RGC-32 was induced by high fat diet in vivo and by glucose or insulin in endothelial cells, and then we set out to investigate the role of endothelial RGC-32 in metabolism. DNA array analysis and qPCR results showed that glutamine-fructose-6-phosphate aminotransferase [isomerizing] 1 (GFPT1), solute carrier family 2 (facilitated glucose transporter), member 12 (SLC2A12, GLUT12) and glucagon-like peptide 2 receptor (GLP2R) may be among possible glucose metabolism related downstream genes of RGC-32. Additionally, in the mice with endothelial specific over-expressed RGC-32, the disposal of carbohydrate was improved without changing insulin sensitivity when mice were faced with high fat diet challenges. Taken together, our findings suggest that RGC-32 in the endothelial cells regulates glucose metabolism related genes and subsequent helps to maintain the homeostasis of blood glucose. PMID:25356107

Guo, Shuzhen; Philbrick, Melissa J; An, Xiaojing; Xu, Ming; Wu, Jiaping

2014-01-01

 
 
 
 
181

Effects of gastric bypass surgery on glucose absorption and metabolism during a mixed meal in glucose-tolerant individuals  

DEFF Research Database (Denmark)

AIMS/HYPOTHESIS: Roux-en-Y gastric bypass surgery (RYGB) improves glucose tolerance in patients with type 2 diabetes, but also changes the glucose profile in response to a meal in glucose-tolerant individuals. We hypothesised that the driving force for the changed postprandial glucose profiles after RYGB is rapid entry of glucose into the systemic circulation due to modified gastrointestinal anatomy, causing hypersecretion of insulin and other hormones influencing glucose disappearance and endogenous glucose production. METHODS: We determined glucose absorption and metabolism and the rate of lipolysis before and 3 months after RYGB in obese glucose-tolerant individuals using the double-tracer technique during a mixed meal. RESULTS: After RYGB, the postprandial plasma glucose profile changed, with a higher peak glucose concentration followed by a faster return to lower than basal levels. These changes were brought about by changes in glucose kinetics: (1) a more rapid appearance of ingested glucose in thesystemic circulation, and a concomitant increase in insulin and glucagon-like peptide-1 secretion; (2) postprandial glucose disappearance was maintained at a high rate for a longer time after RYGB. Endogenous glucose production was similar before and after surgery. Postoperative glucagon secretion increased and showed a biphasic response after RYGB. Adipose tissue basal rate of lipolysis was higher after RYGB. CONCLUSIONS/INTERPRETATION: A rapid rate of absorption of ingested glucose into the systemic circulation, followed by increased insulin secretion and glucose disappearance appears to drive the changes in the glucose profile observed after RYGB, while endogenous glucose production remains unchanged

Jacobsen, Siv Hesse; Bojsen-MØller, KN

2013-01-01

182

Glucose metabolism, enzymic analysis and product formation in chemostat culture of Hanseniaspora uvarum.  

Science.gov (United States)

The physiology of Hanseniaspora uvarum K5 was studied in glucose-limited chemostat cultures and upon glucose pulse. Up to a dilution rate of 0.28 h-1, glucose was completely metabolized in biomass and CO2. Above this value, increase in the dilution rate was accompanied by sequential production of metabolites (glycerol, acetate and ethanol) and decrease in cell yield. Similar results were observed upon glucose pulse. From the enzyme activities (pyruvate dehydrogenase, pyruvate decarboxylase, NAD and NADP-dependent acetaldehyde dehydrogenases, acetyl coenzyme A synthetase and alcohol dehydrogenase) and substrate affinities, the following conclusions were drawn with respect to product formation of cells: (1) pyruvate was preferentially metabolized via pyruvate dehydrogenase, when biomass and CO2 were the only products formed; (2) acetaldehyde formed by pyruvate decarboxylase was preferentially oxidized in acetate by NADP-dependent aldehyde dehydrogenase; acetate accumulation results from insufficient activity of acetyl-CoA synthetase required for the complete oxidation of acetate; (3) acetaldehyde was oxidized in ethanol by alcohol dehydrogenase, in addition to acetate production. PMID:7785333

Venturin, C; Boze, H; Moulin, G; Galzy, P

1995-04-15

183

Analysis of glucose metabolism in diabetic rat retinas.  

Science.gov (United States)

This study was conceived in an effort to understand cause and effect relationships between hyperglycemia and diabetic retinopathy. Numerous studies show that hyperglycemia leads to oxidative stress in the diabetic retinas, but the mechanisms that generate oxidative stress have not been resolved. Increased electron pressure on the mitochondrial electron transfer chain, increased generation of cytosolic NADH, and decreases in cellular NADPH have all been cited as possible sources of reactive oxygen species and nitrous oxide. In the present study, excised retinas from control and diabetic rats were exposed to euglycemic and hyperglycemic conditions. Using a microwave irradiation quenching technique to study retinas of diabetic rats in vivo, glucose, glucose-derived metabolites, and NADH oxidation/reduction status were measured. Studying excised retinas in vitro, glycolytic flux, lactate production, and tricarboxylic acid cycle flux were evaluated. Enzymatically assayed glucose 6-phosphate and fructose 6-phosphate were only slightly elevated by hyperglycemia and/or diabetes, but polyols were increased dramatically. Cytosolic NADH-to-NAD ratios were not elevated by hyperglycemia nor by diabetes in vivo or in vitro. Tricarboxylic acid cycle flux was not increased by the diabetic state nor by hyperglycemia. On the other hand, small increases in glycolytic flux were observed with hyperglycemia, but glycolytic flux was always lower in diabetic compared with control animals. An observed decrease in activity of glyceraldehyde-3-phosphate dehydrogenase may be partially responsible for slow glycolytic flux for retinas of diabetic rats. Therefore, it is concluded that glucose metabolism, downstream of hexokinase, is not elevated by hyperglycemia or diabetes. Metabolites upstream of glucose such as the sorbitol pathway (which decreases NADPH) and polyol synthesis are increased. PMID:16380392

Ola, M Shamsul; Berkich, Deborah A; Xu, Yuping; King, M Todd; Gardner, Thomas W; Simpson, Ian; LaNoue, Kathryn F

2006-06-01

184

Glucose challenge increases circulating progenitor cells in Asian Indian male subjects with normal glucose tolerance which is compromised in subjects with pre-diabetes: A pilot study  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Abstract Background Haematopoietic stem cells undergo mobilization from bone marrow to blood in response to physiological stimuli such as ischemia and tissue injury. The aim of study was to determine the kinetics of circulating CD34+ and CD133+CD34+ progenitor cells in response to 75 g glucose load in subjects with normal and impaired glucose metabolism. Methods Asian Indian male subjects (n = 50) with no prior history of glucose...

Bairagi Soumi; Babu Subash S; Mohan Viswanathan; Nathan Abel A; Dixit Madhulika

2011-01-01

185

The G-Protein-Coupled Long-Chain Fatty Acid Receptor GPR40 and Glucose Metabolism  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Free fatty acids (FFAs) play a pivotal role in metabolic control and cell signaling processes in various tissues. In particular, FFAs are known to augment glucose-stimulated insulin secretion by pancreatic beta cells, where fatty acid-derived metabolites, such as long-chain fatty acyl-CoAs, are believed to act as crucial effectors. Recently, G-protein-coupled receptor 40 (GPR40), a receptor for long-chain fatty acids, was reported to be highly expressed in pancreatic beta cells and involved i...

Tomita, Tsutomu; Hosoda, Kiminori; Fujikura, Junji; Inagaki, Nobuya; Nakao, Kazuwa

2014-01-01

186

Epithelial and Mesenchymal Tumor Compartments Exhibit In Vivo Complementary Patterns of Vascular Perfusion and Glucose Metabolism1  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Glucose transport and consumption are increased in tumors, and this is considered a diagnostic index of malignancy. However, there is recent evidence that carcinoma-associated stromal cells are capable of aerobic metabolism with low glucose consumption, at least partly because of their efficient vascular supply. In the present study, using dynamic contrast-enhanced magnetic resonance imaging and [F-18]fluorodeoxyglucose (FDG) positron emission tomography (PET), we mapped in vivo the vascular ...

Galie, Mirco; Farace, Paolo; Nanni, Cristina; Spinelli, Antonello; Nicolato, Elena; Boschi, Federico; Magnani, Paolo; Trespidi, Silvia; Ambrosini, Valentina; Fanti, Stefano; Merigo, Flavia; Osculati, Francesco; Marzola, Pasquina; Sbarbati, Andrea

2007-01-01

187

Overexpression of the Pdx-1 Homeodomain Transcription Factor Impairs Glucose Metabolism in Cultured Rat Hepatocytes  

Directory of Open Access Journals (Sweden)

Full Text Available The Pdx-1 transcription factor plays crucial functions both during pancreas development and in the adult β cells. Previous studies have indicated that ectopic Pdx-1 expression in liver or intestinal primary and immortalized cells is sufficient to promote activation of insulin gene expression. This work is focused on the molecular and physiological consequences of Pdx-1 overexpression in liver cells. We present evidence that Pdx-1 affects the level of expression of one of the four mammalian hexokinase isozymes. These are glucose phosphorylating enzymes involved in essential cellular functions such as glucose sensing, metabolic energy production and apoptosis. Specifically, our data show that over-expression of Pdx-1 in cultured hepatocytes is able to repress the expression of hexokinase 2 (Hxk 2 and the phenomenon is mediated via binding of Pdx-1 to a specific sequence on the Hxk 2 gene promoter. As a consequence, liver cells over-expressing Pdx-1 present interesting alterations concerning glucose metabolism.

Gianfranco Risuleo

2008-10-01

188

Cerebral glucose metabolism in neurofibromatosis type 1 assessed with [18F]-2-fluoro-2-deoxy-D-glucose and PET.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Cerebral PET with [18F]-2-fluoro-2-deoxy-D-glucose has been performed in four patients with neurofibromatosis type 1 (NF1) to assess the relation between cerebral metabolic activity, MRI, and the presence of neurological symptoms, including seizures, as well as mental and language retardation. Widespread hypometabolism occurred in three of the patients. The lesions on MRI, which were localised in the subcortical white matter and grey structures, had normal rates of glucose metabolism. This fi...

Balestri, P.; Lucignani, G.; Fois, A.; Magliani, L.; Calistri, L.; Grana, C.; Di Bartolo, R. M.; Perani, D.; Fazio, F.

1994-01-01

189

Effect of naproxen on glucose metabolism and tolbutamide kinetics and dynamics in maturity onset diabetics.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

1 The influence of the nonsteroidal anti-inflammatory drug naproxen on glucose metabolism and on tolbutamide pharmacokinetics and pharmacodynamics has been studied in ten maturity-onset diabetics. 2 Comparison of both plasma glucose decay curves and insulin responses during an intravenous glucose tolerance test before and after eight 12 hourly doses of naproxen revealed that naproxen had no significant influence on fasting glucose levels or on rates of glucose elimination. 3 When the subjects...

Whiting, B.; Williams, R. L.; Lorenzi, M.; Varady, J. C.; Robins, D. S.

1981-01-01

190

Patient-specific Glucose Metabolism Models for Model Predictive Control of T1DM Glycemia  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The development of a predictive control algorithm for glycaemia regulation in diabetic subjects requires patient-specific models of the glucose metabolism which are physiologically relevant, parsimonious, yet able to accurately forecast blood glucose. Given the measured data: total plasma insulin mIU/L; plasma glucose mg/dL; plasma glucose rate of appearance after intestinal absorption mg/kg/min, the objective was to find individualized, simple and plausible glucose-insulin int...

Cescon, Marzia; Johansson, Rolf

2012-01-01

191

Starch digestion and glucose metabolism in the ruminant: a review  

Scientific Electronic Library Online (English)

Full Text Available SciELO Venezuela | Language: English Abstract in portuguese Neste trabalho se revisa a digestão do amido em ruminantes por ação de diferentes enzimas produzidas pelas glândulas salivares, microorganismos ruminais, pâncreas e intestino delgado. Também se discute o metabolismo de glicose em rúmen, sua absorção pos rumina e os requerimentos de glicose no rumina [...] nte. Abstract in spanish En este trabajo se revisa la digestión del almidón en rumiantes por acción de diferentes enzimas producidas por las glándulas salivales, microorganismos ruminales, páncreas e intestino delgado. También se discute el metabolismo de glucosa en rumen, su absorción postruminal y los requerimientos de gl [...] ucosa en el rumiante. Abstract in english The objective of this manuscript is to review starch digestion to glucose in ruminants by the action of several enzymes produced by the salivary glands, rumen microorganisms, the pancreas and small intestine. Glucose metabolism in the rumen and its post-ruminal absorption and glucose requirements of [...] the ruminant are also discussed.

M. Esther, Ortega Cerrilla; Germán, Mendoza Martínez.

2003-07-01

192

Predicting glucose intolerance with normal fasting plasma glucose by the components of the metabolic syndrome  

Directory of Open Access Journals (Sweden)

Full Text Available Background: Surprisingly, it is estimated that about half of type 2 diabetics remain undetected. The possible causes may be partly attributable to people with normal fasting plasma glucose (FPG but abnormal postprandial hyperglycemia. We attempted to develop an effective predictive model by using the metabolic syndrome (MeS components as parameters to identify such persons. Subjects and Methods: All participants received a standard 75-g oral glucose tolerance test, which showed that 106 had normal glucose tolerance, 61 had impaired glucose tolerance, and 6 had diabetes-on-isolated postchallenge hyperglycemia. We tested five models, which included various MeS components. Model 0: FPG; Model 1 (clinical history model: family history (FH, FPG, age and sex; Model 2 (MeS model: Model 1 plus triglycerides, high-density lipoprotein cholesterol, body mass index, systolic blood pressure and diastolic blood pressure; Model 3: Model 2 plus fasting plasma insulin (FPI; Model 4: Model 3 plus homeostasis model assessment of insulin resistance. A receiver-operating characteristic (ROC curve was used to determine the predictive discrimination of these models. Results: The area under the ROC curve of the Model 0 was significantly larger than the area under the diagonal reference line. All the other 4 models had a larger area under the ROC curve than Model 0. Considering the simplicity and lower cost of Model 2, it would be the best model to use. Nevertheless, Model 3 had the largest area under the ROC curve. Conclusion: We demonstrated that Model 2 and 3 have a significantly better predictive discrimination to identify persons with normal FPG at high risk for glucose intolerance.

Pei Dee

2007-01-01

193

Predicting glucose intolerance with normal fasting plasma glucose by the components of the metabolic syndrome  

International Nuclear Information System (INIS)

Surprisingly it is estimated that about half of type 2 diabetics remain undetected. The possible causes may be partly attributable to people with normal fasting plasma glucose (FPG) but abnormal postprandial hyperglycemia. We attempted to develop an effective predictive model by using the metabolic syndrome (MeS) components as parameters to identify such persons. All participants received a standard 75 gm oral glucose tolerance test which showed that 106 had normal glucose tolerance, 61 had impaired glucose tolerance and 6 had diabetes on isolated postchallenge hyperglycemia. We tested five models which included various MeS components. Model 0: FPG; Model 1 (Clinical history model): family history (FH), FPG, age and sex; Model 2 (MeS model): Model 1 plus triglycerides, high-density lipoprotein cholesterol, body mass index, systolic blood pressure and diastolic blood pressure; Model 3: Model 2 plus fasting plasma insulin (FPI); Model 4: Model 3 plus homeostasis model assessment of insulin resistance. A receiver-operating characteristic (ROC) curve was used to determine the predictive discrimination of these models. The area under the ROC curve of the Model 0 was significantly larger than the area under the diagonal reference line. All the other 4 models had a larger area under the ROC curve than Model 0. Considering the simplicity and lower cost of Model 2, it would be the best model to use. Nevertheless, Model 3 had the largest area under the ROC curve. We demonstratet area under the ROC curve. We demonstrated that Model 2 and 3 have a significantly better predictive discrimination to identify persons with normal FPG at high risk for glucose intolerance. (author)

194

Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis.  

Science.gov (United States)

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the premetastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients, and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the premetastatic niche. Mechanistically, cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase. In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that, by modifying glucose utilization by recipient premetastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression. PMID:25621950

Fong, Miranda Y; Zhou, Weiying; Liu, Liang; Alontaga, Aileen Y; Chandra, Manasa; Ashby, Jonathan; Chow, Amy; O'Connor, Sean Timothy Francis; Li, Shasha; Chin, Andrew R; Somlo, George; Palomares, Melanie; Li, Zhuo; Tremblay, Jacob R; Tsuyada, Akihiro; Sun, Guoqiang; Reid, Michael A; Wu, Xiwei; Swiderski, Piotr; Ren, Xiubao; Shi, Yanhong; Kong, Mei; Zhong, Wenwan; Chen, Yuan; Wang, Shizhen Emily

2015-02-01

195

Glucose activates prenyltransferases in pancreatic islet ?-cells  

International Nuclear Information System (INIS)

A growing body of evidence implicates small G-proteins [e.g., Cdc42 and Rac1] in glucose-stimulated insulin secretion [GSIS] in the islet ?-cell. These signaling proteins undergo post-translational modifications [e.g., prenylation] at their C-terminal cysteine residue and appear to be essential for the transport and fusion of insulin-containing secretory granules with the plasma membrane and the exocytotic secretion of insulin. However, potential regulation of the prenylating enzymes by physiological insulin secretogues [e.g., glucose] has not been investigated thus far. Herein, we report immunological localization, sub-cellular distribution and regulation of farnesyltransferases [FTases] and geranylgeranyltransferase [GGTase] by glucose in insulin-secreting INS 832/13 ?-cells and normal rat islets. Our findings suggest that an insulinotropic concentration of glucose [20 mM] markedly stimulated the expression of the ?-subunits of FTase/GGTase-1, but not the ?-subunits of FTase or GGTase-1 without significantly affecting the predominantly cytosolic distribution of these holoenzymes in INS 832/13 cells and rodent islets. Under these conditions, glucose significantly stimulated [2.5- to 4.0-fold over basal] the activities of both FTase and GGTase-1 in both cell types. Together, these findings provide the first evidence to suggest that GSIS involves activation of the endogenous islet prenyltransferases by glucose, culminating in the activation of their respective G-protein substrates, which is necessary for cytoskeletal rearrangement, vesicular transport, fusion and secretion of insulin.

196

A novel 3D liver organoid system for elucidation of hepatic glucose metabolism.  

Science.gov (United States)

Hepatic glucose metabolism is a key player in diseases such as obesity and diabetes as well as in antihyperglycemic drugs screening. Hepatocytes culture in two-dimensional configurations is limited in vitro model for hepatocytes to function properly, while truly practical platforms to perform three-dimensional (3D) culture are unavailable. In this work, we present a practical organoid culture method of hepatocytes for elucidation of glucose metabolism under nominal and stress conditions. Employing this new method of culturing cells within a hollow fiber reactor, hepatocytes were observed to self-assemble into 3D spherical organoids with preservation of tight junctions and display increased liver-specific functions. Compared to both monolayer culture and sandwich culture, the hepatocyte organoids displayed higher intracellular glycogen content, glucose consumption, and gluconeogenesis and approached the in vivo values, as also confirmed by gene expression of key enzymes. Moreover, hepatocyte organoids demonstrated more realistic sensitivity to hormonal challenges with insulin, glucagon, and dexamethasone. Finally, the exposure to high glucose demonstrated toxicities including alteration of mitochondrial membrane potential, lipid accumulation, and reactive oxygen species formation, similar to the in vivo responses, which was not captured by monolayer cultures. Collectively, hepatocyte organoids mimicked the in vivo functions better than hepatocyte monolayer and sandwich cultures, suggesting suitability for applications such as antihyperglycemic drugs screening. PMID:22006574

Lu, Yanhua; Zhang, Guoliang; Shen, Chong; Uygun, Korkut; Yarmush, Martin L; Meng, Qin

2012-02-01

197

A Regulatory Mutant of Hansenula polymorpha Exhibiting Methanol Utilization Metabolism and Peroxisome Proliferation in Glucose  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Mutant LGM-128 of Hansenula polymorpha harbors the recessive mutation glr2-1 which confers a complex pleiotropic phenotype, the major feature of which is the metabolically unnecessary induction of methanol utilization metabolism (C1 metabolism) during growth on glucose, whether or not methanol is in the medium. Therefore, in this mutant, peroxisomes are formed and proliferate upon cultivation in glucose-containing media. In these media, LGM-128 shows induction levels of C1 metabolism that are...

Parpinello, Giuseppinia; Berardi, Enrico; Strabbioli, Rosanna

1998-01-01

198

Antilipolytic drug boosts glucose metabolism in prostate cancer  

International Nuclear Information System (INIS)

Introduction: The antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts. Methods: Subcutaneous tumors were produced in nude mice by injection of PC3 and CWR22Rv1 PCa cells. The mice were divided into two groups (Acipimox vs. controls). Acipimox (50 mg/kg) was administered by oral gavage 1 h before injection of tracers. 1 h after i.v. co-injection of 8.2 MBq (222 ± 6.0 ?Ci) 18 F-FDG and ? 0.0037 MBq (0.1 ?Ci) 14C-acetate, 18 F-FDG imaging was performed using a small-animal PET scanner. Counting rates in reconstructed images were converted to activity concentrations. Quantification was obtained by region-of-interest analysis using dedicated software. The mice were euthanized, and blood samples and organs were harvested. 18 F radioactivity was measured in a calibrated ?-counter using a dynamic counting window and decay correction. 14C radioactivity was determined by liquid scintillation counting using external standard quench corrections. Counts were converted into activity, and percentage of the injected dose per gram (%ID/g) tissue was calculated. Results: FDG biodistribution data in mice with PC3 xenografts demonstrated doubled average %ID/g tumor tissue after administration of Acipimox compared to controls (7.21 ± 1.93 vs. 3.59 ± 1.35, P = 0.02). Tumor-to-organ ratios were generally higher in mice treated with Acipimox. This was supported by PET imaging data, both semi-quantitatively (mean tumor FDG uptake) and visually (tumor-to-background ratios). In mice with CWR22Rv1 xenografts there was no effect of Acipimox on FDG uptake, either in biodistribution or PET imaging. 14C-acetate uptake was unaffected in PC3 and CWR22Rv1 xenografts. Conclusions: In mice with PC3 PCa xenografts, acute administration of Acipimox increases tumor uptake of 18 F-FDG with general improvements in tumor-to-background ratios. Data indicate that administration of Acipimox prior to 18 F-FDG PET scans has potential to improve sensitivity and specificity in patients with castration-resistant advanced PCa

199

Delivery-Corrected Imaging of Fluorescently-Labeled Glucose Reveals Distinct Metabolic Phenotypes in Murine Breast Cancer  

Science.gov (United States)

When monitoring response to cancer therapy, it is important to differentiate changes in glucose tracer uptake caused by altered delivery versus a true metabolic shift. Here, we propose an optical imaging method to quantify glucose uptake and correct for in vivo delivery effects. Glucose uptake was measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-D-glucose (2-NBDG) in mice implanted with dorsal skin flap window chambers. Additionally, vascular oxygenation (SO2) was calculated using only endogenous hemoglobin contrast. Results showed that the delivery factor proposed for correction, “RD”, reported on red blood cell velocity and injected 2-NBDG dose. Delivery-corrected 2-NBDG uptake (2-NBDG60/RD) inversely correlated with blood glucose in normal tissue, indicating sensitivity to glucose demand. We further applied our method in metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas. The ratio 2-NBDG60/RD was increased in 4T1 tumors relative to 4T07 tumors yet average SO2 was comparable, suggesting a shift toward a “Warburgian” (aerobic glycolysis) metabolism in the metastatic 4T1 line. In heterogeneous regions of both 4T1 and 4T07, 2-NBDG60/RD increased slightly but significantly as vascular oxygenation decreased, indicative of the Pasteur effect in both tumors. These data demonstrate the utility of delivery-corrected 2-NBDG and vascular oxygenation imaging for differentiating metabolic phenotypes in vivo. PMID:25526261

Frees, Amy E.; Rajaram, Narasimhan; McCachren, Samuel S.; Fontanella, Andrew N.; Dewhirst, Mark W.; Ramanujam, Nimmi

2014-01-01

200

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased ?-Aminobutyric Acid Shunt*  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Pancreatic beta cells are hyper-responsive to amino acids but have decreased glucose sensitivity after deletion of the sulfonylurea receptor 1 (SUR1) both in man and mouse. It was hypothesized that these defects are the consequence of impaired integration of amino acid, glucose, and energy metabolism in beta cells. We used gas chromatography-mass spectrometry methodology to study intermediary metabolism of SUR1 knock-out (SUR1-/-) and control mouse islets with d-[U...

Li, Changhong; Nissim, Itzhak; Chen, Pan; Buettger, Carol; Najafi, Habiba; Daikhin, Yevgeny; Nissim, Ilana; Collins, Heather W.; Yudkoff, Marc; Stanley, Charles A.; Matschinsky, Franz M.

2008-01-01

 
 
 
 
201

Berberine Improves Glucose Metabolism through Induction of Glycolysis  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has been reported to activate AMPK recently. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after five week administration. Fasting insulin and HOMA-IR were decreased by 46% and 48% in the rats, respectively. In cell lines includin...

Yin, Jun; Gao, Zhanguo; Liu, Dong; Liu, Zhijun; Ye, Jianping

2007-01-01

202

Expression of the glucose-6-phosphatase system in endocrine cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Glucose-6-phosphatase (G6pase) is a multi-component enzyme system, which regulates the catalysis of gluco se-6 -phosphate (G6P) to glucose and inorganic phosphate. This reaction constitutes the final steps of both gluconeogenesis and glycogenolysis, processes that are critical in the maintenance of glucose homeostasis. While glucokinase, the rate limiting enzyme in glucose metabolism in liver and pancreatic islets, phosphorylates glucose to G6P, G6pase dephosphorylates G6P t...

Goh, Bee-hoon

2006-01-01

203

Cytotoxicity,radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose In vitro  

Directory of Open Access Journals (Sweden)

Full Text Available The glucose analog 2-deoxy-D-glucose (2-DG, an inhibitor of glucose transport and glycolytic ATP production, is the most widely investigated metabolic inhibitor for targeting glucose metabolism. Besides depleting energy in cells, 2-DG has also been found to alter N-linked glycosylation leading to unfolded protein responses and induce changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and apoptosis. Inhibition of cell proliferation and induction of apoptosis have been observed as cytotoxic effects in a wide variety of tumor cells in vitro, while sensitization of tumor cells to ionizing radiation and certain chemotherapeutic drugs is associated with enhanced mitotic as well as apoptotic cell death induced by the primary therapeutic agent. Therefore, there has been a considerable amount of interest in developing 2-DG as a therapeutic agent or adjuvant in the radiotherapy and chemotherapy of tumors.

Dwarakanath B

2009-09-01

204

Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Nutrient deprivation has been shown to cause cancer cell death. To exploit nutrient deprivation as anti-cancer therapy, we investigated the effects of the anti-metabolite 2-deoxy-D-glucose on breast cancer cells in vitro. This compound has been shown to inhibit glucose metabolism. Treatment of human breast cancer cell lines with 2-deoxy-D-glucose results in cessation of cell growth in a dose dependent manner. Cell viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazol...

Aft, R. L.; Zhang, F. W.; Gius, D.

2002-01-01

205

Reciprocal effects of 2-fluoro-2-deoxy-D-glucose and glucose on their metabolism in Saccharomyces cerevisiae studied by multi-nuclear NMR spectroscopy  

International Nuclear Information System (INIS)

The effects of various concentrations of 2-fluoro-2-deoxy-D-glucose (FDG) on the aerobic metabolism of glucose and the reciprocal effect of glucose on the metabolism of FDG in glucose-grown repressed Saccharomyces cerevisiae cells were studied at 30 deg C in a standard pyrophosphate medium containing 5 x 107 cells/ml by 1H-, 19F-, 31P-NMR and biochemical techniques. The glucose consumption rate is reduced by about 57% and 71% in the presence of 5 mM FDG and 10 mM FDG respectively. Under the same conditions, the ethanol production rate also decreases about 54% and 68%, respectively. When FDG is the unique carbon source, the ?- and ?-anomers of 2-fluoro-2-deoxy-D-glucose-6-phosphate (FDG6P) and a much smaller quantity of 2-fluoro-2-deoxy-gluconic acid (FDGA) were observed. The quantities of ? and ?-FDG6P reach their maximum values within 1 h of incubation and then decrease continuously. In contrast, Glc favors the consumption of FDG and the synthesis of FDG6P and uridine-5'-diphosphate fluoro-deoxy-glucose (UDP-FDG). In the presence of GLC, FDG6P reaches a plateau after 1 h or 2 h of incubation while UDP-FDG increases regularly with time. Apart from trehalose, no other disaccharide such as fluoro-dideoxy-trehalose (FDG-FDG) or fluoro-deoxy-trehalose (FDG-Glc) were observed. Thus, in contrast to UDP-Glc, UDP-DG, Glc6P and DG6P, UDP-FDG and FDG6P are not good substrates for trehalose-6-P synthetase. The effect of DG and FDG synthetase. The effect of DG and FDG on the cell growth in standard nutrient media was also investigated at 37 deg C. The cell growth was found to be completely inhibited upon addition of 1 mM FDG and only slowed down in the presence of 1 mM DG. In the latter case, the doubling time ? is about 3 h instead of 1 h 25' in the absence of DG and FDG. The reciprocal effects of FDG and Glc on their metabolism, the toxicity of FDG and the blockage level of enzymes induced by FDG are discussed in comparison with 2-deoxy-D-glucose (DG) and Glc. The above results clearly show that the metabolism and the toxicity of a drug strongly depend on the physiological state of cells. (authors). 17 refs., 6 figs., 1 scheme

206

Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage  

International Nuclear Information System (INIS)

Tumour hypoxia and elevated glycolysis (Warburg effect) predict poor prognosis. Each parameter is assessable separately with positron emission tomography, but they are linked through anaerobic glycolysis (Pasteur effect). Here, we compare the oxygenation-dependent retention of fluoroazomycin arabinoside ([18F]FAZA), a promising but not well-characterised hypoxia-specific tracer, and fluorodeoxyglucose ([18F]FDG) in four carcinoma cell lines. Cells seeded on coverslips were positioned in modified Petri dishes that allow physically separated cells to share the same tracer-containing medium pool. Following oxic, hypoxic or anoxic tracer incubation, coverslips were analysed for radioactivity ([18F]FDG+[18F]FAZA) or re-incubated in tracer-free oxygenated medium and then measured ([18F]FAZA). Next, we tested the reliability of [18F]FDG as a relative measure of glucose metabolic rate. Finally, from two cell lines, xenografts were established in mice, and the tracer distribution between hypoxic and well-oxygenated areas were deduced from tissue sections. Three hours of anoxia strongly stimulated [18F]FAZA retention with anoxic-to-oxic uptake ratios typically above 30. Three out of four cell lines displayed similar selectivity of [18F]FDG versus glucose, but oxic uptake and anoxic-to-oxic uptake ratio of [18F]FDG varied considerably. Although less pronounced, [18F]FAZAough less pronounced, [18F]FAZA also showed superior in vivo hypoxia specificity compared with [18F]FDG. [18F]FAZA displays excellent in vitro characteristics for hypoxia imaging including modest cell-to-cell line variability and no binding in oxic cells. In contrast, the usability of [18F]FDG as a surrogate marker for hypoxia is questionable due to large variations in baseline (oxic) glucose metabolism and magnitudes of the Pasteur effects. (orig.)

207

Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage  

Energy Technology Data Exchange (ETDEWEB)

Tumour hypoxia and elevated glycolysis (Warburg effect) predict poor prognosis. Each parameter is assessable separately with positron emission tomography, but they are linked through anaerobic glycolysis (Pasteur effect). Here, we compare the oxygenation-dependent retention of fluoroazomycin arabinoside ([{sup 18}F]FAZA), a promising but not well-characterised hypoxia-specific tracer, and fluorodeoxyglucose ([{sup 18}F]FDG) in four carcinoma cell lines. Cells seeded on coverslips were positioned in modified Petri dishes that allow physically separated cells to share the same tracer-containing medium pool. Following oxic, hypoxic or anoxic tracer incubation, coverslips were analysed for radioactivity ([{sup 18}F]FDG+[{sup 18}F]FAZA) or re-incubated in tracer-free oxygenated medium and then measured ([{sup 18}F]FAZA). Next, we tested the reliability of [{sup 18}F]FDG as a relative measure of glucose metabolic rate. Finally, from two cell lines, xenografts were established in mice, and the tracer distribution between hypoxic and well-oxygenated areas were deduced from tissue sections. Three hours of anoxia strongly stimulated [{sup 18}F]FAZA retention with anoxic-to-oxic uptake ratios typically above 30. Three out of four cell lines displayed similar selectivity of [{sup 18}F]FDG versus glucose, but oxic uptake and anoxic-to-oxic uptake ratio of [{sup 18}F]FDG varied considerably. Although less pronounced, [{sup 18}F]FAZA also showed superior in vivo hypoxia specificity compared with [{sup 18}F]FDG. [{sup 18}F]FAZA displays excellent in vitro characteristics for hypoxia imaging including modest cell-to-cell line variability and no binding in oxic cells. In contrast, the usability of [{sup 18}F]FDG as a surrogate marker for hypoxia is questionable due to large variations in baseline (oxic) glucose metabolism and magnitudes of the Pasteur effects. (orig.)

Busk, Morten; Horsman, Michael R.; Overgaard, Jens [Aarhus University Hospital, Department of Experimental Clinical Oncology, Aarhus C (Denmark); Jakobsen, Steen [Aarhus University Hospital, PET Centre, Aarhus (Denmark); Bussink, Johan; Kogel, Albert van der [Radboud University Nijmegen Medical Centre, Department of Radiation Oncology, Nijmegen (Netherlands)

2008-12-15

208

Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage  

DEFF Research Database (Denmark)

PURPOSE: Tumour hypoxia and elevated glycolysis (Warburg effect) predict poor prognosis. Each parameter is assessable separately with positron emission tomography, but they are linked through anaerobic glycolysis (Pasteur effect). Here, we compare the oxygenation-dependent retention of fluoroazomycin arabinoside ([(18)F]FAZA), a promising but not well-characterised hypoxia-specific tracer, and fluorodeoxyglucose ([(18)F]FDG) in four carcinoma cell lines. METHODS: Cells seeded on coverslips were positioned in modified Petri dishes that allow physically separated cells to share the same tracer-containing medium pool. Following oxic, hypoxic or anoxic tracer incubation, coverslips were analysed for radioactivity ([(18)F]FDG + [(18)F]FAZA) or re-incubated in tracer-free oxygenated medium and then measured ([(18)F]FAZA). Next, we tested the reliability of [(18)F]FDG as a relative measure of glucose metabolic rate. Finally, from two cell lines, xenografts were established in mice, and the tracer distribution between hypoxic and well-oxygenated areas were deduced from tissue sections. RESULTS: Three hours of anoxia strongly stimulated [(18)F]FAZA retention with anoxic-to-oxic uptake ratios typically above 30. Three out of four cell lines displayed similar selectivity of [(18)F]FDG versus glucose, but oxic uptake and anoxic-to-oxic uptake ratio of [(18)F]FDG varied considerably. Although less pronounced, [(18)F]FAZA also showed superior in vivo hypoxia specificity compared with [(18)F]FDG. CONCLUSIONS: [(18)F]FAZA displays excellent in vitro characteristics for hypoxia imaging including modest cell-to-cell line variability and no binding in oxic cells. In contrast, the usability of [(18)F]FDG as a surrogate marker for hypoxia is questionable due to large variations in baseline (oxic) glucose metabolism and magnitudes of the Pasteur effects.

Busk, Morten; Horsman, Michael R

2008-01-01

209

The measurement of the nigrostriatal dopaminergic function and glucose metabolism in patients with movement disorders  

International Nuclear Information System (INIS)

The nigrostriatal dopaminergic function and glucose metabolism were evaluated in 34 patients with various movement disorders by using positron emission tomography with 18F-Dopa and 18F-FDG respectively. The 18F-Dopa uptake in the striatum (the caudate head and the putamen) decreased in patients with Parkinson's disease but was relatively unaffected in the caudate. The cerebral glucose metabolism was normal in patients with Parkinson's disease. The 18F-Dopa uptake in the striatum also decreased in cases of atypical parkinsonism and in cases of progressive supranuclear palsy, but there was no difference in the uptake between the caudate and the putamen. The glucose metabolism decreased in the cerebral hemisphere including the striatum; this finding was also different from those of Parkinson's disease. A normal 18F-Dopa uptake in the striatum with a markedly decreased striatal glucose metabolism and a mildly decreased cortical glucose metabolism was observed in cases of Huntington's disease and Wilson's disease. The 18F-Dopa uptake in the striatum increased and the glucose metabolism was normal in cases of idiopathic dystonia. Various patterns of 18F-Dopa uptake and glucose metabolism were thus observed in the various movement disorders. These results suggest that the measurements of the 18F-Dopa uptake and the cerebral glucose metabolism would be useful for the evaluation of the strid be useful for the evaluation of the striatal function in various movement disorders. (author)

210

Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry.  

Science.gov (United States)

Lateral hypothalamic area (LHA) orexin neurons modulate reward-based feeding by activating ventral tegmental area (VTA) dopamine (DA) neurons. We hypothesize that signals of peripheral energy status influence reward-based feeding by modulating the glucose sensitivity of LHA orexin glucose-inhibited (GI) neurons. This hypothesis was tested using electrophysiological recordings of LHA orexin-GI neurons in brain slices from 4 to 6week old male mice whose orexin neurons express green fluorescent protein (GFP) or putative VTA-DA neurons from C57Bl/6 mice. Low glucose directly activated ~60% of LHA orexin-GFP neurons in both whole cell and cell attached recordings. Leptin indirectly reduced and ghrelin directly enhanced the activation of LHA orexin-GI neurons by glucose decreases from 2.5 to 0.1mM by 53±12% (n=16, P<0.001) and 41±24% (n=8, P<0.05), respectively. GABA or neurotensin receptor blockade prevented leptin's effect on glucose sensitivity. Fasting increased activation of LHA orexin-GI neurons by decreased glucose, as would be predicted by these hormonal effects. We also evaluated putative VTA-DA neurons in a novel horizontal slice preparation containing the LHA and VTA. Decreased glucose increased the frequency of spontaneous excitatory post-synaptic currents (sEPSCs; 125 ± 40%, n=9, P<0.05) and action potentials (n=9; P<0.05) in 45% (9/20) of VTA DA neurons. sEPSCs were completely blocked by AMPA and NMDA glutamate receptor antagonists (CNQX 20 ?M, n=4; APV 20?M, n=4; respectively), demonstrating that these sEPSCs were mediated by glutamatergic transmission onto VTA DA neurons. Orexin-1 but not 2 receptor antagonism with SB334867 (10?M; n=9) and TCS-OX2-29 (2?M; n=5), respectively, blocks the effects of decreased glucose on VTA DA neurons. Thus, decreased glucose increases orexin-dependent excitatory glutamate neurotransmission onto VTA DA neurons. These data suggest that the glucose sensitivity of LHA orexin-GI neurons links metabolic state and reward-based feeding. PMID:25107627

Sheng, Zhenyu; Santiago, Ammy M; Thomas, Mark P; Routh, Vanessa H

2014-09-01

211

13C isotopomer analysis of glucose and alanine metabolism reveals cytosolic pyruvate compartmentation as part of energy metabolism in astrocytes.  

Science.gov (United States)

After incubation of glial cells with both (13)C-labeled and unlabeled glucose and alanine, (13)C isotopomer analysis indicates two cytosolic pyruvate compartments in astrocytes. One pyruvate pool is in an exchange equilibrium with exogenous alanine and preferentially synthesizes releasable lactate. The second pyruvate pool, which is of glycolytic origin, is more closely related to mitochondrial pyruvate, which is oxidized via tri carbonic acid (TCA) cycle activity. In order to provide 2-oxoglutarate as a substrate for cytosolic alanine aminotransferase, glycolytic activity is increased in the presence of exogenous alanine. Furthermore, in the presence of alanine, glutamate is accumulated in astrocytes without subsequent glutamine synthesis. We suggest that the conversion of alanine to releasable lactate proceeds at the expense of flux of glycolytic pyruvate through lactate dehydrogenase, which is used for ammonia fixation by alanine synthesis in the cytosol and for mitochondrial TCA cycle activity. In addition, an intracellular trafficking occurs between cytosol and mitochondria, by which these two cytosolic pyruvate pools are partly connected. Thus, exogenous alanine modifies astrocytic glucose metabolism for the synthesis of releasable lactate disconnected from glycolysis. The data are discussed in terms of astrocytic energy metabolism and the metabolic trafficking via a putative alanine-lactate shuttle between astrocytes and neurons. PMID:11329182

Zwingmann, C; Richter-Landsberg, C; Leibfritz, D

2001-05-01

212

Glucose metabolism following human traumatic brain injury: methods of assessment and pathophysiological findings.  

Science.gov (United States)

The pathophysiology of traumatic brain (TBI) injury involves changes to glucose uptake into the brain and its subsequent metabolism. We review the methods used to study cerebral glucose metabolism with a focus on those used in clinical TBI studies. Arterio-venous measurements provide a global measure of glucose uptake into the brain. Microdialysis allows the in vivo sampling of brain extracellular fluid and is well suited to the longitudinal assessment of metabolism after TBI in the clinical setting. A recent novel development is the use of microdialysis to deliver glucose and other energy substrates labelled with carbon-13, which allows the metabolism of glucose and other substrates to be tracked. Positron emission tomography and magnetic resonance spectroscopy allow regional differences in metabolism to be assessed. We summarise the data published from these techniques and review their potential uses in the clinical setting. PMID:25413449

Jalloh, Ibrahim; Carpenter, Keri L H; Helmy, Adel; Carpenter, T Adrian; Menon, David K; Hutchinson, Peter J

2014-11-21

213

Dendritic cell metabolism.  

Science.gov (United States)

The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism. PMID:25534620

Pearce, Edward J; Everts, Bart

2014-12-23

214

Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans.  

Science.gov (United States)

Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure. PMID:25497115

Lennerz, Belinda S; Vafai, Scott B; Delaney, Nigel F; Clish, Clary B; Deik, Amy A; Pierce, Kerry A; Ludwig, David S; Mootha, Vamsi K

2015-01-01

215

An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism.  

Science.gov (United States)

Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V(max)) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRP-associated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes. PMID:17028192

Futamura, Mayumi; Hosaka, Hideka; Kadotani, Akito; Shimazaki, Hiroko; Sasaki, Kaori; Ohyama, Sumika; Nishimura, Teruyuki; Eiki, Jun-Ichi; Nagata, Yasufumi

2006-12-01

216

Detoxification of ammonia in mouse cortical GABAergic cell cultures increases neuronal oxidative metabolism and reveals an emerging role for release of glucose-derived alanine  

DEFF Research Database (Denmark)

Cerebral hyperammonemia is believed to play a pivotal role in the development of hepatic encephalopathy (HE), a debilitating condition arising due to acute or chronic liver disease. In the brain, ammonia is thought to be detoxified via the activity of glutamine synthetase, an astrocytic enzyme. Moreover, it has been suggested that cerebral tricarboxylic acid (TCA) cycle metabolism is inhibited and glycolysis enhanced during hyperammonemia. The aim of this study was to characterize the ammonia-detoxifying mechanisms as well as the effects of ammonia on energy-generating metabolic pathways in a mouse neuronal-astrocytic co-culture model of the GABAergic system. We found that 5 mM ammonium chloride affected energy metabolism by increasing the neuronal TCA cycle activity and switching the astrocytic TCA cycle toward synthesis of substrate for glutamine synthesis. Furthermore, ammonia exposure enhanced the synthesis and release of alanine. Collectively, our results demonstrate that (1) formation of glutamine is seminal for detoxification of ammonia; (2) neuronal oxidative metabolism is increased in the presence of ammonia; and (3) synthesis and release of alanine is likely to be important for ammonia detoxification as a supplement to formation of glutamine.

Leke, Renata; Bak, Lasse Kristoffer

2011-01-01

217

Detoxification of Ammonia in Mouse Cortical GABAergic Cell Cultures Increases Neuronal Oxidative Metabolism and Reveals an Emerging Role for Release of Glucose-Derived Alanine  

DEFF Research Database (Denmark)

Cerebral hyperammonemia is believed to play a pivotal role in the development of hepatic encephalopathy (HE), a debilitating condition arising due to acute or chronic liver disease. In the brain, ammonia is thought to be detoxified via the activity of glutamine synthetase, an astrocytic enzyme. Moreover, it has been suggested that cerebral tricarboxylic acid (TCA) cycle metabolism is inhibited and glycolysis enhanced during hyperammonemia. The aim of this study was to characterize the ammonia-detoxifying mechanisms as well as the effects of ammonia on energy-generating metabolic pathways in a mouse neuronal-astrocytic co-culture model of the GABAergic system. We found that 5 mM ammonium chloride affected energy metabolism by increasing the neuronal TCA cycle activity and switching the astrocytic TCA cycle toward synthesis of substrate for glutamine synthesis. Furthermore, ammonia exposure enhanced the synthesis and release of alanine. Collectively, our results demonstrate that (1) formation of glutamine is seminal for detoxification of ammonia; (2) neuronal oxidative metabolism is increased in the presence of ammonia; and (3) synthesis and release of alanine is likely to be important for ammonia detoxification as a supplement to formation of glutamine.

Leke, Renata; Bak, Lasse K

2011-01-01

218

Relationship between glucose metabolism and hepatic encephalopathy in patients with liver cirrhosis  

Directory of Open Access Journals (Sweden)

Full Text Available ObjectiveTo observe the changes in blood glucose in patients with liver cirrhosis and investigate the relationship between glucose metabolism and hepatic encephalopathy (HE. MethodsSixty patients with liver cirrhosis (cirrhosis group and 30 patients without liver cirrhosis (control group, who were hospitalized in Department of Gastroenterology, Jiading District Central Hospital from August 2008 to August 2010, were included in the study. The general data were collected; the consciousness of patients was observed; the physical examination was performed for detecting flapping tremors; blood samples were collected for measuring blood glucose. The cirrhosis group was further divided into flapping tremor subgroup and non-flapping tremor subgroup. The cirrhosis group and control group were compared in terms of the incidence rate of abnormal glucose metabolism. The patients were divided into normal glucose metabolism group and abnormal glucose metabolism group, and the two groups were compared in terms of the incidence rates of flapping tremors and HE. ResultsOf the 60 patients in cirrhosis group, 28 had no flapping tremors, and 32 had flapping tremors. The incidence rate of abnormal glucose metabolism was significantly lower in the control group than in the cirrhosis group (13.33% vs 26.67%; ?2=2?058, P?0.05. The incidence rates of flapping tremors and HE were 50.00% and 34.09% in the normal glucose metabolism group, versus 62.50% and 37.50% in the abnormal glucose metabolism group (P?0.05. ConclusionThe patients with liver cirrhosis have abnormal glucose metabolism, but which is not necessarily associated with HE. It suggests that the patients with HE may have impaired glucose utilization in the brain.

ZHANG Lihang

2013-07-01

219

Dynamics of glucose and insulin concentration connected to the ??cell cycle: model development and analysis  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Diabetes mellitus is a group of metabolic diseases with increased blood glucose concentration as the main symptom. This can be caused by a relative or a total lack of insulin which is produced by the ??cells in the pancreatic islets of Langerhans. Recent experimental results indicate the relevance of the ??cell cycle for the development of diabetes mellitus. Methods This paper introduces a mathematical model that connects the dynamics of glucose and insulin concentration with the ??cell cycle. The interplay of glucose, insulin, and ??cell cycle is described with a system of ordinary differential equations. The model and its development will be presented as well as its mathematical analysis. The latter investigates the steady states of the model and their stability. Results Our model shows the connection of glucose and insulin concentrations to the ??cell cycle. In this way the important role of glucose as regulator of the cell cycle and the capability of the ??cell mass to adapt to metabolic demands can be presented. Simulations of the model correspond to the qualitative behavior of the glucose?insulin regulatory system showed in biological experiments. Conclusions This work focusses on modeling the physiological situation of the glucose?insulin regulatory system with a detailed consideration of the ??cell cycle. Furthermore, the presented model allows the simulation of pathological scenarios. Modification of different parameters results in simulation of either type 1 or type 2 diabetes.

Gallenberger Martina

2012-11-01

220

Inhibitory effects of 2-deoxy-D-glucose on methanol metabolism in Torulopsis sp  

International Nuclear Information System (INIS)

Inhibitory effects of 2-deoxy-D-glucose (2dG) on methanol metabolism in Torulopsis A-12 were investigated. The remarkable inhibition was observed on growth in the presence of 50 ?g/ml of 2dG when methanol was used as a carbon source. At the earlier time of incubation with 2dG, the incorporation of 14C-methanol into hexose-phosphate by intact cells was inhibited by 2dG, and this led to the reduction of the intracellular concentration of hexosephosphates. In the later period of incubation the specific activity of alcohol oxidase reduced, and formate accumulated extracellularly. (auth.)

 
 
 
 
221

Anorexia and impaired glucose metabolism in mice with hypothalamic ablation of glut4 neurons.  

Science.gov (United States)

The central nervous system (CNS) uses glucose independent of insulin. Nonetheless, insulin receptors and insulin-responsive glucose transporters (Glut4) often colocalize in neurons (Glut4 neurons) in anatomically and functionally distinct areas of the CNS. The apparent heterogeneity of Glut4 neurons has thus far thwarted attempts to understand their function. To answer this question, we used Cre-dependent, diphtheria toxin-mediated cell ablation to selectively remove basal hypothalamic Glut4 neurons and investigate the resulting phenotypes. After Glut4 neuron ablation, mice demonstrate altered hormone and nutrient signaling in the CNS. Accordingly, they exhibit negative energy balance phenotype characterized by reduced food intake and increased energy expenditure, without locomotor deficits or gross neuronal abnormalities. Glut4 neuron ablation affects orexigenic melanin-concentrating hormone neurons but has limited effect on neuropeptide Y/agouti-related protein and proopiomelanocortin neurons. The food intake phenotype can be partially normalized by GABA administration, suggesting that it arises from defective GABAergic transmission. Glut4 neuron-ablated mice show peripheral metabolic defects, including fasting hyperglycemia and glucose intolerance, decreased insulin levels, and elevated hepatic gluconeogenic genes. We conclude that Glut4 neurons integrate hormonal and nutritional cues and mediate CNS actions of insulin on energy balance and peripheral metabolism. PMID:25187366

Ren, Hongxia; Lu, Taylor Y; McGraw, Timothy E; Accili, Domenico

2015-02-01

222

Glucose metabolism in mice during and after whole-body hyperthermia  

International Nuclear Information System (INIS)

Researchers studied glucose turnover in male inbred mice during and after whole-body hyperthermia for 1 hour at 40 degrees or 41 degrees C by giving them injections of [14C]glucose with and without a glucose load and measuring the expired 14Co2. Expiration of 14CO2 was increased during hyperthermia but decreased considerably afterward. The latter effect was enhanced by a glucose load. This inhibition depended on the glucose concentration. Metabolic studies showed a depletion of several glycolytic metabolites, especially glycogen and lactate, after whole-body hyperthermia. Combined treatment of hyperthermia and a glucose injection 1 hour later led to an increased level of glucose 6-phosphate, which indicated a block in glycolysis between glucose 6-phosphate and fructose 1,6-diphosphate. This inhibition did not occur when glucose was given before the hyperthermia treatment. Lactate accumulation was not observed under any conditions

223

Normal glucose uptake in the brain and heart requires an endothelial cell-specific HIF-1?–dependent function  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Although intimately positioned between metabolic substrates in the bloodstream and the tissue parenchymal cells that require these substrates, a major role of the vascular endothelium in the regulation of tissue metabolism has not been widely appreciated. We hypothesized that via control of transendothelial glucose transport and contributing paracrine mechanisms the endothelium plays a major role in regulating organ and tissue glucose metabolism. We further hypothesized that the hypoxia-induc...

Huang, Yan; Lei, Li; Liu, Dinggang; Jovin, Ion; Russell, Raymond; Johnson, Randall S.; Di Lorenzo, Annarita; Giordano, Frank J.

2012-01-01

224

Regional brain glucose metabolism and blood flow in streptozocin-induced diabetic rats  

Energy Technology Data Exchange (ETDEWEB)

Brain regional glucose metabolism and regional blood flow were measured from autoradiographs by the uptake of ({sup 3}H)-2-deoxy-D-glucose and ({sup 14}C)iodoantipyrine in streptozocin-induced diabetic (STZ-D) rats. After 2 days of diabetes, glucose metabolism in the neocortex, basal ganglia, and white matter increased by 34, 37, and 8%, respectively, whereas blood flow was unchanged. After 4 mo, glucose metabolism in the same three regions was decreased by 32, 43, and 60%. This reduction was paralleled by a statistically nonsignificant reduction in blood flow in neocortex and basal ganglia. It is suggested that the decrease of brain glucose metabolism in STZ-D reflects increased ketone body oxidation and reduction of electrochemical work.

Jakobsen, J.; Nedergaard, M.; Aarslew-Jensen, M.; Diemer, N.H. (Univ. of Copenhagen (Denmark))

1990-04-01

225

Developmental role for endocannabinoid signaling in regulating glucose metabolism and growth.  

Science.gov (United States)

Treatment of ob/ob (obese) mice with a cannabinoid receptor 1 (Cnr1) antagonist reduces food intake, suggesting a role for endocannabinoid signaling in leptin action. We further evaluated the role of endocannabinoid signaling by analyzing the phenotype of Cnr1 knockout ob/ob mice. Double mutant animals show a more severe growth retardation than ob/ob mice with similar levels of adiposity and reduced IGF-I levels without alterations of growth hormone (GH) levels. The double mutant mice are also significantly more glucose intolerant than ob/ob mice. This is in contrast to treatment of ob/ob mice with a Cnr1 antagonist that had no effect on glucose metabolism, suggesting a possible requirement for endocannabinoid signaling during development for normal glucose homeostasis. Double mutant animals also showed similar leptin sensitivity as ob/ob mice, suggesting that there are developmental changes that compensate for the loss of Cnr1 signaling. These data establish a role for Cnr1 during development and suggest that compensatory changes during development may mitigate the requirement for Cnr1 in mediating the effects of leptin. The data also suggest a developmental role for Cnr1 to promote growth, regulate the GH/IGF-I axis, and improve ?-cell function and glucose homeostasis in the setting of leptin deficiency. PMID:23423572

Li, Zhiying; Schmidt, Sarah F; Friedman, Jeffrey M

2013-07-01

226

Taurine modulates kallikrein activity and glucose metabolism in insulin resistant rats.  

Science.gov (United States)

Taurine, a potent antioxidant has been reported to show an anti-diabetic effect in streptozotocin-induced diabetes mellitus in which the development of hyperglycemia results from the damage to beta cells of pancreas by reactive oxygen species. In addition, taurine also increases the excretion of nitrite and enhances the formation of kinins and would be expected to improve insulin resistance. The effect of taurine on insulin sensitivity was examined in the high fructose-fed rats, an animal model of insulin resistance. Male Wistar rats of body weight 170-190g were divided into 4 groups: a control group and taurine-supplemented control group, taurine supplemented and unsupplemented fructose-fed group. An intravenous glucose tolerance test (IVGTT) and a steady state plasma glucose level (SSPG) were performed before the sacrifice. The fructose-fed rats displayed hyperglycemia and insulin resistance and they had a greater accumulation of glycogen than did control rats. Hyperglycemia and insulin resistance were significantly lower in the taurine supplemented fructose-fed group than in the unsupplemented fructose-fed group. Urinary kallikrein activity was higher in taurine-treated animals than in the rats fed only fructose. The activity of membrane bound ATPases were significantly lower in fructose-fed rats than in the control rats and were significantly higher in the taurine supplemented group than in the fructose-fed group. Taurine effectively improves glucose metabolism in fructose-fed rats presumably via improved insulin action and glucose tolerance. PMID:12025872

Nandhini, A T Anitha; Anuradha, C V

2002-01-01

227

Reciprocal effects of 2-fluoro-2-deoxy-D-glucose and glucose on their metabolism in Saccharomyces cerevisiae studied by multi-nuclear NMR spectroscopy  

Energy Technology Data Exchange (ETDEWEB)

The effects of various concentrations of 2-fluoro-2-deoxy-D-glucose (FDG) on the aerobic metabolism of glucose and the reciprocal effect of glucose on the metabolism of FDG in glucose-grown repressed Saccharomyces cerevisiae cells were studied at 30 deg C in a standard pyrophosphate medium containing 5 x 10{sup 7} cells/ml by {sup 1}H-, {sup 19}F-, {sup 31}P-NMR and biochemical techniques. The glucose consumption rate is reduced by about 57% and 71% in the presence of 5 mM FDG and 10 mM FDG respectively. Under the same conditions, the ethanol production rate also decreases about 54% and 68%, respectively. When FDG is the unique carbon source, the {alpha}- and {beta}-anomers of 2-fluoro-2-deoxy-D-glucose-6-phosphate (FDG6P) and a much smaller quantity of 2-fluoro-2-deoxy-gluconic acid (FDGA) were observed. The quantities of {alpha} and {beta}-FDG6P reach their maximum values within 1 h of incubation and then decrease continuously. In contrast, Glc favors the consumption of FDG and the synthesis of FDG6P and uridine-5`-diphosphate fluoro-deoxy-glucose (UDP-FDG). In the presence of GLC, FDG6P reaches a plateau after 1 h or 2 h of incubation while UDP-FDG increases regularly with time. Apart from trehalose, no other disaccharides were observed. Thus, in contrast to UDP-Glc, UDP-DG, Glc6P and DG6P, UDP-FDG and FDG6P are not good substrates for trehalose-6-P synthetase. The effect of DG and FDG on the cell growth in standard nutrient media was also investigated at 37 deg C. The cell growth was found to be completely inhibited upon addition of 1 mM FDG and only slowed down in the presence of 1 mM DG. In the latter case, the doubling time {tau} is about 3 h instead of 1 h 25` in the absence of DG and FDG. The reciprocal effects of FDG and Glc on their metabolism, the toxicity of FDG and the blockage level of enzymes induced by FDG are discussed in comparison with 2-deoxy-D-glucose (DG) and Glc. (Abstract Truncated)

Tran-Dinh, S.; Courtois, A.; Wietzerbin, J. [CEA Centre d`Etudes de Saclay, 91-Gif-sur-Yvette (France). Dept. de Biologie Cellulaire et Moleculaire; Bouet, F. [CEA Centre d`Etudes de Saclay, 91 -Gif-sur-Yvette (France). Direction des Sciences du Vivant; Herve, M. [CEA Centre d`Etudes de Saclay, 91 Gif-sur-Yvette (France). Dept. de Biologie Cellulaire et Moleculaire (France)]|[Paris-13 Univ., 93 -Saint-Denis (France)

1995-12-31

228

Inhibition of murine splenic T lymphocyte proliferation by 2-deoxy-D-glucose-induced metabolic stress  

Science.gov (United States)

Female Swiss-Webster mice were injected with the glucose analogue 2-deoxy-D-glucose (2-DG), which when administered to rodents induces acute periods of metabolic stress. A single or multiple injections of 2-DG invoked a stress response, as evidenced by increases in serum corticosterone levels. The influence of this metabolic stressor on the blastogenic potential of splenic T lymphocytes was then examined. It was found that one, two, or three injections of 2-DG resulted in depressed T cell proliferative responses, with an attenuation of the effect occurring by the fifth injection. The 2-DG-induced inhibition of T cell proliferation was not attributable to 2-DG-induced cytolysis, as in vitro incubation of naive T cells with varying concentrations of 2-DG did not result in a reduction in cell number or viability, and flow cytometric analysis demonstrated that percentages of CD3, CD4, and CD8 splenic T cells were not altered as a result of 2-DG-induced stress. Incubating naive T cells in varying concentrations of 2-DG resulted in a dose-dependent inhibition of T cell blastogenic potential. Following in vivo exposure to 2-DG, T cell proliferation did not return to normal levels until 3 days after the cessation of 2-DG injections. Administering the beta-adrenergic receptor antagonist propranolol did not reverse the inhibited lymphoproliferation in 2-DG-treated mice. The inhibition in T cell proliferation was not observed, however, in mice that had been adrenalectomized or hypophysectomized and injected with 2-DG.(ABSTRACT TRUNCATED AT 250 WORDS).

Miller, E. S.; Klinger, J. C.; Akin, C.; Koebel, D. A.; Sonnenfeld, G.

1994-01-01

229

A link between hepatic glucose production and peripheral energy metabolism via hepatokines.  

Science.gov (United States)

Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes. PMID:25061558

Abdul-Wahed, Aya; Gautier-Stein, Amandine; Casteras, Sylvie; Soty, Maud; Roussel, Damien; Romestaing, Caroline; Guillou, Hervé; Tourette, Jean-André; Pleche, Nicolas; Zitoun, Carine; Gri, Blandine; Sardella, Anne; Rajas, Fabienne; Mithieux, Gilles

2014-08-01

230

Hydrocortisone stimulates the development of oligodendrocytes in primary glial cultures and affects glucose metabolism and lipid synthesis in these cultures  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Cultures of glial cells were prepared from the brains of one-week-old rat pups. After one day in culture, serum was omitted from the medium and replaced by a combination of growth-stimulating hormones and other factors that enhanced the percentage of oligodendrocytes in the cultures. We investigated the effects of hydrocortisone on the development of oligodendrocytes, on the activities of oligodendrocyte-specific enzymes and on glucose- and lipid-metabolism of the glial cells. (1) Hydrocortis...

Warringa, R. A. J.; Hoeben, R. C.; Koper, W. J.; Sykes, J. E. C.; Golde, L. M. G.; Lopes-cardozo, M.

1987-01-01

231

Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass.  

Science.gov (United States)

The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations (12.3 ± 2.2 vs. 18.1 ± 3.1 nmol/6 h, P = 0.002) and the ?-cell response to glucose (Total, 13 ± 1 vs. 11 ± 1 × 10(-9) min(-1), P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB. PMID:24089513

Shah, Meera; Law, Jennie H; Micheletto, Francesco; Sathananthan, Matheni; Dalla Man, Chiara; Cobelli, Claudio; Rizza, Robert A; Camilleri, Michael; Zinsmeister, Alan R; Vella, Adrian

2014-02-01

232

Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass.  

Science.gov (United States)

The resolution of type 2 diabetes after Roux-en-Y gastric bypass (RYGB) attests to the important role of the gastrointestinal tract in glucose homeostasis. Previous studies in RYGB-treated rats have shown that the Roux limb displays hyperplasia and hypertrophy. Here, we report that the Roux limb of RYGB-treated rats exhibits reprogramming of intestinal glucose metabolism to meet its increased bioenergetic demands; glucose transporter-1 is up-regulated, basolateral glucose uptake is enhanced, aerobic glycolysis is augmented, and glucose is directed toward metabolic pathways that support tissue growth. We show that reprogramming of intestinal glucose metabolism is triggered by the exposure of the Roux limb to undigested nutrients. We demonstrate by positron emission tomography-computed tomography scanning and biodistribution analysis using 2-deoxy-2-[18F]fluoro-D-glucose that reprogramming of intestinal glucose metabolism renders the intestine a major tissue for glucose disposal, contributing to the improvement in glycemic control after RYGB. PMID:23888041

Saeidi, Nima; Meoli, Luca; Nestoridi, Eirini; Gupta, Nitin K; Kvas, Stephanie; Kucharczyk, John; Bonab, Ali A; Fischman, Alan J; Yarmush, Martin L; Stylopoulos, Nicholas

2013-07-26

233

[Activity of glucose-6-phosphate metabolism enzymes in the livers of rats with experimental valekson poisoning].  

Science.gov (United States)

The activity of hexokinase, glucose-6-phosphatase and glucose-6-phosphoric dehydrogenase was studied in the liver of rats after one hour, one and five days after a single oral administration of organic phosphorus insecticide valekson. It was determined that administration of the preparation led to an increase of activity in the homogenate and solubilization of glucose-6-phosphatase, activation of glucose-6-phosphoric dehydrogenase and inhibition of hexokinase. The changes were maximum one hour after the administration of the compound. The results show that a decrease of the intensity of glucose-6-phosphate formation and metabolism is one of the pathogenetic factors in the development of valekson-induced intoxication. PMID:202353

Kuz'minskaia, U A; Bersan, L V; Pis'mennaia, M V

1977-12-01

234

Thalamic, brainstem, and cerebellar glucose metabolism in the hemiplegic monkey  

International Nuclear Information System (INIS)

Unilateral ablation of cerebral cortical areas 4 and 6 of Brodmann in the macaque monkey results in a contralateral hemiplegia that resolves partially with time. During the phase of dense hemiplegia, local cerebral metabolic rate for glucose (1CMRG1c) is decreased significantly in most of the thalamic nuclei ipsilateral to the ablation, and there are slight contralateral decreases. The lCMRGlc is reduced bilaterally in most of the brainstem nuclei and bilaterally in the deep cerebellar nuclei, but only in the contralateral cerebellar cortex. During the phase of partial motor recovery, lCMRGlc is incompletely restored in many of the thalamic nuclei ipsilateral to the ablation and completely restored in the contralateral nuclei. In the brainstem and deep cerebellar nuclei, poor to moderate recovery occurs bilaterally. Moderate recovery occurs in the contralateral cerebellar cortex. The findings demonstrate that a unilateral cerebral cortical lesion strongly affects lCMRGlc in the thalamus ipsilaterally and in the cerebellar cortex contralaterally, but in the brainstem bilaterally. Partial recovery of lCMRGlc accompanies the progressive motor recovery. The structures affected include those with direct, and also those with indirect, connections to the areas ablated

235

Thalamic, brainstem, and cerebellar glucose metabolism in the hemiplegic monkey  

Energy Technology Data Exchange (ETDEWEB)

Unilateral ablation of cerebral cortical areas 4 and 6 of Brodmann in the macaque monkey results in a contralateral hemiplegia that resolves partially with time. During the phase of dense hemiplegia, local cerebral metabolic rate for glucose (1CMRG1c) is decreased significantly in most of the thalamic nuclei ipsilateral to the ablation, and there are slight contralateral decreases. The lCMRGlc is reduced bilaterally in most of the brainstem nuclei and bilaterally in the deep cerebellar nuclei, but only in the contralateral cerebellar cortex. During the phase of partial motor recovery, lCMRGlc is incompletely restored in many of the thalamic nuclei ipsilateral to the ablation and completely restored in the contralateral nuclei. In the brainstem and deep cerebellar nuclei, poor to moderate recovery occurs bilaterally. Moderate recovery occurs in the contralateral cerebellar cortex. The findings demonstrate that a unilateral cerebral cortical lesion strongly affects lCMRGlc in the thalamus ipsilaterally and in the cerebellar cortex contralaterally, but in the brainstem bilaterally. Partial recovery of lCMRGlc accompanies the progressive motor recovery. The structures affected include those with direct, and also those with indirect, connections to the areas ablated.

Shimoyama, I.; Dauth, G.W.; Gilman, S.; Frey, K.A.; Penney, J.B. Jr.

1988-12-01

236

Effect of erythropoietin on the glucose transport of rat erythrocytes and bone marrow cells  

International Nuclear Information System (INIS)

The effect of Ep on radioactive glucose and methyl-alpha-D-glucoside transport by rat erythrocytes and bone marrow cells were studied. There is initial linearity followed by saturation kinetics of [14C]glucose transport by the erythrocytes of starved and starved plus Ep-treated rats at different concentrations of glucose. Starvation caused slight inhibition of glucose transport which increased markedly on Ep administration to starved rats. Normal animals failed to show any significant change in glucose transport after Ep treatment. Methyl-alpha-D-glucoside inhibited the Ep-stimulated glucose transport significantly. Ep also stimulated the transport of radioactive methyl-alpha-D-glucoside which was competitively inhibited in presence of D-glucose. Glucose transport in erythrocytes was found to be sensitive to metabolic inhibitors like azide and DNP. A sulfhydryl reagent and ouabain also inhibited the transport process. Ep stimulated glucose and methyl-alpha-D-glucoside transport in the bone marrow cells of starved rats. The sugar analog competitively inhibited the glucose transport in bone marrow cells and vice versa

237

Portal glucose delivery stimulates muscle but not liver protein metabolism  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Portal vein glucose delivery (the portal glucose signal) stimulates glucose uptake and glycogen storage by the liver, whereas portal amino acid (AA) delivery (the portal AA signal) induces an increase in protein synthesis by the liver. During a meal, both signals coexist and may interact. In this study, we compared the protein synthesis rates in the liver and muscle in response to portal or peripheral glucose infusion during intraportal infusion of a complete AA mixture. Dogs were surgically ...

Kraft, Guillaume; Coate, Katie C.; Dardevet, Dominique; Farmer, Ben; Donahue, E. Patrick; Williams, Phillip E.; Cherrington, Alan D.; Moore, Mary Courtney

2012-01-01

238

Cerebrospinal fluid ionic regulation, cerebral blood flow, and glucose use during chronic metabolic alkalosis  

International Nuclear Information System (INIS)

Chronic metabolic alkalosis was induced in rats by combining a low K+ diet with a 0.2 M NaHCO3 solution as drinking fluid for either 15 or 27 days. Local cerebral blood flow and local cerebral glucose utilization were measured in 31 different structures of the brain in conscious animals by means of the iodo-[14C]antipyrine and 2-[14C]deoxy-D-glucose method. The treatment induced moderate [15 days, base excess (BE) 16 mM] to severe (27 days, BE 25 mM) hypochloremic metabolic alkalosis and K+ depletion. During moderate metabolic alkalosis no change in cerebral glucose utilization and blood flow was detectable in most brain structures when compared with controls. Cerebrospinal fluid (CSF) K+ and H+ concentrations were significantly decreased. During severe hypochloremic alkalosis, cerebral blood flow was decreased by 19% and cerebral glucose utilization by 24% when compared with the control values. The decrease in cerebral blood flow during severe metabolic alkalosis is attributed mainly to the decreased cerebral metabolism and to a lesser extent to a further decrease of the CSF H+ concentration. CSF K+ concentration was not further decreased. The results show an unaltered cerebral blood flow and glucose utilization together with a decrease in CSF H+ and K+ concentrations at moderate metabolic alkalosis and a decrease in cerebral blood flow and glucose utilization together with a further decreased CSF H+ concentration at severe metabolic alkalosisetabolic alkalosis

239

Azelnidipine and glucose tolerance: possible indications and treatment selection for hypertensive patients with metabolic disorders.  

Science.gov (United States)

Azelnidipine is a unique dihydropyridine calcium channel blocker with selectivity for L-type calcium channels that has been launched for the treatment of hypertension. Azelnidipine exhibits long-acting blood pressure-lowering effects without increasing heart rate. High blood pressure is associated with many metabolic disorders, including glucose intolerance and insulin resistance. Antihypertensive medications that interfere with various steps in the renin-angiotensin system improve glucose tolerance and insulin resistance; however, the effects of calcium channel blockers on glucose metabolism and insulin resistance remain controversial. Recent studies have demonstrated that azelnidipine could improve insulin resistance and glucose tolerance by potentially inhibiting sympathetic nerve activity. In addition, azelnidipine exhibits anti-inflammatory and anti-oxidative effects, suggesting that it is a beneficial antihypertensive agent with anti-atherogenic and cardioprotective effects for the treatment of not only hypertensive patients with glucose intolerance, but also those with metabolic disorders. PMID:25434474

Shimada, Kazunori; Miyauchi, Katsumi; Daida, Hiroyuki

2015-01-01

240

Response gene to complement 32 (RGC-32) in endothelial cells is induced by glucose and helpful to maintain glucose homeostasis  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Endothelium dysfunction has been understood primarily in terms of abnormal vasomotor function, which plays an important role in the pathogenesis of diabetes and chronic diabetic complications. However, it has not been fully studied that the endothelium may regulate metabolism itself. The response gene to complement 32 (RGC-32) has be considered as an angiogenic inhibitor in the context of endothelial cells. We found that RGC-32 was induced by high fat diet in vivo and by glucose or insulin in...

Guo, Shuzhen; Philbrick, Melissa J.; An, Xiaojing; Xu, Ming; Wu, Jiaping

2014-01-01

 
 
 
 
241

Assessment of regional glucose metabolism in aging brain and dementia with positron-emission tomography  

Energy Technology Data Exchange (ETDEWEB)

This paper explores the alterations in regional glucose metabolism that occur in elderly subjects and those with senile dementia compared to normal young volunteers. Results showed a tendency for the frontal regions to have a lower metabolic rate in patients with dementia although this did not reach the level of significance when compared to the elderly control subjects. The changes in glucose metabolism were symmetrical in both the left and right hemispheres. There was a lack of correlation between the mean cortical metabolic rates for glucose and the global mental function in the patients with senile dementia. This is at variance with most of the regional cerebral blood flow data that has been collected. This may be partly related to the use of substrates other than glucose by the brain in elderly and demented subjects. (PSB)

Reivich, M.; Alavi, A.; Ferris, S.; Christman, D.; Fowler, J.; MacGregor, R.; Farkas, T.; Greenberg, J.; Dann, R.; Wolf, A.

1981-01-01

242

Small is Fast: Astrocytic Glucose and Lactate Metabolism at Cellular Resolution  

Directory of Open Access Journals (Sweden)

Full Text Available Brain tissue is highly dynamic in terms of electrical activity and energy demand. Relevant energy metabolites have turnover times ranging from milliseconds to seconds and are rapidly exchanged between cells and within cells. Until recently these fast metabolic events were inaccessible, because standard isotopic techniques require use of populations of cells and/or involve integration times of tens of minutes. Thanks to fluorescent probes and recently available genetically-encoded optical nanosensors, this Technology Report shows how it is now possible to monitor the concentration of metabolites in real-time and in single cells. In combination with ad hoc inhibitor-stop protocols, these probes have revealed a key role for K+ in the acute stimulation of astrocytic glycolysis by synaptic activity. They have also permitted detection of the Warburg effect in single cancer cells. Genetically-encoded nanosensors currently exist for glucose, lactate, NADH and ATP, and it is envisaged that other metabolite nanosensors will soon be available. These optical tools together with improved expression systems and in vivo imaging, herald an exciting era of single-cell metabolic analysis.

L FelipeBarros

2013-03-01

243

Glucose and fatty acid metabolism in normal and diabetic rabbit cerebral microvessels  

Energy Technology Data Exchange (ETDEWEB)

Rabbit cerebral microvessels were used to study fatty acid metabolism and its utilization relative to glucose. Microvessels were incubated with either (6-/sup 14/C)glucose or (1-/sup 14/C)oleic acid and the incorporation of radioactivity into /sup 14/CO/sub 2/, lactate, triglyceride, cholesterol ester, and phospholipid was determined. The inclusion of 5.5 mM glucose in the incubation mixture reduced oleate oxidation by 50% and increased esterification into both phospholipid and triglyceride. Glucose oxidation to CO/sub 2/ was reduced by oleate addition, whereas lactate production was unaffected. 2'-Tetradecylglycidic acid, an inhibitor of carnitine acyltransferase I, blocked oleic acid oxidation in the presence and absence of glucose. It did not effect fatty acid esterification when glucose was absent and eliminated the inhibition of oleate on glucose oxidation. Glucose oxidation to /sup 14/CO/sub 2/ was markedly suppressed in microvessels from alloxan-treated diabetic rabbits but lactate formation was unchanged. Fatty acid oxidation to CO/sub 2/ and incorporation into triglyceride, phospholipid, and cholesterol ester remained unchanged in the diabetic state. The experiments show that both fatty acid and glucose can be used as a fuel source by the cerebral microvessels, and the interactions found between fatty acid and glucose metabolism are similar to the fatty acid-glucose cycle, described previously.

Hingorani, V.; Brecher, P.

1987-05-01

244

INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells  

International Nuclear Information System (INIS)

Highlights: •HIF-1?-regulated INPP4B enhances glycolysis. •INPP4B regulates aerobic glycolysis by inducing HK2 via Akt-mTOR pathway. •Blockage of INPP4B and HK2 sensitizes radioresistant laryngeal cancer cells to radiation and anticancer drug. •INPP4B is associated with HK2 in human laryngeal cancer tissues. -- Abstract: Inositol polyphosphate 4-phosphatase type II (INPP4B) was recently identified as a tumor resistance factor in laryngeal cancer cells. Herein, we show that INPP4B-mediated resistance is associated with increased glycolytic phenotype. INPP4B expression was induced by hypoxia and irradiation. Intriguingly, overexpression of INPP4B enhanced aerobic glycolysis. Of the glycolysis-regulatory genes, hexokinase 2 (HK2) was mainly regulated by INPP4B and this regulation was mediated through the Akt-mTOR pathway. Notably, codepletion of INPP4B and HK2 markedly sensitized radioresistant laryngeal cancer cells to irradiation or anticancer drug. Moreover, INPP4B was significantly associated with HK2 in human laryngeal cancer tissues. Therefore, these results suggest that INPP4B modulates aerobic glycolysis via HK2 regulation in radioresistant laryngeal cancer cells

245

INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells  

Energy Technology Data Exchange (ETDEWEB)

Highlights: •HIF-1?-regulated INPP4B enhances glycolysis. •INPP4B regulates aerobic glycolysis by inducing HK2 via Akt-mTOR pathway. •Blockage of INPP4B and HK2 sensitizes radioresistant laryngeal cancer cells to radiation and anticancer drug. •INPP4B is associated with HK2 in human laryngeal cancer tissues. -- Abstract: Inositol polyphosphate 4-phosphatase type II (INPP4B) was recently identified as a tumor resistance factor in laryngeal cancer cells. Herein, we show that INPP4B-mediated resistance is associated with increased glycolytic phenotype. INPP4B expression was induced by hypoxia and irradiation. Intriguingly, overexpression of INPP4B enhanced aerobic glycolysis. Of the glycolysis-regulatory genes, hexokinase 2 (HK2) was mainly regulated by INPP4B and this regulation was mediated through the Akt-mTOR pathway. Notably, codepletion of INPP4B and HK2 markedly sensitized radioresistant laryngeal cancer cells to irradiation or anticancer drug. Moreover, INPP4B was significantly associated with HK2 in human laryngeal cancer tissues. Therefore, these results suggest that INPP4B modulates aerobic glycolysis via HK2 regulation in radioresistant laryngeal cancer cells.

Min, Joong Won [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Kwang Il [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Hyun-Ah; Kim, Eun-Kyu; Noh, Woo Chul [Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Jeon, Hong Bae [Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul (Korea, Republic of); Cho, Dong-Hyung [Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do (Korea, Republic of); Oh, Jeong Su [Department of Genetic Engineering, Sungkyunkwan University, Suwon (Korea, Republic of); Park, In-Chul; Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Jae-Sung, E-mail: jaesung@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

2013-10-11

246

Metabolism of glucose and xylose as single and mixed feed in Debaryomyces nepalensis NCYC 3413: production of industrially important metabolites.  

Science.gov (United States)

Efficient conversion of hexose and pentose (glucose and xylose) by a single strain is a very important factor for the production of industrially important metabolites using lignocellulose as the substrate. The kinetics of growth and polyol production by Debaryomyces nepalensis NCYC 3413 was studied under single and mixed substrate conditions. In the presence of glucose, the strain produced ethanol (35.8?±?2.3 g/l), glycerol (9.0?±?0.2 g/l), and arabitol (6.3?±?0.2 g/l). In the presence of xylose, the strain produced xylitol (38?±?1.8 g/l) and glycerol (18?±?1.0 g/l) as major metabolites. Diauxic growth was observed when the strain was grown with different combinations of glucose/xylose, and glucose was the preferred substrate. The presence of glucose enhanced the conversion of xylose to xylitol. By feeding a mixture of glucose at 100 g/l and xylose at 100 g/l, it was found that the strain produced a maximum of 72?±?3 g/l of xylitol. A study of important enzymes involved in the synthesis of xylitol (xylose reductase (XR) and xylitol dehydrogenase (XDH)), glycerol (glycerol-3-phosphate dehydrogenase (G3PDH)) and ethanol (alcohol dehydrogenase (ADH)) in cells grown in the presence of glucose and xylose revealed high specific activity of G3PDH and ADH in cells grown in the presence of glucose, whereas high specific activity of XR, XDH, and G3PDH was observed in cells grown in the presence of xylose. To our knowledge, this is the first study to elaborate the glucose and xylose metabolic pathway in this yeast strain. PMID:21085948

Kumar, Sawan; Gummadi, Sathyanarayana N

2011-03-01

247

Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men  

DEFF Research Database (Denmark)

We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp (HI), 40 mU/m(2) x min], 3-(3)H-glucose, indirect calorimetry, and iv glucose tolerance test. Free fatty acid concentrations were similar during basal steady state but 3.7- to 13-fold higher during clamps. P-glucagon increased and the insulin/glucagon ratio decreased at both LI and HI during Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action.insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes.

Jensen, Christine B; Storgaard, Heidi

2003-01-01

248

Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men.  

DEFF Research Database (Denmark)

We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp (HI), 40 mU/m(2) x min], 3-(3)H-glucose, indirect calorimetry, and iv glucose tolerance test. Free fatty acid concentrations were similar during basal steady state but 3.7- to 13-fold higher during clamps. P-glucagon increased and the insulin/glucagon ratio decreased at both LI and HI during Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action.insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes.

Jensen, Christine B; Storgaard, Heidi

2003-01-01

249

Paricalcitol does not improve glucose metabolism in patients with stage 3-4 chronic kidney disease  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Patients with chronic kidney disease are often insulin resistant and glucose intolerant; abnormalities that promote cardiovascular disease. Administration of 1,25-dihydroxyvitamin D (calcitriol) has improved glucose metabolism in patients with end stage renal disease. We conducted a randomized, placebo-controlled clinical trial to test whether paricalcitol, a 1,25-dihydroxyvitamin D analogue, changes glucose tolerance in earlier stages of chronic kidney disease. In a cross-over design, 22 non...

Boer, Ian H.; Sachs, Michael; Hoofnagle, Andrew N.; Utzschneider, Kristina M.; Kahn, Steven E.; Kestenbaum, Bryan; Himmelfarb, Jonathan

2012-01-01

250

Uncoupling of fatty acid and glucose metabolism in malignant lymphoma: a PET study  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Increased use of glucose through glycolysis is characteristic for neoplastic growth while the significance of serum-free fatty acids for regulation of energy metabolism in cancer is poorly understood. We studied whether serum-free fatty acids (FFA) interfere with glycolytic metabolism of lymphoproliferative neoplasms as assessed with 2-F18-fluoro-2-deoxy-D-glucose ([F18]FDG) and positron emission tomography (PET). Twelve patients with newly diagnosed non-Hodgkin's lymphoma (n = 9) or Hodgkin'...

Nuutinen, J.; Minn, H.; Bergman, J.; Haaparanta, M.; Ruotsalainen, U.; Laine, H.; Knuuti, J.

1999-01-01

251

Covarying alterations in A? deposition, glucose metabolism, and gray matter volume in cognitively normal elderly  

Digital Repository Infrastructure Vision for European Research (DRIVER)

?-amyloid (A?), a feature of Alzheimer’s disease (AD) pathology, may precede reduced glucose metabolism and gray matter volume and cognitive decline in AD patients. Accumulation of A?, however, has been also reported in cognitively intact older people, although it remains unresolved whether and how A? deposition, glucose metabolism, and gray matter volume relate to one another in cognitively normal elderly. Fifty-two cognitively normal older adults underwent Pittsburgh Compound B positr...

Oh, Hwamee; Habeck, Christian; Madison, Cindee; Jagust, William

2012-01-01

252

The Coupling of Cerebral Metabolic Rate of Glucose and Cerebral Blood Flow In Vivo  

DEFF Research Database (Denmark)

The energy supplied to the brain by metabolic substrate is largely utilized for maintaining synaptic transmission. In this regulation cerebral blood flow and glucose consumption is tightly coupled as well in the resting condition as during activation. Quantification of cerebral blood flow and metabolism was originally performed using the Kety-Schmidt method and this method still represent the gold standard by which subsequent methods have been evaluated. However, in its classical setting, the method overestimates cerebral blood flow. Studies of metabolic changes during activation must take this into account, and subsequent methods for measurement of regional glucose metabolism must be corrected accordingly in order to allow reliable quantitative comparisons of metabolite changes in activation studies. For studies of regional metabolic changes during activation quantification poses further difficulties due to limitation in resolution and partial volume effects. In contrast to the tight coupling between regional glucose metabolism and cerebral blood flow, there is an uncoupling between flow and oxygen consumption as the latter only increases to a limited extend. The excess glucose uptake is thus not used for aerobic metabolism. Although some of the excess glucose uptake can be explained by lactate production, this phenomenon can still not account for the excess glucose uptake. Thus, more complex metabolic patterns in the brain might be reflected in the excess glucose uptake during activation, and especially temporal relationships must be taken into account. What triggers the flow increase during functional brain activation is not entirely elucidated. The demand for excess glucose uptake may be important and a possible oxygen deficit in tissue distant from the capillaries is probably of minor importance. The mechanism by which cerebral blood flow increases during activation may incorporate changes in glycolytic substrates or local changes in astrocytes or neurons that triggers the production of vasoactive substances.

Hasselbalch, Steen; Paulson, Olaf Bjarne

2012-01-01

253

Interaction between glucose and free fatty acid metabolism in human skeletal muscle.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The mechanism by which FFA metabolism inhibits intracellular insulin-mediated muscle glucose metabolism in normal humans is unknown. We used the leg balance technique with muscle biopsies to determine how experimental maintenance of FFA during hyperinsulinemia alters muscle glucose uptake, oxidation, glycolysis, storage, pyruvate dehydrogenase (PDH), or glycogen synthase (GS). 10 healthy volunteers had two euglycemic insulin clamp experiments. On one occasion, FFA were maintained by lipid emu...

Kelley, D. E.; Mokan, M.; Simoneau, J. A.; Mandarino, L. J.

1993-01-01

254

Histamine Regulation in Glucose and Lipid Metabolism via Histamine Receptors : Model for Nonalcoholic Steatohepatitis in Mice  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Histamine has been proposed to be an important regulator of energy intake and expenditure. The aim of this study was to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet. Histamine regulation of glucose and lipid metabolism, adipocytokine production, and development of hyperlipidemia-induced hepatic injury were studied in histamine H1 (H1R?/?) and H2 (H2R?/?) receptor knockout and wild-type m...

Wang, Ke-yong; Tanimoto, Akihide; Yamada, Sohsuke; Guo, Xin; Ding, Yan; Watanabe, Teruo; Watanabe, Takeshi; Kohno, Kimitoshi; Hirano, Ken-ichi; Tsukada, Hideo; Sasaguri, Yasuyuki

2010-01-01

255

Altered glucose metabolism of tumors: an attractive target for improving radiation and chemotherapy of tumors  

International Nuclear Information System (INIS)

Poorly differentiated and rapidly growing malignant tumors are generally characterized by higher rates of glucose usage and glycolysis as compared to corresponding normal tissues. Therefore, modulating the glucose metabolism using 2-DG provides a unique opportunity to selectively destroy tumors and significantly enhance the efficacy of radio and chemotherapy

256

Effects of dehydroepiandrosterone (DHEA) on glucose metabolism in isolated hepatocytes from Zucker rats  

Energy Technology Data Exchange (ETDEWEB)

DHEA has been shown to competitively inhibit the pentose phosphate shunt (PPS) enzyme glucose-6-phosphate dehydrogenase (G6PD) when added in vitro to supernatants or homogenates prepared from mammalian tissues. However, no consistent effect on G6PD activity has been determined in tissue removed from DHEA-treated rats. To explore the effects of DHEA on PPS, glucose utilization was measured in hepatocytes from lean and obese male Zucker rats (8 wks of age) following 1 wk of DHEA treatment (0.6% in diet). Incubation of isolated hepatocytes from treated lean Zucker rats with either (1-/sup 14/C) glucose or (6-/sup 14/C) glucose resulted in significant decreases in CO/sub 2/ production and total glucose utilization. DHEA-lean rats also had lowered fat pad weights. In obese rats, there was no effect of 1 wk of treatment on either glucose metabolism or fat pad weight. The calculated percent contribution of the PPS to glucose metabolism in hepatocytes was not changed for either DHEA-lean or obese rats when compared to control rats. In conclusion, 1 wk of DHEA treatment lowered overall glucose metabolism in hepatocytes of lean Zucker rats, but did not selectively affect the PPS. The lack of an effect of short-term treatment in obese rats may be due to differences in their metabolism or storage/release of DHEA in tissues in comparison to lean rats.

Finan, A.; Cleary, M.P.

1986-03-05

257

Effects of dehydroepiandrosterone (DHEA) on glucose metabolism in isolated hepatocytes from Zucker rats  

International Nuclear Information System (INIS)

DHEA has been shown to competitively inhibit the pentose phosphate shunt (PPS) enzyme glucose-6-phosphate dehydrogenase (G6PD) when added in vitro to supernatants or homogenates prepared from mammalian tissues. However, no consistent effect on G6PD activity has been determined in tissue removed from DHEA-treated rats. To explore the effects of DHEA on PPS, glucose utilization was measured in hepatocytes from lean and obese male Zucker rats (8 wks of age) following 1 wk of DHEA treatment (0.6% in diet). Incubation of isolated hepatocytes from treated lean Zucker rats with either [1-14C] glucose or [6-14C] glucose resulted in significant decreases in CO2 production and total glucose utilization. DHEA-lean rats also had lowered fat pad weights. In obese rats, there was no effect of 1 wk of treatment on either glucose metabolism or fat pad weight. The calculated percent contribution of the PPS to glucose metabolism in hepatocytes was not changed for either DHEA-lean or obese rats when compared to control rats. In conclusion, 1 wk of DHEA treatment lowered overall glucose metabolism in hepatocytes of lean Zucker rats, but did not selectively affect the PPS. The lack of an effect of short-term treatment in obese rats may be due to differences in their metabolism or storage/release of DHEA in tissues in comparison to lean rats

258

Glucose metabolism in relation to perfusion in patients with ischaemic heart disease  

International Nuclear Information System (INIS)

In order to correlate myocardial perfusion and residual metabolism in patients with coronary artery disease, the regional metabolic rate of glucose (rMRGlu) was compared with regional perfusion under glucose loading state (GL) and fasting state (FA). Fluorine-18 deoxyglucose dynamic scan was obtained in ten patients after oral GL and in 16 patients under FA. rMRGlu in seven segments was calculated using Patlak graphic analysis for comparison with normalized percent uptake of nitrogen-13 ammonia at rest in each segment. When perfusion was less than 45%, no segment showed an increase in rMRGlu (? 0.3 ?mol/min/g) under either FA (0/6 segment) or GL (0/8 segments), indicating a certain threshold of perfusion for maintenance of glucose metabolism. When perfusion exceeded 45%, rMRGlu was higher in GL (0.37 ± 0.18 ?mol/min/g) than FA (0.15 ± 0.12 ?mol/min/g, P < 0.001) but there was very wide scatter of rMRGlu values under both states. Thus, both myocardium with preserved and myocardium with reduced glucose metabolism may exist when the perfusion exceeds 45%. In conclusion, a minimum threshold of perfusion for the maintenance of glucose metabolism may exist under both FA and GL. Below the threshold, irreversible damage may occur in the myocardium. Above the threshold, quantitative analysis of glucose metabolism should play an important role in differentiating reversibly injured myocardium from necrotic myocardium. (orig.)

259

Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond.  

Science.gov (United States)

The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D. PMID:24631413

Cani, P D; Geurts, L; Matamoros, S; Plovier, H; Duparc, T

2014-09-01

260

Activation of Src induces mitochondrial localisation of de2-7EGFR (EGFRvIII) in glioma cells: implications for glucose metabolism  

Digital Repository Infrastructure Vision for European Research (DRIVER)

A common mutation of the epidermal growth factor receptor in glioma is the de2-7EGFR (or EGFRvIII). Glioma cells expressing de2-7EGFR contain an intracellular pool of receptor with high levels of mannose glycosylation, which is consistent with delayed processing. We now show that this delay occurs in the Golgi complex. Low levels of de2-7EGFR were also seen within the mitochondria. Src activation dramatically increased the amount of mitochondrial de2-7EGFR, whereas its pharmacological inhibit...

Cvrljevic, Anna N.; Akhavan, David; Wu, Min; Martinello, Paul; Furnari, Frank B.; Johnston, Amelia J.; Guo, Deliang; Pike, Lisa; Cavenee, Webster K.; Scott, Andrew M.; Mischel, Paul S.; Hoogenraad, Nick J.; Johns, Terrance G.

2011-01-01

 
 
 
 
261

Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder  

International Nuclear Information System (INIS)

The cerebral metabolic rate for glucose was studied in 18 adults with childhood-onset obsessive-compulsive disorder (OCD) and in age- and sex-matched controls using positron emission tomography and fludeoxyglucose F 18. Both groups were scanned during rest, with reduced auditory and visual stimulation. The group with OCD showed an increased glucose metabolism in the left orbital frontal, right sensorimotor, and bilateral prefrontal and anterior cingulate regions as compared with controls. Ratios of regional activity to mean cortical gray matter metabolism were increased for the right prefrontal and left anterior cingulate regions in the group with OCD as a whole. Correlations between glucose metabolism and clinical assessment measures showed a significant relationship between metabolic activity and both state and trait measurements of OCD and anxiety as well as the response to clomipramine hydrochloride therapy. These results are consistent with the suggestion that OCD may result from a functional disturbance in the frontal-limbic-basal ganglia system

262

Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis.  

Science.gov (United States)

We performed silencing and overexpression studies of flavin containing monooxygenase (FMO) 3 in hyperlipidemic mouse models to examine its effects on trimethylamine N-oxide (TMAO) levels and atherosclerosis. Knockdown of hepatic FMO3 in LDL receptor knockout mice using an antisense oligonucleotide resulted in decreased circulating TMAO levels and atherosclerosis. Surprisingly, we also observed significant decreases in hepatic lipids and in levels of plasma lipids, ketone bodies, glucose, and insulin. FMO3 overexpression in transgenic mice, on the other hand, increased hepatic and plasma lipids. Global gene expression analyses suggested that these effects of FMO3 on lipogenesis and gluconeogenesis may be mediated through the PPAR? and Kruppel-like factor 15 pathways. In vivo and in vitro results were consistent with the concept that the effects were mediated directly by FMO3 rather than trimethylamine/TMAO; in particular, overexpression of FMO3 in the human hepatoma cell line, Hep3B, resulted in significantly increased glucose secretion and lipogenesis. Our results indicate a major role for FMO3 in modulating glucose and lipid homeostasis in vivo, and they suggest that pharmacologic inhibition of FMO3 to reduce TMAO levels would be confounded by metabolic interactions. PMID:25378658

Shih, Diana M; Wang, Zeneng; Lee, Richard; Meng, Yonghong; Che, Nam; Charugundla, Sarada; Qi, Hannah; Wu, Judy; Pan, Calvin; Brown, J Mark; Vallim, Thomas; Bennett, Brian J; Graham, Mark; Hazen, Stanley L; Lusis, Aldons J

2015-01-01

263

The role of estrogen in adipose tissue metabolism: insights into glucose homeostasis regulation [Review].  

Science.gov (United States)

Adipose tissue is an organ with active endocrine function involved in the regulation of energy balance and glucose homeostasis via multiple metabolic signaling pathways targeting the brain, liver, skeletal muscle, pancreas, and other organs. There is increasing evidence demonstrating that the female sex hormone, estrogen, regulates adipose development and improves systemic glucose homeostasis in both males and females. The underlying mechanism linking estrogenic regulation in adipose tissue and systemic glucose metabolism has not been fully elucidated, but is thought to include interactions of estrogen receptor signaling events involving lipolytic and/or lipogenic enzyme activity, free fatty acid metabolism, and adipocytokine production. Thus, understanding the effects of estrogen replacement on adipose tissue biology and metabolism is important in determining the risk of developing obesity-related metabolic disorders in patients undergoing treatment for sex hormone deficiency. In this report, we review literature regarding the role of estrogens and their corresponding receptors in the control of adipose metabolism and glucose homeostasis in both rodents and humans. We also discuss the effects of selective estrogen receptor modulators on glucose metabolism. PMID:25109846

Kim, Jun Ho; Cho, Hyung Taek; Kim, Young Jun

2014-11-28

264

Glucose challenge increases circulating progenitor cells in Asian Indian male subjects with normal glucose tolerance which is compromised in subjects with pre-diabetes: A pilot study  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Haematopoietic stem cells undergo mobilization from bone marrow to blood in response to physiological stimuli such as ischemia and tissue injury. The aim of study was to determine the kinetics of circulating CD34+ and CD133+CD34+ progenitor cells in response to 75 g glucose load in subjects with normal and impaired glucose metabolism. Methods Asian Indian male subjects (n = 50 with no prior history of glucose imbalance were subjected to 2 hour oral glucose tolerance test (OGTT. 24 subjects had normal glucose tolerance (NGT, 17 subjects had impaired glucose tolerance (IGT and 9 had impaired fasting glucose (IFG. The IGT and IFG subjects were grouped together as pre-diabetes group (n = 26. Progenitor cell counts in peripheral circulation at fasting and 2 hour post glucose challenge were measured using direct two-color flow cytometry. Results The pre-diabetes group was more insulin resistant (p + cells (p = 0.003 and CD133+CD34+ (p = 0.019 cells was seen 2 hours post glucose challenge in the NGT group. This increase for both the cell types was attenuated in subjects with IGT. CD34+ cell counts in response to glucose challenge inversely correlated with neutrophil counts (? = -0.330, p = 0.019, while post load counts of CD133+CD34+ cells inversely correlated with serum creatinine (? = -0.312, p = 0.023. Conclusion There is a 2.5-fold increase in the circulating levels of haematopoietic stem cells in response to glucose challenge in healthy Asian Indian male subjects which is attenuated in subjects with pre-diabetes.

Bairagi Soumi

2011-01-01

265

The use of /sup 11/C-glucose and positron emission tomography to measure brain glucose metabolism  

International Nuclear Information System (INIS)

To measure regional cerebral metabolism of glucose (CMRGlu) with positron emission tomography (PET), but avoid the potential problems inherent in the use of /sup 18/F-fluoro-deoxyglucose, (e.g. regional variation in regional rate constants and instability of the ''lumped constant''), the authors have developed a method using uniformly labeled /sup 11/C-glucose. The method employs a 4-compartment model that accounts for vascular tracer, transport of tracer in and out of the extravascular space, metabolism of tracer, and the production of labeled carbon dioxide, which is free to leave the tissue with blood flow. The differential equations for this model, when solved for CMRGlu, yield CMRGlu=k/sub 1/ . k/sub 3/ . CBF . C/sub B//[k/sub 1/ . k/sub 3/+CBF/CBV . (k/sub 2/+k/sub 3/)] where CBF and CBV are cerebral blood flow and volume, C/sub B/ is unlabeled blood glucose content, k/sub 1/ and k/sub 2/ are transport rate constants and k/sub 3/ is the metabolism rate constant. The authors have begun implementing this technique in baboons and human subjects by first measuring regional CBV and CBF with extant PET methods, then after injection of 20-40mCi of U-/sup 11/C-glucose, estimating the rate constants from 40 sequential PET scans taken over 20 minutes. Resulting white-to-gray matter range in CMRGlu for one typical human subject was 2.9 to 6.3 mg/(min . 100 mg). Oxygen metabolism (CMRO/sub 2/) was also measured at the same sitting with PET and the molar ratio of CMRO/sub 2//CMRGlu ranged from 5.8 to 6.4 as would be expected. These results demonstrate that it may be feasible to avoid the difficulties of an analogue tracer in the measurement of CMRGlu by using /sup 11/C-glucose

266

Facilitative Glucose Transporter 9 Expression Affects Glucose Sensing in Pancreatic ?-Cells  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Facilitative glucose transporters (GLUTs) including GLUT9, accelerate the facilitative diffusion of glucose across the plasma membrane. Studies in GLUT2-deficient mice suggested the existence of another GLUT in the mammalian ?-cell responsible for glucose sensing. The objective of this study was to determine the expression and function of GLUT9 in murine and human ?-cells. mRNA and protein expression levels were determined for both isoforms of GLUT9 in murine and human isolated islets as we...

Evans, Sarah A.; Doblado, Manuel; Chi, Maggie M.; Corbett, John A.; Moley, Kelle H.

2009-01-01

267

Cardiac stem cell regeneration in metabolic syndrome.  

Science.gov (United States)

The metabolic syndrome (MetS) is a constellation of multiple metabolic risk factors including obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. Individuals with MetS are found to be afflicted with an increased risk of type 2 diabetes mellitus and overall cardiovascular diseases. One of the common comorbidities of MetS is the impairment of heart function en route to loss of cardiomyocytes and ultimately heart failure. Although it is accepted that cardiomyocytes are terminally differentiated, recent evidence has challenged this concept to indicate the ability of cardiomyocytes to regenerate from progenitor cells of the heart and other organs. Moreover, it has been suggested that pathological conditions such as MetS may play a role in the regulation of cardiomyocyte regeneration. This mini-review will discuss the role of MetS in the regulatory machineries of cardiomyocyte regeneration. PMID:23323616

Xu, Xihui; Ren, Jun

2013-01-01

268

suPAR associates to glucose metabolic aberration during glucose stimulation in HIV-infected patients on HAART.  

DEFF Research Database (Denmark)

OBJECTIVE: We have recently shown that the level of soluble urokinase plasminogen activator receptor (suPAR), which is associated with the immune status of HIV-infected patients undergoing highly active antiretroviral therapy (HAART), correlates with the insulin action of such patients. Here we extend these findings by investigating the association of suPAR to glucose metabolic insufficiency during an oral glucose challenge (OGTT). METHODS: In 16 HIV-infected patients with lipodystrophy and 15 HIV-infected patients without lipodystrophy, glucose tolerance, insulin sensitivity (ISI(composite)), prehepatic insulin secretion, proinsulin level and suppression of free fatty acids (FFA) were determined during an OGTT. Stability of suPAR was tested in 6 HIV-infected patients during a 3h OGTT. RESULTS: Lipodystrophy was associated with a 70% increase in plasma suPAR (P<0.05). During the OGTT, plasma suPAR correlated inversely with ISI(composite) and positively with 2h plasma glucose, fasting insulin secretion, fasting intact proinsulin and FFA level during the OGTT (all P<0.05). In multiple regression analyses, in which anthropometric measures (BMI, limbadiposity and fat mass), immune markers (CD4, HIV-RNA, duration of HIV infection), and dyslipidemia (plasma total cholesterol, triglyceride and free fatty acid level during the OGTT) were included, suPAR remained a significant marker of glucose tolerance and insulin sensitivity. Plasma suPAR exhibited a small CV (11%) during the 3h OGTT. CONCLUSIONS: suPAR associated to important glucose metabolic aberrations in HIV-infected patients on HAART. Moreover, suPAR was stable after a glucose challenge. Future research is required to confirm these findings and explore the potential of suPAR as marker of dysmetabolism in HIV-infected patients.

Andersen, Ove; Eugen-Olsen, Jesper

2008-01-01

269

High glucose inhibits gene expression of tyrosyl-tRNA synthetase in osteoblast cells.  

Science.gov (United States)

It has been suggested that bone metabolism disorders are one of the major complications of diabetes mellitus. However, the exact mechanisms as to how diabetes affects bone metabolism are yet to be determined. In the present study, we have searched for high glucose regulated genes in osteoblast-like UMR-106 cells. UMR-106 cells were treated with normal glucose (5.5 mM), high glucose (16.5 mM or 30.5 mM) and mannitol (16.5 mM) as a hyperosmotic control. Following the isolation of total RNA, GeneFishing differential display-PCR (DDPCR) was carried out and followed by cloning, sequencing and searching in a gene bank data base to identify the high glucose induced gene(s). Through the DD-PCR technique which employs Annealing Control Primer, or ACP, it has been found that expression of a PCR product was significantly decreased by high glucose treatment: it was identified as tyrosyl-tRNA synthetase. Furthermore, reverse transcriptase PCR analysis confirmed that high glucose significantly decreases mRNA expression of tyrosyl-tRNA synthetase, whereas mannitol treatment does not cause any change in such expression. These results suggest that high glucose may play a significant role in the protein synthesis process of osteoblast cells by decreasing expression of tyrosyl-tRNA synthetase. In a Western blot analysis, the protein expression of tyrosyl-tRNA synthetase was also decreased by high glucose treatment. Taken together, these results suggest that high glucose could affect bone metabolism by regulating the expression of tyrosyl-tRNA synthetase genes. PMID:20140272

Kim, Jun Hoe; Kim, Yun-Young; Kim, Sung-Jin

2009-12-01

270

Acute effect of glucose on cerebral blood flow, blood oxygenation, and oxidative metabolism.  

Science.gov (United States)

While it is known that specific nuclei of the brain, for example hypothalamus, contain glucose-sensing neurons thus their activity is affected by blood glucose level, the effect of glucose modulation on whole-brain metabolism is not completely understood. Several recent reports have elucidated the long-term impact of caloric restriction on the brain, showing that animals under caloric restriction had enhanced rate of tricarboxylic acid cycle (TCA) cycle flux accompanied by extended life span. However, acute effect of postprandial blood glucose increase has not been addressed in detail, partly due to a scarcity and complexity of measurement techniques. In this study, using a recently developed noninvasive MR technique, we measured dynamic changes in global cerebral metabolic rate of O2 (CMRO2 ) following a 50 g glucose ingestion (N?=?10). A time dependent decrease in CMRO2 was observed, which was accompanied by a reduction in oxygen extraction fraction (OEF) with unaltered cerebral blood flow (CBF). At 40 min post-ingestion, the amount of CMRO2 reduction was 7.8?±?1.6%. A control study without glucose ingestion was performed (N?=?10), which revealed no changes in CMRO2 , CBF, or OEF, suggesting that the observations in the glucose study was not due to subject drowsiness or fatigue after staying inside the scanner. These findings suggest that ingestion of glucose may alter the rate of cerebral metabolism of oxygen in an acute setting. Hum Brain Mapp 36:707-716, 2015. © 2014 Wiley Periodicals, Inc. PMID:25324201

Xu, Feng; Liu, Peiying; Pascual, Juan M; Xiao, Guanghua; Huang, Hao; Lu, Hanzhang

2015-02-01

271

In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas  

International Nuclear Information System (INIS)

Abnormalities in the oxidative metabolism of glucose in human cerebral gliomas have been studied in seven patients using positron emission tomography. Measurements of regional cerebral blood flow and oxygen consumption were obtained using the oxygen-15 steady-state inhalation technique. Values of regional cerebral glucose consumption were obtained using fluorine 18-labeled 2-fluoro-2-deoxy-D-glucose and a simplification of the method of Sokoloff. Functional values were obtained for regions of tumor and brain tissue in the middle cerebral artery territory of the contralateral cortex. Values of regional glucose consumption were calculated for both regions using a value of the lumped constant quoted for normal brain tissue (0.42). Tumor regional cerebral blood flow was comparable to that in the contralateral cortex, whereas regional cerebral oxygen consumption was depressed. This depression resulted in low tumor values of the fractional oxygen extraction ratio (0.21 +/- 0.07), indicating that oxygen supply exceeded the metabolic demand. In contrast, tumor regional cerebral glucose consumption was not depressed and regional glucose extraction ratios were similar for tumor and brain tissue. The metabolic uncoupling between regional oxygen consumption and regional glucose consumption (CMRO2/CMRGlu . 0.24 +/- 0.07 ml of oxygen per milligram of glucose) is indicative of increased aerobic glycolysis

272

Alleviation of glucose repression of maltose metabolism by MIG1 disruption in Saccharomyces cerevisiae  

DEFF Research Database (Denmark)

The MIG1 gene was disrupted in a haploid laboratory strain (B224) and in an industrial polyploid strain (DGI 342) of Saccharomyces cerevisiae. The alleviation of glucose repression of the expression of MAL genes and alleviation of glucose control of maltose metabolism were investigated in batch cultivations on glucose-maltose mixtures. In the MIG1-disrupted haploid strain, glucose repression was partly alleviated; i.e., maltose metabolism was initiated at higher glucose concentrations than in the corresponding wild-type strain. In contrast, the polyploid Delta mig1 strain exhibited an even more stringent glucose control of maltose metabolism than the corresponding wild-type strain, which could be explained by a more rigid catabolite inactivation of maltose permease, affecting the uptake of maltose. Growth on the glucose-sucrose mixture showed that the polyploid Delta mig1 strain was relieved of glucose repression of the SUC genes. The disruption of MIG1 was shown to bring about pleiotropic effects, manifestedin changes in the pattern of secreted metabolites and in the specific growth rate.

Klein, Christopher; Olsson, Lisbeth

1996-01-01

273

Investigation of 18F-2-deoxyglucose for the measure of myocardial glucose metabolism  

International Nuclear Information System (INIS)

18F labeled 2-deoxyglucose (18FDG) was studied as a glucose analog. Myocardial uptake and retention, blood clearance, species (dog, monkey, man) dependence and effect of diet on uptake were investigated. Normal myocardial uptake of 18FDG was 3 to 4% in dog and monkey and 1 to 4% of injected dose in man compared to brain uptake of 2% in dog, 5 to 6% in monkey and 4 to 8% in man. The metabolic rate (MR) for glucose in non-fasting (glycolytic state) was 2.8 times greater than in fasting (ketogenic state). Human subjects showed higher myocardial uptake after a normal meal than after meal containing mostly free fatty acids (FFA). Blood clearance was rapid with initial clearance t1/2 of 0.2 to 0.3 min followed by a t1/2 of 8.4 +- 1.2 min in dog and 11.6 +- 1.1 min in man. A small third component had a t1/2 of 59 +- 10 min and 88 +- 4 min in dog and man, respectively. High image contrast ratios between heart and blood (dog 3.5/1; man 14/1), heart and lung (dog 9/1; man 20/1), heart and liver (dog 15/1; man 10/1) were found with the ECAT positron tomograph. 18FDG was found to be rapidly taken up by the myocardium without any significant tissue clearance over a 4 hour period. 18FDG is transported, phosphorylated to 18FDG-6-PO4 and trapped in myocardial cells in the same manner as has been found for brain and exhibits excellent imaging properties. Determination of glucose and FFA MR in vivo with ECT provides a method for investigation and assessment of changing aerobic and anaerobic metabolic rates in ischemic heart disease in man

274

Studies on citrate metabolism in liver injuries. 2. Response of liver citrate to glucose load.  

Directory of Open Access Journals (Sweden)

Full Text Available The effect of glucose load on the levels of blood glucose, serum non-esterified fatty acids (NEFA and liver citrate was investigated in carbontetrachloride-intoxicated (injured rats and compared with non-intoxicated controls. The citrate level in the liver from injured animals showed 15-fold of the value of the control. Glucose load on these animals caused gradual decrease in the citrate level, whereas similar administration to the control caused inverse results. The serum NEFA levels were lowered by glucose load in both of injured and control animals. The pattern of changes in the citrate level after glucose load in the liver from injured animals was similar to that in the muscle from the control, suggesting a similarity on citrate metabolism between the injured liver and the muscle.The possible mechanisms for these results were discussed in relation to the difference in citrate metabolism between the liver and the muscle.

Kaneshige,Junji

1975-02-01

275

Mouse embryonic stem cells established in physiological-glucose media express the high KM Glut2 glucose transporter expressed by normal embryos.  

Science.gov (United States)

Glut2 is one of the facilitative glucose transporters expressed by preimplantation and early postimplantation embryos. Glut2 is important for survival before embryonic day 10.5. The Glut2 KM (?16 mmol/liter) is significantly higher than physiologic glucose concentrations (?5.5 mmol/liter), suggesting that Glut2 normally performs some essential function other than glucose transport. Nevertheless, Glut2 efficiently transports glucose when extracellular glucose concentrations are above the Glut2 KM. Media containing 25 mmol/liter glucose are widely used to establish and propagate embryonic stem cells (ESCs). Glut2-mediated glucose uptake by embryos induces oxidative stress and can cause embryo cell death. Here we tested the hypothesis that low-glucose embryonic stem cells (LG-ESCs) isolated in physiological-glucose (5.5 mmol/liter) media express a functional Glut2 glucose transporter. LG-ESCs were compared with conventional D3 ESCs that had been cultured only in high-glucose media. LG-ESCs expressed Glut2 mRNA and protein at much higher levels than D3 ESCs, and 2-deoxyglucose transport by LG-ESCs, but not D3 ESCs, exhibited high Michaelis-Menten kinetics. Glucose at 25 mmol/liter induced oxidative stress in LG-ESCs and inhibited expression of Pax3, an embryo gene that is inhibited by hyperglycemia, in neuronal precursors derived from LG-ESCs. These effects were not observed in D3 ESCs. These findings demonstrate that ESCs isolated in physiological-glucose media retain a functional Glut2 transporter that is expressed by embryos. These cells are better suited to the study of metabolic regulation characteristic of the early embryo and may be advantageous for therapeutic applications. PMID:24167319

Jung, Jin Hyuk; Wang, Xiao Dan; Loeken, Mary R

2013-12-01

276

Increased glucose metabolism and glycerolipid formation by fatty acids and GPR40 receptor signaling underlies the fatty acid potentiation of insulin secretion.  

Science.gov (United States)

Acute fatty acid (FA) exposure potentiates glucose-stimulated insulin secretion in ? cells through metabolic and receptor-mediated effects. We assessed the effect of fatty acids on the dynamics of the metabolome in INS-1 cells following exposure to [U-(13)C]glucose to assess flux through metabolic pathways. Metabolite profiling showed a fatty acid-induced increase in long chain acyl-CoAs that were rapidly esterified with glucose-derived glycerol-3-phosphate to form lysophosphatidic acid, mono- and diacylglycerols, and other glycerolipids, some implicated in augmenting insulin secretion. Glucose utilization and glycolytic flux increased, along with a reduction in the NADH/NAD(+) ratio, presumably by an increase in conversion of dihydroxyacetone phosphate to glycerol-3-phosphate. The fatty acid-induced increase in glycolysis also resulted in increases in tricarboxylic cycle flux and oxygen consumption. Inhibition of fatty acid activation of FFAR1/GPR40 by an antagonist decreased glycerolipid formation, attenuated fatty acid increases in glucose oxidation, and increased mitochondrial FA flux, as evidenced by increased acylcarnitine levels. Conversely, FFAR1/GPR40 activation in the presence of low FA increased flux into glycerolipids and enhanced glucose oxidation. These results suggest that, by remodeling glucose and lipid metabolism, fatty acid significantly increases the formation of both lipid- and TCA cycle-derived intermediates that augment insulin secretion, increasing our understanding of mechanisms underlying ? cell insulin secretion. PMID:24675078

El-Azzouny, Mahmoud; Evans, Charles R; Treutelaar, Mary K; Kennedy, Robert T; Burant, Charles F

2014-05-01

277

The direct effect of incretin hormones on glucose and glycerol metabolism and hemodynamics  

DEFF Research Database (Denmark)

The objective of this study was to assess the insulin-independent effects of incretin hormones on glucose and glycerol metabolism and hemodynamics under eu- and hyperglycemic conditions. Young, healthy males (n=10) underwent three trials in a randomized, controlled, cross-over study. Each trial consisted of a 2-stage (eu- and hyperglycemia) pancreatic clamp (using somatostatin to prevent endogenous insulin secretion). Glucose and lipid metabolism were measured via infusion of stable glucose and glycerol isotopic tracers. Hemodynamic variables (femoral, brachial and common carotid artery blood flow; and flow-mediated dilation [FMD] of brachial artery) were also measured. The three trials differed by the following additional infusions: (I) Saline (control; CON); (II) GLP-1 (0.5 pmol/kg/min); and (III) GIP (1.5 pmol/kg/min). No between-trial differences in glucose infusion rates (GIR), glucose or glycerol kinetics were seen during euglycemia, whereas hyperglycemia resulted in increased GIR and glucose rate of disappearance (Rd) during GLP-1 compared to CON and GIP (P<0.01 for all). However, when normalized to insulin levels, no differences between trials were seen for GIR or glucose Rd. Besides a higher femoral blood flow during hyperglycemia in GIP (vs. CON and GLP-1, P<0.001), no between-trial differences were seen for the hemodynamic variables. In conclusion, GLP-1 and GIP have no direct effect on whole body glucose metabolism or hemodynamics during euglycemia. On contrary, during hyperglycemia, GIP increases femoral artery blood flow with no effect on glucose metabolism, whereas GLP-1 increases glucose disposal, potentially, however, due to increased insulin levels.

Karstoft, Kristian; Mortensen, Stefan

2015-01-01

278

Age-related metabolic fatigue during low glucose conditions in rat hippocampus.  

Science.gov (United States)

Previous reports have indicated that with aging, intrinsic brain tissue changes in cellular bioenergetics may hamper the brain's ability to cope with metabolic stress. Therefore, we analyzed the effects of age on neuronal sensitivity to glucose deprivation by monitoring changes in field excitatory postsynaptic potentials (fEPSPs), tissue Po2, and NADH fluorescence imaging in the CA1 region of hippocampal slices obtained from F344 rats (1-2, 3-6, 12-20, and >22 months). Forty minutes of moderate low glucose (2.5 mM) led to approximately 80% decrease of fEPSP amplitudes and NADH decline in all 4 ages that reversed after reintroduction of 10 mM glucose. However, tissue slices from 12 to 20 months and >22-month-old rats were more vulnerable to low glucose: fEPSPs decreased by 50% on average 8 minutes faster compared with younger slices. Tissue oxygen utilization increased after onset of 2.5 mM glucose in all ages of tissue slices, which persisted for 40 minutes in younger tissue slices. But, in older tissue slices the increased oxygen utilization slowly faded and tissue Po2 levels increased toward baseline values after approximately 25 minutes of glucose deprivation. In addition, with age the ability to regenerate NADH after oxidation was diminished. The NAD(+)/NADH ratio remained relatively oxidized after low glucose, even during recovery. In young slices, glycogen levels were stable throughout the exposure to low glucose. In contrast, with aging utilization of glycogen stores was increased during low glucose, particularly in hippocampal slices from >22 months old rats, indicating both inefficient metabolism and increased demand for glucose. Lactate addition (20 mM) improved oxidative metabolism by directly supplementing the mitochondrial NADH pool and maintained fEPSPs in young as well as aged tissue slices, indicating that inefficient metabolism in the aging tissue can be improved by directly enhancing NADH regeneration. PMID:25443286

Galeffi, Francesca; Shetty, Pavan K; Sadgrove, Matthew P; Turner, Dennis A

2015-02-01

279

Program for PET image alignment: Effects on calculated differences in cerebral metabolic rates for glucose  

International Nuclear Information System (INIS)

A program was developed to align positron emission tomography images from multiple studies on the same subject. The program allowed alignment of two images with a fineness of one-tenth the width of a pixel. The indications and effects of misalignment were assessed in eight subjects from a placebo-controlled double-blind crossover study on the effects of cocaine on regional cerebral metabolic rates for glucose. Visual examination of a difference image provided a sensitive and accurate tool for assessing image alignment. Image alignment within 2.8 mm was essential to reduce variability of measured cerebral metabolic rates for glucose. Misalignment by this amount introduced errors on the order of 20% in the computed metabolic rate for glucose. These errors propagate to the difference between metabolic rates for a subject measured in basal versus perturbed states

280

Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography  

Energy Technology Data Exchange (ETDEWEB)

The cerebral metabolic rate for glucose was studied in ten men (mean age = 26 years) with well-documented histories of infantile autism and in 15 age-matched normal male controls using positron emission tomography and (F-18) 2-fluoro-2-deoxy-D-glucose. Positron emission tomography was completed during rest, with reduced visual and auditory stimulation. While the autistic group as a whole showed significantly elevated glucose utilization in widespread regions of the brain, there was considerable overlap between the two groups. No brain region showed a reduced metabolic rate in the autistic group. Significantly more autistic, as compared with control, subjects showed extreme relative metabolic rates (ratios of regional metabolic rates to whole brain rates and asymmetries) in one or more brain regions.

Rumsey, J.M.; Duara, R.; Grady, C.; Rapoport, J.L.; Margolin, R.A.; Rapoport, S.I.; Cutler, N.R.

1985-05-01

 
 
 
 
281

Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography  

International Nuclear Information System (INIS)

The cerebral metabolic rate for glucose was studied in ten men (mean age = 26 years) with well-documented histories of infantile autism and in 15 age-matched normal male controls using positron emission tomography and (F-18) 2-fluoro-2-deoxy-D-glucose. Positron emission tomography was completed during rest, with reduced visual and auditory stimulation. While the autistic group as a whole showed significantly elevated glucose utilization in widespread regions of the brain, there was considerable overlap between the two groups. No brain region showed a reduced metabolic rate in the autistic group. Significantly more autistic, as compared with control, subjects showed extreme relative metabolic rates (ratios of regional metabolic rates to whole brain rates and asymmetries) in one or more brain regions

282

The effect of glucose on proteoglycans produced by cultured mesangial cells.  

Science.gov (United States)

Altered proteoglycan metabolism may play a role in the development of diabetic glomerulopathy. This study was conducted to examine the effects of glucose on the production and physical characteristics of proteoglycans generated by rat mesangial cells in culture. Rat mesangial cells were exposed to elevated glucose media (500 mg/dl) or standard glucose media (200 mg/dl) for 8-10 days, and proteoglycan synthesis was determined using 35S-labeling in conjunction with anion exchange and sizing chromatography. Rat mesangial cells generated predominantly chondroitin/dermatan sulfate proteoglycans, with small amounts of heparan sulfate proteoglycans. High glucose did not alter the number of rat mesangial cells after 24 h or after 8-10 days, compared with cells grown under standard glucose conditions. The total amount of glycosaminoglycan generated and the sizes of the major proteoglycans were not different between cultures grown in standard and elevated glucose medium. Levels of mRNA for the proteoglycan, biglycan (as assessed by Northern blot analysis), also were comparable between the standard and elevated glucose conditions. Exposure to media high in glucose did not change the rate of secretion of proteoglycans from the cell layer to the medium, but did result in a greater quantity of radiolabeled proteoglycan deposited in the extracellular matrix. The cell, extracellular matrix and medium proteoglycans isolated from the elevated glucose cultures, consistently eluted from the anion exchange column at a lower [NaCl] compared with those generated under standard glucose conditions, indicating a loss of anionic charges.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7694880

Silbiger, S; Schlondorff, D; Crowley, S; Rosenberg, L; Choi, H; Hatcher, V; Gordon, P

1993-12-01

283

Metabolism Of C(14)-Glucose By Eurytrema Pancreaticum.  

Science.gov (United States)

1. The glucose uptake rate by Eurytrema pancreaticum was a mean value of 16.44 +/- 2.42 micro moles/hr/g, and total CO2 production rate by the fluke averaged 5.82 +/- 0.97 micro moles/hr/g. The relative specific activity of respiratory CO2 showed a mean value of 5.75 +/- 0.84 per cent. The rate of CO2 production derived from medium C(14)-glucose was a mean of 0.33 +/- 0.10 micor-mole/hr/g. Therefore, the average value of 0.32 +/- 0.04 per cent of glucose utilized by the flukes from the medium C(14)-glucose was oxidized to respiratory CO2. 2. The tissue concentration of glycogen in E. pancreaticum was a mean of 45.50 +/- 2.18 mg/g or 4.55 +/- 0.22 %/g. But the turnover rate of glycogen pool was a mean of 0.027 +/- 0.003 %/hr or 0.009 +/- 0.002 mg/hr/g. The average value of 0.64 +/- 0.23 percent of glucose utilized by the flukes from the medium C(14)-glucose was incorporated into the glycogen. 3. These data account for that only 1 per cent of the utilized glucose by the flukes participated in furnishing the oxidation into respiratory CO2 and the synthetic process into glycogen. PMID:12913599

Seo, Byong Seol; Rim, Han Jong; Kim, Kwang Soo; Lee, Myung Sang; Kim, Yeong Uhn; Song, Hi Yong

1964-12-01

284

Polychlorinated biphenyl exposure and glucose metabolism in Danish children aged 9 years  

DEFF Research Database (Denmark)

Context: Human exposure to polychlorinated biphenyls (PCBs) has been associated to type 2 diabetes in adults. Objectives: To determine whether concurrent serum PCB concentration was associated with markers of glucose metabolism in healthy children. Design: Cross-sectional study. Settings and participants: A total of 771 healthy Danish third grade school children aged 8-10 years in the municipality of Odense were recruited in 1997 through a two-stage cluster sampling from 25 different schools stratified according to location and socioeconomic character; 509 (9.7±0.8 years, 53% girls) had adequate amounts available for PCB and analyses. Main outcome measures: Fasting plasma glucose and serum insulin were measured and a homeostasis assessment model of insulin resistance (HOMA-IR) and ?-cell function (HOMA-B) calculated. Serum PCB congeners and other persistent compounds were measured and ?PCB calculated. Results: PCBs were present in serum at low concentrations, median 0.19? g/g lipid (interquartile range, IQR: 0.12-0.31). After adjustment for putative confounding factors, the second, third, fourth and fifth quintiles of total PCB were significantly inversely associated with serum insulin (-14.6%, -21.7%, -18.9%, -23.1%, p-trend<0.01), compared to the first quintile, but not with plasma glucose (p=0.45). HOMA-IR and HOMA-B were affected in the same direction due to the declining insulin levels with increasing PCB exposure. Similar results were found for individual PCB congeners, for ?HCB and pp-DDE. Conclusion: A strong inverse association between serum insulin and PCB exposure was found while fasting plasma glucose remained within the expected narrow range. Our findings suggest that PCB may not exert effect through decreased peripheral insulin sensitivity, as seen in obese and low fit children, but rather through a toxicity to ?-cells. It remains to be shown if lower HOMA-B is caused by destruction of ?-cell reducing peripheral insulin resistance and thereby increase fasting plasma glucose as previously found.

Jensen, Tina K; Timmermann, Amalie G

2014-01-01

285

Loss of HIF-1? impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells.  

Science.gov (United States)

Defects in glucose uptake by the skeletal muscle cause diseases linked to metabolic disturbance such as type 2 diabetes. The molecular mechanism determining glucose disposal in the skeletal muscle in response to cellular stimuli including insulin, however, remains largely unknown. The hypoxia-inducible factor-1? (HIF-1?) is a transcription factor operating in the cellular adaptive response to hypoxic conditions. Recent studies have uncovered pleiotropic actions of HIF-1? in the homeostatic response to various cellular stimuli, including insulin under normoxic conditions. Thus we hypothesized HIF-1? is involved in the regulation of glucose metabolism stimulated by insulin in the skeletal muscle. To this end, we generated C2C12 myocytes in which HIF-1? is knocked down by short-hairpin RNA and examined the intracellular signaling cascade and glucose uptake subsequent to insulin stimulation. Knockdown of HIF-1? expression in the skeletal muscle cells resulted in abrogation of insulin-stimulated glucose uptake associated with impaired mobilization of glucose transporter 4 (GLUT4) to the plasma membrane. Such defect seemed to be caused by reduced phosphorylation of the protein kinase B substrate of 160 kDa (AS160). AS160 phosphorylation and GLUT4 translocation by AMP-activated protein kinase activation were abrogated as well. In addition, expression of the constitutively active mutant of HIF-1? (CA-HIF-1?) or upregulation of endogenous HIF-1? in C2C12 cells shows AS160 phosphorylation comparable to the insulin-stimulated level even in the absence of insulin. Accordingly GLUT4 translocation was increased in the cells expressing CA-HIF1?. Taken together, HIF-1? is a determinant for GLUT4-mediated glucose uptake in the skeletal muscle cells thus as a possible target to alleviate impaired glucose metabolism in, e.g., type 2 diabetes. PMID:24619881

Sakagami, Hidemitsu; Makino, Yuichi; Mizumoto, Katsutoshi; Isoe, Tsubasa; Takeda, Yasutaka; Watanabe, Jun; Fujita, Yukihiro; Takiyama, Yumi; Abiko, Atsuko; Haneda, Masakazu

2014-05-01

286

Alterations of hippocampal glucose metabolism by even versus uneven medium chain triglycerides  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 we...

Mcdonald, Tanya S.; Tan, Kah Ni; Hodson, Mark P.; Borges, Karin

2013-01-01

287

Portal glucose delivery stimulates muscle but not liver protein metabolism.  

Science.gov (United States)

Portal vein glucose delivery (the portal glucose signal) stimulates glucose uptake and glycogen storage by the liver, whereas portal amino acid (AA) delivery (the portal AA signal) induces an increase in protein synthesis by the liver. During a meal, both signals coexist and may interact. In this study, we compared the protein synthesis rates in the liver and muscle in response to portal or peripheral glucose infusion during intraportal infusion of a complete AA mixture. Dogs were surgically prepared with hepatic sampling catheters and flow probes. After a 42-h fast, they underwent a 3-h hyperinsulinemic (4× basal) hyperglucagonemic (3× basal) hyperglycemic (?160 mg/dl) hyperaminoacidemic (hepatic load 1.5× basal; delivered intraportally) clamp (postprandial conditions). Glucose was infused either via a peripheral (PeG; n = 7) or the portal vein (PoG; n = 8). Protein synthesis was assessed with a primed, continuous [(14)C]leucine infusion. Net hepatic glucose uptake was stimulated by portal glucose infusion (+1 mg·kg(-1)·min(-1), P < 0.05) as expected, but hepatic fractional AA extraction and hepatic protein synthesis did not differ between groups. There was a lower arterial AA concentration in the PoG group (-19%, P < 0.05) and a significant stimulation (+30%) of muscle protein synthesis associated with increased expression of LAT1 and ASCT2 AA transporters and p70S6 phosphorylation. Concomitant portal glucose and AA delivery enhances skeletal muscle protein synthesis compared with peripheral glucose and portal AA delivery. These data suggest that enteral nutrition support may have an advantage over parenteral nutrition in stimulating muscle protein synthesis. PMID:23011060

Kraft, Guillaume; Coate, Katie C; Dardevet, Dominique; Farmer, Ben; Donahue, E Patrick; Williams, Phillip E; Cherrington, Alan D; Moore, Mary Courtney

2012-11-15

288

Metabolism of [1-13C]-glucose in spheroids from rat prostate tumors  

International Nuclear Information System (INIS)

As the U.S. population ages, the number of prostatic cancers, which currently account for 20% of all male cancers, will substantially increase. Prostatic adenocarcinomas vary markedly in their growth characteristics for individual patients. Improvement of the diagnosis and therapy of these tumors requires an enhanced understanding of their biology. In order to evaluate metabolic subclasses of these tumors, the authors have developed a spheroid model from two Dunning rat prostatic tumor cell line (R 3327 H) that differ in their degree of differentiation. The spheroid diameter of the well-differentiated line (HI) increases 100 microns/24 hrs, while that of the poorly-differentiated line (AT1) increases 228 microns/24 hrs. Analysis of perfused tumor spheroids by 13CNMR spectroscopy, utilizing [1-13C]-glucose, has revealed metabolic differences between these two lines, most notably in the rates of glutamate, alanine, and citrate synthesis. The growth characteristics, as well as the metabolic patterns detectable by NMR, discriminating between the well- and poorly-differentiated spheroids will be presented in detail

289

High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and ?-cell apoptosis  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Patients with type 2 diabetes lose ? cells, but the underlying mechanisms are incompletely understood. Glucose-6-phosphate dehydrogenase (G6PD) is the principal source of the major intracellular reductant, NADPH, which is required by many enzymes, including enzymes of the antioxidant pathway. Previous work from our laboratory has shown that high glucose impairs G6PD activity in endothelial and kidney cells, which leads to decreased cell survival. Pancreatic ? cells are highly sensitive to i...

Zhang, Zhaoyun; Liew, Chong Wee; Handy, Diane E.; Zhang, Yingyi; Leopold, Jane A.; Hu, Ji; Guo, Lili; Kulkarni, Rohit N.; Loscalzo, Joseph; Stanton, Robert C.

2010-01-01

290

PINK1 deficiency in ?-cells increases basal insulin secretion and improves glucose tolerance in mice.  

Science.gov (United States)

The Parkinson's disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in ?-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1-deficient ?-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic ?-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in ?-cell function. PMID:24806840

Deas, Emma; Piipari, Kaisa; Machhada, Asif; Li, Abi; Gutierrez-del-Arroyo, Ana; Withers, Dominic J; Wood, Nicholas W; Abramov, Andrey Y

2014-01-01

291

Temporal analysis of myocardial glucose metabolism by 2-[18F]fluoro-2-deoxy-D-glucose  

International Nuclear Information System (INIS)

To assess kinetic changes of myocardial glucose metabolism after physiological interventions, we perfused isolated working rat hearts with glucose and 2-[18F]fluoro-2-deoxy-D-glucose (2-FDG). Tissue uptake of 2-FDG and the input function were measured on-line by external detection. The fractional rate of 2-FDG phosphorylation was determined by graphical analysis of time-activity curves. The steady-state uptake of 2-FDG was linear with time, and the tracer was retained predominantly in its phosphorylated form. Tissue accumulation of 2-FDG decreased with a reduction in work load and with the addition of competing substrates. Insulin caused a significant increase in 2-FDG accumulation in hearts from fasted but not from fed animals. We conclude that in the isolated working rat heart there is rapid adjustment of exogenous substrate utilization and that most interventions known to alter glucose metabolism induce parallel changes in 2-FDG uptake. Qualitative differences in the in vitro response to insulin may be affected by the presence of either endogenous insulin or glycogen

292

Glucose metabolism in different regions of the rat brain under hypokinetic stress influence  

Science.gov (United States)

Glucose metabolism in rats kept under long term hypokinetic stress was studied in 7 brain regions. Determination was made of the regional levels of glucose, lactate, glutamate, glutamine, aspartate, gamma-aminobutyrate and the incorporation of C-14 from plasma glucose into these metabolites, in glycogen and protein. From the content and activity data the regional glucose flux was approximated quantitatively. Under normal conditions the activity gradient cortex and frontal pole cerebellum, thalamus and mesencephalon, hypothalamus and pons and medulla is identical with that of the regional blood supply (measured with I131 serum albumin as the blood marker). Within the first days of immobilization a functional hypoxia occurred in all brain regions and the utilization of cycle amino acids for protein synthesis was strongly diminished. After the first week of stress the capillary volumes of all regions increased, aerobic glucose metabolism was enhanced (factors 1.3 - 2.0) and the incorporation of glucose C-14 via cycle amino acids into protein was considerably potentiated. The metabolic parameters normalized between the 7th and 11th week of stress. Blood supply and metabolic rate increased most in the hypothalamus.

Konitzer, K.; Voigt, S.

1980-01-01

293

Correlation of regional glucose metabolism with gender, health status, and aging as determined by PET-FDG technique  

International Nuclear Information System (INIS)

The present study presents the findings in a series of 85 volunteers who participated in a protocol to evaluate the effects of aging and dementia on brain glucose metabolism. Positron emission tomography permits noninvasive assessment of both whole brain and regional glucose metabolism and other biochemical functions. Absolute regional and whole brain glucose metabolism can be determined by using the fluorine deoxyglucose (FDG) method. (author). 3 refs

294

Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice.  

Science.gov (United States)

Histamine has been proposed to be an important regulator of energy intake and expenditure. The aim of this study was to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet. Histamine regulation of glucose and lipid metabolism, adipocytokine production, and development of hyperlipidemia-induced hepatic injury were studied in histamine H1 (H1R(-/-)) and H2 (H2R(-/-)) receptor knockout and wild-type mice. H1R(-/-) mice showed mildly increased insulin resistance. In contrast, H2R(-/-) mice manifested profound insulin resistance and glucose intolerance. High-fat/high-cholesterol feeding enhanced insulin resistance and glucose intolerance. Studies with two-deoxy-2-[(18)F]-fluoro-d-glucose and positron emission tomography showed a brain glucose allocation in H1R(-/-) mice. In addition, severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose and lipid metabolism and development of hyperlipidemia-induced NASH. PMID:20566747

Wang, Ke-Yong; Tanimoto, Akihide; Yamada, Sohsuke; Guo, Xin; Ding, Yan; Watanabe, Teruo; Watanabe, Takeshi; Kohno, Kimitoshi; Hirano, Ken-Ichi; Tsukada, Hideo; Sasaguri, Yasuyuki

2010-08-01

295

Demographic and metabolic characteristics of individuals with progressive glucose tolerance  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english We evaluated changes in glucose tolerance of 17 progressors and 62 non-progressors for 9 years to improve our understanding of the pathogenesis of type 2 diabetes mellitus. Changes in anthropometric measurements and responses to an oral glucose tolerance test (OGTT) were analyzed. We identified 14 p [...] airs of individuals, one from each group, who were initially normal glucose tolerant and were matched for gender, age, weight, and girth. We compared initial plasma glucose and insulin curves (from OGTT), insulin secretion (first and second phases) and insulin sensitivity indices (from hyperglycemic clamp assay) for both groups. In the normal glucose tolerant phase, progressors presented: 1) a higher OGTT blood glucose response with hyperglycemia in the second hour and a similar insulin response vs non-progressors; 2) a reduced first-phase insulin secretion (2.0 ± 0.3 vs 2.3 ± 0.3 pmol/L; P

A.L., Mendes; M.L., Santos; C.R., Padovani; W.P., Pimenta.

2009-03-01

296

Network flux analysis: impact of 13C-substrates on metabolism in Arabidopsis thaliana cell suspension cultures.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The aim of this study was to test the assumption that (13)C-enrichment of respiratory substrate does not perturb metabolism. Cell suspension cultures of Arabidopsis thaliana were grown in MS medium containing unlabelled glucose (with (13)C at natural abundance), 100% [1-(13)C]glucose, 100% [U-(13)C(6)]glucose or 10% [U-(13)C(6)]glucose plus 90% unlabelled glucose. There was no significant difference in the metabolism of [U-(14)C]glucose between the cultures. Similarly, the pattern of (14)CO(2...

Kruger, Nj; Huddleston, Je; Le Lay, P.; Brown, Nd; Ratcliffe, Rg

2007-01-01

297

Cerebral glucose metabolism change in patients with complex regional pain syndrome. A PET study  

International Nuclear Information System (INIS)

The aim of this study was to examine abnormalities of the central nervous system in patients with chronic pain who were diagnosed with complex regional pain syndrome (CRPS). Brain activity was assessed using 18F-fluorodeoxyglucose positron emission tomography. The data collected from 18 patients were compared with data obtained from 13 normal age-matched controls. Our results showed that glucose metabolism was bilaterally increased in the secondary somatosensory cortex, mid-anterior cingulated cortex (ACC) or posterior cingulated cortex (PCC) (or both), parietal cortex, posterior parietal cortex (PPC), and cerebellum as well as in the right posterior insula and right thalamus in our patients. In contrast, glucose metabolism was reduced contralaterally in the dorsal prefrontal cortex and primary motor cortex. Glucose metabolism was bilaterally elevated in the mid-ACC/PCC and the PPC, which correlated with pain duration. These data suggested that glucose metabolism in the brains of patients with CRPS changes dramatically at each location. In particular, glucose metabolism was increased in the areas concerned with somatosensory perception, possibly due to continuous painful stimulation. (author)

298

Glucose Deprivation Regulates KATP Channel Trafficking via AMP-Activated Protein Kinase in Pancreatic ?-Cells  

Science.gov (United States)

OBJECTIVE AMP-activated protein kinase (AMPK) and the ATP-sensitive K+ (KATP) channel are metabolic sensors that become activated during metabolic stress. AMPK is an important regulator of metabolism, whereas the KATP channel is a regulator of cellular excitability. Cross talk between these systems is poorly understood. RESEARCH DESIGN AND METHODS Rat pancreatic ?-cells or INS-1 cells were pretreated for 2 h at various concentrations of glucose. Maximum KATP conductance (Gmax) was monitored by whole-cell measurements after intracellular ATP washout using ATP-free internal solutions. KATP channel activity (NPo) was monitored by inside-out patch recordings in the presence of diazoxide. Distributions of KATP channel proteins (Kir6.2 and SUR1) were examined using immunofluorescence imaging and surface biotinylation studies. Insulin secretion from rat pancreatic islets was measured using an enzyme immunoassay. RESULTS Gmax and NPo in cells pretreated with glucose-free or 3 mmol/l glucose solutions were significantly higher than in cells pretreated in 11.1 mmol/l glucose solutions. Immunofluorescence imaging and biotinylation studies revealed that glucose deprivation induced an increase in the surface level of Kir6.2 without affecting the total cellular amount. Increases in Gmax and the surface level of Kir6.2 were inhibited by compound C, an AMPK inhibitor, and siAMPK transfection. The effects of glucose deprivation on KATP channels were mimicked by an AMPK activator. Glucose deprivation reduced insulin secretion, but this response was attenuated by compound C. CONCLUSIONS KATP channel trafficking is regulated by energy status via AMPK, and this mechanism may play a key role in inhibiting insulin secretion under low energy status. PMID:19720793

Lim, Ajin; Park, Sun-Hyun; Sohn, Jong-Woo; Jeon, Ju-Hong; Park, Jae-Hyung; Song, Dae-Kyu; Lee, Suk-Ho; Ho, Won-Kyung

2009-01-01

299

Ozone induces glucose intolerance and systemic metabolic effects in young and aged brown Norway rats  

International Nuclear Information System (INIS)

Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased ?2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2 > 1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation. - Highlights: • Air pollutants have been associated with increased diabetes in humans. • Acute ozone exposure produces profound metabolic alterations in rats. • Age influences metabolic risk factors in aging BN rats. • Acute metabolic effects are reversible and repeated exposure reduces these effects. • Ozone metabolic effects are only slightly exacerbated in geriatric rats

300

Ozone induces glucose intolerance and systemic metabolic effects in young and aged brown Norway rats  

Energy Technology Data Exchange (ETDEWEB)

Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased ?{sub 2}-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2 > 1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation. - Highlights: • Air pollutants have been associated with increased diabetes in humans. • Acute ozone exposure produces profound metabolic alterations in rats. • Age influences metabolic risk factors in aging BN rats. • Acute metabolic effects are reversible and repeated exposure reduces these effects. • Ozone metabolic effects are only slightly exacerbated in geriatric rats.

Bass, V. [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Gordon, C.J.; Jarema, K.A.; MacPhail, R.C. [Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Cascio, W.E. [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Phillips, P.M. [Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Ledbetter, A.D.; Schladweiler, M.C. [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Andrews, D. [Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Miller, D. [Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC (United States); Doerfler, D.L. [Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Kodavanti, U.P., E-mail: kodavanti.urmila@epa.gov [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States)

2013-12-15

 
 
 
 
301

The Common C49620T Polymorphism in the Sulfonylurea Receptor Gene SUR1 (ABCC8) in Patients with Gestational Diabetes and Subsequent Glucose Metabolism Abnormalities  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Aim. The aim of this study is to investigate the relationship between the common C49620T polymorphism in the sulfonylurea receptor (SUR1) gene and glucose metabolism, ?-cell secretory function and insulin resistance in women with a history of gestational diabetes (GDM). Material and Methods. Study group included 199 women, diagnosed GDM within the last 5–12 years and control group of comparable 50 women in whom GDM was excluded during pregnancy. Blood glucose and insulin levels were measur...

Da, Piotr Mol Amp X.; Czak-kuleta, Agnieszka Bi Amp X.; Katarzyna Homa; Krzysztof Safranow; Zbigniew Celewicz; Anhelli Syrenicz; Ski, Adam Stefa Amp X.; Aneta Fronczyk; Lilianna Majkowska

2012-01-01

302

Role of oxygen vs. glucose in energy metabolism in a mammary carcinoma perfused ex vivo: direct measurement by 31P NMR.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

The role of glycolysis vs. respiration in tumor energy metabolism has been studied, to date, primarily in vitro by using single cells, multicellular spheroids, or tissue slices. With the advent of in vivo NMR spectroscopy, several investigators have shown that tumor energy status depends on its blood flow. Since manipulation of blood flow alters both oxygen and glucose delivery to a solid tumor, these studies have not been able to separate the relative contribution of oxygen vs. glucose in en...

Eskey, C. J.; Koretsky, A. P.; Domach, M. M.; Jain, R. K.

1993-01-01

303

Loss of GLUT4 induces metabolic reprogramming and impairs viability of breast cancer cells.  

Science.gov (United States)

Metabolic reprogramming strategies focus on the normalization of metabolism of cancer cells and constitute promising targets for cancer treatment. Here, we demonstrate that the glucose transporter 4 (GLUT4) has a prominent role in basal glucose uptake in MCF7 and MDA-MB-231 breast cancer cells. We show that shRNA-mediated down-regulation of GLUT4 diminishes glucose uptake and induces metabolic reprogramming by reallocating metabolic flux to oxidative phosphorylation. This reallocation is reflected on an increased activity of the mitochondrial oxidation of pyruvate and lower lactate release. Altogether, GLUT4 inhibition compromises cell proliferation and critically affects cell viability under hypoxic conditions, providing proof-of-principle for the feasibility of using pharmacological approaches to inhibit GLUT4 in order to induce metabolic reprogramming in vivo in breast cancer models. PMID:24931902

Garrido, Pablo; Osorio, Fernando G; Morán, Javier; Cabello, Estefanía; Alonso, Ana; Freije, José M P; González, Celestino

2015-01-01

304

Bradykinin enhances membrane electrical activity of pancreatic beta cells in the presence of low glucose concentrations  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english In most of cells bradykinin (BK) induces intracellular calcium mobilization. In pancreatic beta cells intracellular calcium is a major signal for insulin secretion. In these cells, glucose metabolism yields intracellular ATP which blocks membrane potassium channels. The membrane depolarizes, voltage [...] -dependent Ca2+ channels are activated and the intracellular calcium load allows insulin secretion. Repolarization occurs due to activation of the Ca2+-dependent K+ channel. The insulin secretion depends on the integrity of this oscillatory process (bursts). Therefore, we decided to determine whether BK (100 nM) induces bursts in the presence of a non-stimulatory glucose concentration (5.6 mM). During continuous membrane voltage recording, our results showed that bursts were obtained with 11 mM glucose, blocked with 5.6 mM glucose and recovered with 5.6 mM glucose plus 100 nM BK. Thus, the stimulatory process obtained in the presence of BK and of a non-stimulatory concentration of glucose in the present study suggests that BK may facilitate the action of glucose on beta cell secretion.

A.S., Moura.

1089-10-01

305

Bradykinin enhances membrane electrical activity of pancreatic beta cells in the presence of low glucose concentrations  

Directory of Open Access Journals (Sweden)

Full Text Available In most of cells bradykinin (BK induces intracellular calcium mobilization. In pancreatic beta cells intracellular calcium is a major signal for insulin secretion. In these cells, glucose metabolism yields intracellular ATP which blocks membrane potassium channels. The membrane depolarizes, voltage-dependent Ca2+ channels are activated and the intracellular calcium load allows insulin secretion. Repolarization occurs due to activation of the Ca2+-dependent K+ channel. The insulin secretion depends on the integrity of this oscillatory process (bursts. Therefore, we decided to determine whether BK (100 nM induces bursts in the presence of a non-stimulatory glucose concentration (5.6 mM. During continuous membrane voltage recording, our results showed that bursts were obtained with 11 mM glucose, blocked with 5.6 mM glucose and recovered with 5.6 mM glucose plus 100 nM BK. Thus, the stimulatory process obtained in the presence of BK and of a non-stimulatory concentration of glucose in the present study suggests that BK may facilitate the action of glucose on beta cell secretion.

A.S. Moura

2000-09-01

306

Assessment of the metabolic pathways associated with glucose-stimulated biphasic insulin secretion.  

Science.gov (United States)

Biphasic glucose-stimulated insulin secretion involves a rapid first phase followed by a prolonged second phase of insulin secretion. The biochemical pathways that control these 2 phases of insulin secretion are poorly defined. In this study, we used a gas chromatography mass spectroscopy-based metabolomics approach to perform a global analysis of cellular metabolism during biphasic insulin secretion. A time course metabolomic analysis of the clonal ?-cell line 832/13 cells showed that glycolytic, tricarboxylic acid, pentose phosphate pathway, and several amino acids were strongly correlated to biphasic insulin secretion. Interestingly, first-phase insulin secretion was negatively associated with L-valine, trans-4-hydroxy-L-proline, trans-3-hydroxy-L-proline, DL-3-aminoisobutyric acid, L-glutamine, sarcosine, L-lysine, and thymine and positively with L-glutamic acid, flavin adenine dinucleotide, caprylic acid, uridine 5'-monophosphate, phosphoglycerate, myristic acid, capric acid, oleic acid, linoleic acid, and palmitoleic acid. Tricarboxylic acid cycle intermediates pyruvate, ?-ketoglutarate, and succinate were positively associated with second-phase insulin secretion. Other metabolites such as myo-inositol, cholesterol, DL-3-aminobutyric acid, and L-norleucine were negatively associated metabolites with the second-phase of insulin secretion. These studies provide a detailed analysis of key metabolites that are either negatively or positively associated with biphasic insulin secretion. The insights provided by these data set create a framework for planning future studies in the assessment of the metabolic regulation of biphasic insulin secretion. PMID:24564396

Huang, Mei; Joseph, Jamie W

2014-05-01

307

F-19 MR imaging of glucose metabolism in the rat and rabbit  

International Nuclear Information System (INIS)

MR imaging reflecting regional pathway specific glucose metabolism was performed utilizing F-19 as the MR signal probe and two fluorinated glucose analogues, 2-fluoro-2-deoxy-D-glucose (2-FDG) and 3-fluoro-3-deoxy-D-glucose (3-FDG) as the metabolic probe. 2-FDG-6-phosphate images provides regional quantitative information regarding glycolytic activities, while 2-FDG-6-phosphoglyconate images provide information on the pentose monophosphate shunt activities. 3-FDG-sorbitol and 3-FDG-fructose indicate regional aldose reductase and sorbitol dehydrogenase activities of the aldose reductase sorbitol pathway, respectively. The potential toxicity of 2-FDG in high doses precludes the immediate application of the 2-FDG MR imaging method to humans. The extremely low toxicity of 3-FDG, however, indicates promise for clinical application of 3-FDG MR imaging

308

The Radical Scavenger Edaravone Improves Neurologic Function and Perihematomal Glucose Metabolism after Acute Intracerebral Hemorrhage.  

Science.gov (United States)

Oxidative injury caused by reactive oxygen species plays an important role in the progression of intracerebral hemorrhage (ICH)-induced secondary brain injury. Previous studies have demonstrated that the free radical scavenger edaravone may prevent neuronal injury and brain edema after ICH. However, the influence of edaravone on cerebral metabolism in the early stages after ICH and the underlying mechanism have not been fully investigated. In the present study, we investigated the effect of edaravone on perihematomal glucose metabolism using (18)F-fluorordeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Additionally, the neurologic deficits, brain edemas, and cell death that followed ICH were quantitatively analyzed. After blood infusion, the rats treated with edaravone showed significant improvement in both forelimb placing and corner turn tests compared with those treated with vehicle. Moreover, the brain water content of the edaravone-treated group was significantly decreased compared with that of the vehicle group on day 3 after ICH. PET/CT images of ICH rats exhibited obvious decreases in FDG standardized uptake values in perihematomal region on day 3, and the lesion-to-normal ratio of the edaravone-treated ICH rats was significantly increased compared with that of the control rats. Calculation of the brain injury volumes from the PET/CT images revealed that the volumes of the blood-induced injuries were significantly smaller in the edaravone group compared with the vehicle group. Terminal Deoxynucleotidyl Transferase-mediated dUTP Nick End Labeling assays performed 3 days after ICH revealed that the numbers of apoptotic cells in perihematomal region of edaravone-treated ICH rats were decreased relative to the vehicle group. Thus, the present study demonstrates that edaravone has scavenging properties that attenuate neurologic behavioral deficits and brain edema in the early period of ICH. Additionally, edaravone may improve cerebral metabolism around the hematoma by attenuating apoptotic cell death after ICH. PMID:25440340

Shang, Hanbing; Cui, Derong; Yang, Dehua; Liang, Sheng; Zhang, Weifeng; Zhao, Weiguo

2014-11-12

309

Non-Invasive Glucose Measurement by Use of Metabolic Heat Conformation Method  

Digital Repository Infrastructure Vision for European Research (DRIVER)

A non-invasive glucose measurement system based on the method of metabolic heat conformation (MHC) is presented in this paper. This system consists of three temperature sensors, two humidity sensors, an infrared sensor and an optical measurement device. The glucose level can be deduced from the quantity of heat dissipation, blood flow rate of local tissue and degree of blood oxygen saturation. The methodology of the data process and the measurement error are also analyzed. The system is appli...

Junfeng Li; Dongsheng Wang; Xiaohao Wang; Fei Tang

2008-01-01

310

Glucose Metabolism Disorders in Cirrhosis: Frequency and Risk Factors in Tunisian Population. Results of a Cross-Sectional Study  

Directory of Open Access Journals (Sweden)

Full Text Available Background and aims: Alterations in carbohydrate metabolism are frequently observed in cirrhosis; to determine the frequency of diabetes mellitus and impaired glucose tolerance in Tunisian cirrhotic patients and identify risk factors. Patients and methods: Cross-sectional study; fasting plasma glucose levels were measured in consecutive patients with cirrhosis. Oral glucose tolerance test was performed if fasting plasma glucose level was normal. Glucose metabolism disorders were then classified as: impaired glucose tolerance and diabetes mellitus. Cirrhotics with glucose metabolism disorder were compared to those without. Results: Seventy-seven patients with cirrhosis were included: 68.8% were diagnosed as having glucose metabolism disorder; diabetes in 42.8% and impaired glucose tolerance in 26%. The tests were able to identify 60.4% of glucose metabolism disorders. Univariate analysis disclosed a higher proportion of female gender (p = 0.04 and more frequent familial history of diabetes mellitus (p = 0.005 in the group with glucose metabolism disorder. There were no statistically differences regarding age, etiology and severity of the cirrhosis, and dry body mass index. Multivariate analysis showed that familial history of diabetes was the only independent risk factor (OR = 5.1, p = 0.005. Conclusion: In our study, the frequency of glucose metabolism disorders was 68.8%. Oral glucose tolerance test allowed disclosing nearly half of them, pointing a high incidence of latent glucose metabolism disorders. In this way, it should be routinely evaluated in all patients with cirrhosis. Familial history of diabetes was the only independent risk factor, suggesting that other factors in addition to liver disease may play a role.

Rym Ennaifer

2014-08-01

311

Adverse Effect of High Glucose Concentration on Stem Cell Therapy  

Directory of Open Access Journals (Sweden)

Full Text Available Stem cell therapy could have great potential for the treatment of a wide variety of diseases. Stem cells might have the ability to differentiate into a widespread cell types, and to repopulate and revitalize the damaged cells with healthy tissue, and improve its performance. We provide here the evidence supporting the critical use of stem cell as a treatment in disease conditions existing with high glucose complaint such as diabetes. The reduction of glucose stimulated cell proliferation and high glucose enhanced apoptosis in rat model, which may be a problem in therapeutic strategies based on ex vivo expansion of stem cell, and may also propagate the development of osteoporosis in high glucose complaint such as diabetes. This leads to the hypothesis that, high glucose could be more deleterious to stem cell therapy that may be due to the aggravation of oxidative stress triggered by high glucose. These findings may help to understand the possible reasons associated with high glucose induced detrimental effects on stem cells as well as provide novel therapeutic strategies for preventing the adverse effects of glucose on the development and progression of stem cells in patients with diabetes.

Najmaldin Saki

2013-07-01

312

Designing a highly active soluble PQQ-glucose dehydrogenase for efficient glucose biosensors and biofuel cells  

International Nuclear Information System (INIS)

Research highlights: ? A new mutant of PQQ-GDH designed for glucose biosensors application. ? First mutant of PQQ-GDH with higher activity for D-glucose than the Wild type. ? Position N428 is a key point to increase the enzyme activity. ? Molecular modeling shows that the N428 C mutant displays a better interaction for PQQ than the WT. -- Abstract: We report for the first time a soluble PQQ-glucose dehydrogenase that is twice more active than the wild type for glucose oxidation and was obtained by combining site directed mutagenesis, modelling and steady-state kinetics. The observed enhancement is attributed to a better interaction between the cofactor and the enzyme leading to a better electron transfer. Electrochemical experiments also demonstrate the superiority of the new mutant for glucose oxidation and make it a promising enzyme for the development of high-performance glucose biosensors and biofuel cells.

313

Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice.  

Science.gov (United States)

The Mouse Metabolic Phenotyping Center (MMPC) Consortium was established to address the need to characterize the growing number of mouse models of metabolic diseases, particularly diabetes and obesity. A goal of the MMPC Consortium is to propose standard methods for assessing metabolic phenotypes in mice. In this article, we discuss issues pertaining to the design and performance of various tests of glucose metabolism. We also propose guidelines for the description of methods, presentation of data and interpretation of results. The recommendations presented in this article are based on the experience of the MMPC Consortium and other investigators. PMID:20713647

Ayala, Julio E; Samuel, Varman T; Morton, Gregory J; Obici, Silvana; Croniger, Colleen M; Shulman, Gerald I; Wasserman, David H; McGuinness, Owen P

2010-01-01

314

Glucose-lactate metabolic cooperation in cancer: insights from a spatial mathematical model and implications for targeted therapy.  

Science.gov (United States)

A recent study has hypothesised a glucose-lactate metabolic symbiosis between adjacent hypoxic and oxygenated regions of a developing tumour, and proposed a treatment strategy to target this symbiosis. However, in vivo experimental support remains inconclusive. Here we develop a minimal spatial mathematical model of glucose-lactate metabolism to examine, in principle, whether metabolic symbiosis is plausible in human tumours, and to assess the potential impact of inhibiting it. We find that symbiosis is a robust feature of our model system-although on the length scale at which oxygen supply is diffusion-limited, its occurrence requires very high cellular metabolic activity-and that necrosis in the tumour core is reduced in the presence of symbiosis. Upon simulating therapeutic inhibition of lactate uptake, we predict that targeted treatment increases the extent of tissue oxygenation without increasing core necrosis. The oxygenation effect is correlated strongly with the extent of wild-type hypoxia and only weakly with wild-type symbiotic behaviour, and therefore may be promising for radiosensitisation of hypoxic, lactate-consuming tumours even if they do not exhibit a spatially well-defined symbiosis. Finally, we conduct in vitro experiments on the U87 glioblastoma cell line to facilitate preliminary speculation as to where highly malignant tumours might fall in our parameter space, and find that these experiments suggest a weakly symbiotic regime for U87 cells, thus raising the new question of what relationship might exist between symbiosis and tumour malignancy. PMID:25264268

McGillen, Jessica B; Kelly, Catherine J; Martínez-González, Alicia; Martin, Natasha K; Gaffney, Eamonn A; Maini, Philip K; Pérez-García, Víctor M

2014-11-21

315

Compartmentalized Acyl-CoA Metabolism in Skeletal Muscle Regulates Systemic Glucose Homeostasis.  

Science.gov (United States)

The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-specific deficiency of long-chain acyl-CoA synthetase (ACSL)1. ACSL1 deficiency caused a 91% loss of ACSL-specific activity and a 60-85% decrease in muscle FA oxidation. Acsl1(M-/-) mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1(M-/-) mice ran only 48% as far as controls. At the time that Acsl1(M-/-) mice were exhausted but control mice continued to run, liver and muscle glycogen and triacylglycerol stores were similar in both genotypes; however, plasma glucose concentrations in Acsl1(M-/-) mice were ?40 mg/dL, whereas glucose concentrations in controls were ?90 mg/dL. Excess use of glucose and the likely use of amino acids for fuel within muscle depleted glucose reserves and diminished substrate availability for hepatic gluconeogenesis. Surprisingly, the content of muscle acyl-CoA at exhaustion was markedly elevated, indicating that acyl-CoAs synthesized by other ACSL isoforms were not available for ?-oxidation. This compartmentalization of acyl-CoAs resulted in both an excessive glucose requirement and severely compromised systemic glucose homeostasis. PMID:25071025

Li, Lei O; Grevengoed, Trisha J; Paul, David S; Ilkayeva, Olga; Koves, Timothy R; Pascual, Florencia; Newgard, Christopher B; Muoio, Deborah M; Coleman, Rosalind A

2015-01-01

316

Metabolic network analysis of Bacillus clausii on minimal and semirich medium using C-13-Labeled glucose  

DEFF Research Database (Denmark)

Using C-13-labeled glucose fed to the facultative alkalophilic Bacillus clausii producing the alkaline serine protease Savinase, the intracellular fluxes were quantified in continuous cultivation and in batch cultivation on a minimal medium. The flux through the pentose phosphate pathway was found to increase with increasing specific growth rate but at a much lower level than previously reported for Bacillus subtilis. Two futile cycles in the pyruvate metabolism were included in the metabolic network. A substantial flux in the futile cycle involving malic enzyme was estimated, whereas only a very small or zero flux through PEP carboxykinase was estimated, indicating that the latter enzyme was not active during growth on glucose. The uptake of the amino acids in a semirich medium containing 15 of the 20 amino acids normally present in proteins was estimated using fully labeled glucose in batch cultivations. It was found that leucine, isoleucine, and phenylalanine were taken up from the medium and not synthesized de novo from glucose. In contrast, serine and threonine were completely synthesized from other metabolites and not taken up from the medium. Valine, proline, and lysine were partly taken up from the medium and partly synthesized from glucose. The metabolic network analysis was extended to include analysis of growth on the semirich medium containing amino acids, and the metabolic flux distribution on this medium was estimated and compared with growth on minimal medium.

Christiansen, Torben; Christensen, Bjarke

2002-01-01

317

Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells.  

Science.gov (United States)

Heme oxygenase-1 (HO-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury, such as heme and inflammatory molecules. Incubation of endothelial cells in a high-glucose (33 mmol/L) medium for 7 days resulted in a decrease of HO activity by 34% and a decrease in HO-1 and HO-2 proteins compared with cells exposed to low glucose (5 mmol/L) (PSnMP), an inhibitor of HO activity, reversed the HO-1-mediated decrease of p21 and p27 in cells overexpressing HO-1. These findings identify a novel effect of HO-1 on endothelial cell growth and indicate that heme metabolism and HO-1 expression regulate signaling systems in cells exposed to high glucose, which controls cell-cycle progression. PMID:12933701

Abraham, Nader G; Kushida, Taketoshi; McClung, Jack; Weiss, Melvin; Quan, Shuo; Lafaro, Rocky; Darzynkiewicz, Zbigniew; Wolin, Michael

2003-09-19

318

Islet cell responses to glucose in human transplanted pancreas.  

Science.gov (United States)

Postsurgery, pancreas transplantation results in alterations of carbohydrate metabolism. Additionally, immunosuppressive therapy impacts on glucose regulation. We evaluated the hormonal and metabolic responses of pancreas allografts, utilizing the hyperglycemic clamp technique coupled with the tritiated glucose methodology, in 11 volunteers who had received simultaneous pancreas-kidney transplantation (P-K) with systemic drainage. Their responses were compared with seven volunteers who had received only a kidney (K) graft and with seven normal control (C) volunteers. Although basal glucose and hepatic glucose output were similar in all three groups, basal insulin, C-peptide, glucagon, and pancreatic polypeptide were highest in the P-K group and lowest in normal subjects. During hyperglycemia, all groups showed a similar characteristic, initial complete suppression of hepatic glucose production, with recovery followed by a later suppression. Peripheral glucose uptake was similar in P-K and C subjects but decreased in K patients. Systemic insulin levels were fourfold higher in the pancreas transplant patients than in healthy subjects. Thus, under basal and hyperglycemic stimulation, 1) hepatic glucose homeostasis is regulated normally, even with pancreatic drainage into the systemic circulation; 2) overall glucose disposal is normal in P-K patients because of marked hyperinsulinemia; and 3) there is loss of tonic inhibition of endocrine pancreatic function secondary to pancreatic denervation. PMID:1767840

Elahi, D; Clark, B A; McAloon-Dyke, M; Wong, G; Brown, R; Shapiro, M; Minaker, K L; Flanagan, T L; Pruett, T; Gingerich, R

1991-12-01

319

SGLT2 Deletion Improves Glucose Homeostasis and Preserves Pancreatic ?-Cell Function  

Science.gov (United States)

OBJECTIVE Inhibition of the Na+-glucose cotransporter type 2 (SGLT2) is currently being pursued as an insulin-independent treatment for diabetes; however, the behavioral and metabolic consequences of SGLT2 deletion are unknown. Here, we used a SGLT2 knockout mouse to investigate the effect of increased renal glucose excretion on glucose homeostasis, insulin sensitivity, and pancreatic ?-cell function. RESEARCH DESIGN AND METHODS SGLT2 knockout mice were fed regular chow or a high-fat diet (HFD) for 4 weeks, or backcrossed onto the db/db background. The analysis used metabolic cages, glucose tolerance tests, euglycemic and hyperglycemic clamps, as well as isolated islet and perifusion studies. RESULTS SGLT2 deletion resulted in a threefold increase in urine output and a 500-fold increase in glucosuria, as well as compensatory increases in feeding, drinking, and activity. SGLT2 knockout mice were protected from HFD-induced hyperglycemia and glucose intolerance and had reduced plasma insulin concentrations compared with controls. On the db/db background, SGLT2 deletion prevented fasting hyperglycemia, and plasma insulin levels were also dramatically improved. Strikingly, prevention of hyperglycemia by SGLT2 knockout in db/db mice preserved pancreatic ?-cell function in vivo, which was associated with a 60% increase in ?-cell mass and reduced incidence of ?-cell death. CONCLUSIONS Prevention of renal glucose reabsorption by SGLT2 deletion reduced HFD- and obesity-associated hyperglycemia, improved glucose intolerance, and increased glucose-stimulated insulin secretion in vivo. Taken together, these data support SGLT2 inhibition as a viable insulin-independent treatment of type 2 diabetes. PMID:21357472

Jurczak, Michael J.; Lee, Hui-Young; Birkenfeld, Andreas L.; Jornayvaz, Francois R.; Frederick, David W.; Pongratz, Rebecca L.; Zhao, Xiaoxian; Moeckel, Gilbert W.; Samuel, Varman T.; Whaley, Jean M.; Shulman, Gerald I.; Kibbey, Richard G.

2011-01-01

320

The impact of ethnicity on glucose regulation and the metabolic syndrome following gestational diabetes.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

AIMS/HYPOTHESIS: We assessed the impact of ethnic origin on metabolism in women following gestational diabetes mellitus (GDM). MATERIALS AND METHODS: Glucose regulation and other features of the metabolic syndrome were studied at 20.0 (18.2-22.1) months (geometric mean [95% CI]) post-partum in women with previous GDM (185 European, 103 Asian-Indian, 80 African-Caribbean). They were compared with the same features in 482 normal control subjects who had normal glucose regulation during and foll...

Kousta, E.; Efstathiadou, Z.; Lawrence, Nj; Jeffs, Ja; Godsland, If; Barrett, Sc; Dore?, Cj; Penny, A.; Anyaoku, V.; Millauer, Ba; Cela, E.; Robinson, S.; Mccarthy, Mi; Johnston, DG

2006-01-01

 
 
 
 
321

Influence of insulin on glucose metabolism and energy expenditure in septic patients  

Science.gov (United States)

Introduction It is recognized that administration of insulin with glucose decreases catabolic response in sepsis. The aim of the present study was to compare the effects of two levels of insulinaemia on glucose metabolism and energy expenditure in septic patients and volunteers. Methods Glucose uptake, oxidation and storage, and energy expenditure were measured, using indirect calorimetry, in 20 stable septic patients and 10 volunteers in a two-step hyperinsulinaemic (serum insulin levels 250 and 1250 mIU/l), euglycaemic (blood glucose concentration 5 mmol/l) clamp. Differences between steps of the clamp (from serum insulin 1250 to 250 mIU/l) for all parameters were calculated for each individual, and compared between septic patients and volunteers using the Wilcoxon nonpaired test. Results Differences in glucose uptake and storage were significantly less in septic patients. The differences in glucose oxidation between the groups were not statistically significant. Baseline energy expenditure was significantly higher in septic patients, and there was no significant increase in either step of the clamp in this group; when comparing the two groups, the differences between steps were significantly greater in volunteers. Conclusion A hyperdynamic state of sepsis leads to a decrease in glucose uptake and storage in comparison with healthy volunteers. An increase in insulinaemia leads to an increase in all parameters of glucose metabolism, but the increases in glucose uptake and storage are significantly lower in septic patients. A high level of insulinaemia in sepsis increases glucose uptake and oxidation significantly, but not energy expenditure, in comparison with volunteers. PMID:15312220

Rusavy, Zdenek; Sramek, Vladimir; Lacigova, Silvie; Novak, Ivan; Tesinsky, Pavel; Macdonald, Ian A

2004-01-01

322

Alterations of hippocampal glucose metabolism by even versus uneven medium chain triglycerides.  

Science.gov (United States)

Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 weeks. Enzymatic assays and targeted metabolomics by liquid chromatography tandem mass spectrometry were used to quantify metabolites in extracts from the hippocampal formations (HFs). Both oils increased the levels of ?-hydroxybutyrate, but no other significant metabolic alterations were observed after triheptanoin feeding. The levels of glucose 6-phosphate and fructose 6-phosphate were increased in the HF of mice fed trioctanoin, whereas levels of metabolites further downstream in the glycolytic pathway and the pentose phosphate pathway were reduced. This indicates that trioctanoin reduces glucose utilization because of a decrease in phosphofructokinase activity. Trioctanoin and triheptanoin showed similar anticonvulsant effects in the 6?Hz seizure model, but it remains unknown to what extent the anticonvulsant mechanism(s) are shared. In conclusion, triheptanoin unlike trioctanoin appears to not alter glucose metabolism in the healthy brain. PMID:24169853

McDonald, Tanya S; Tan, Kah Ni; Hodson, Mark P; Borges, Karin

2014-01-01

323

Impact of the reg1 mutation glycocen accumulation and glucose consumption rates in Saccharomyces cerevisiae cells based on a macrokinetic model  

Digital Repository Infrastructure Vision for European Research (DRIVER)

In S. cerevisiae, catabolite repression controls glycogen accumulation and glucose consumption. Glycogen is responsible for stress resistance, and its accumulation in derepression conditions results in a yeast with good quality. In yeast cells, catabolite repression also named glucose effect takes place at the transcriptional levels, decreasing enzyme respiration and causing the cells to enter a fermentative metabolism, low cell mass yield and yeast with poor quality. Since glucose is always ...

Rocha-Leão M.H.M.; Coelho M. A. Z.; Araújo O. Q. F.

2003-01-01

324

Regulation of renal brush-border glucose transport in response to metabolic dysregulation  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Diabetic nephropathy is a consequence of hyperglycaemia-induced renal cell damage and a major contributor to end-stage renal disease in later stages of diabetes. Previous studies, in type I diabetes, observed PKC-?I-dependent GLUT2 recruitment to the proximal tubule brush-border membrane (BBM) as a direct result of elevated plasma glucose. The up-regulation of glucose transporters at the proximal tubule BBM causes a rise in intracellular glucose concentration; tubular injury in diabetic neph...

Chichger, H.

2011-01-01

325

Role of Glucose Metabolism and ATP in Maintaining PINK1 Levels during Parkin-mediated Mitochondrial Damage Responses.  

Science.gov (United States)

Mutations in several genes, including PINK1 and Parkin, are known to cause autosomal recessive cases of Parkinson disease in humans. These genes operate in the same pathway and play a crucial role in mitochondrial dynamics and maintenance. PINK1 is required to recruit Parkin to mitochondria and initiate mitophagy upon mitochondrial depolarization. In this study, we show that PINK1-dependent Parkin mitochondrial recruitment in response to global mitochondrial damage by carbonyl cyanide m-chlorophenylhydrazine (CCCP) requires active glucose metabolism. Parkin accumulation on mitochondria and subsequent Parkin-dependent mitophagy is abrogated in glucose-free medium or in the presence of 2-deoxy-d-glucose upon CCCP treatment. The defects in Parkin recruitment correlate with intracellular ATP levels and can be attributed to suppression of PINK1 up-regulation in response to mitochondria depolarization. Low levels of ATP appear to prevent PINK1 translation instead of affecting PINK1 mRNA expression or reducing its stability. Consistent with a requirement of ATP for elevated PINK1 levels and Parkin mitochondrial recruitment, local or individual mitochondrial damage via photoirradiation does not affect Parkin recruitment to damaged mitochondria as long as a pool of functional mitochondria is present in the photoirradiated cells even in glucose-free or 2-deoxy-d-glucose-treated conditions. Thus, our data identify ATP as a key regulator for Parkin mitochondrial translocation and sustaining elevated PINK1 levels during mitophagy. PINK1 functions as an AND gate and a metabolic sensor coupling biogenetics of cells and stress signals to mitochondria dynamics. PMID:25404737

Lee, Schuyler; Zhang, Conggang; Liu, Xuedong

2015-01-01

326

Noninvasive measurement of regional myocardial glucose metabolism by positron emission computed tomography. [Dogs  

Energy Technology Data Exchange (ETDEWEB)

While the results of regional myocardial glucose metabolism measurements using positron emission computed tomography (/sup 13/N-ammonia) are promising, their utility and value remains to be determined in man. If this technique can be applied to patients with acute myocardial ischemia or infarction it may permit delineation of regional myocardial segments with altered, yet still active metabolism. Further, it may become possible to evaluate the effects of interventions designed to salvage reversibly injured myocardium by this technique.

Schelbert, H.R.; Phelps, M.E.

1980-06-01

327

Butyrate and glucose metabolism by colonocytes in experimental colitis in mice  

Digital Repository Infrastructure Vision for European Research (DRIVER)

BACKGROUND/AIMS—Impaired colonocyte metabolism of butyrate has been implicated in the aetiopathogenesis of ulcerative colitis. Colonocyte butyrate metabolism was investigated in experimental colitis in mice.?METHODS—Colitis was induced in Swiss outbred white mice by oral administration of 4% dextran sulphate sodium (DSS). Colonocytes isolated from colitic and normal control mice were incubated with [14C]butyrate or glucose, and production of 14CO2, as well as of intermediate metabolites...

Ahmad, M.; Krishnan, S.; Ramakrishna, B.; Mathan, M.; Pulimood, A.; Murthy, S.

2000-01-01

328

Cortical Glucose Metabolism Positively Correlates with Gamma-Oscillations in Nonlesional Focal Epilepsy  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Why do the epileptogenic foci appear hypometabolic on interictal glucose metabolism positron emission tomography (PET) in a substantial proportion of patients with focal epilepsy but appear normo- or even hyper-metabolic in others? Such observations on interictal PET have not been fully explained by the frequency of interictal spike discharges alone. In the present study using digital electrocorticography monitoring system with high-frequency sampling, we determined how well regression models...

Nishida, Masaaki; Juha?sz, Csaba; Sood, Sandeep; Chugani, Harry T.; Asano, Eishi

2008-01-01

329

Noninvasive measurement of regional myocardial glucose metabolism by positron emission computed tomography  

International Nuclear Information System (INIS)

While the results of regional myocardial glucose metabolism measurements using positron emission computed tomography (13N-ammonia) are promising, their utility and value remains to be determined in man. If this technique can be applied to patients with acute myocardial ischemia or infarction it may permit delineation of regional myocardial segments with altered, yet still active metabolism. Further, it may become possible to evaluate the effects of interventions designed to salvage reversibly injured myocardium by this technique

330

Dose-response relationship between probability of pathologic tumor control and glucose metabolic rate measured with FDG PET after preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer  

International Nuclear Information System (INIS)

Purpose: To determine the dose-response relationship between the probability of tumor control on the basis of pathologic tumor response (pTCP) and the residual metabolic rate of glucose (MRglc) in response to preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer and to define the level of residual MRglc that corresponds to pTCP 50% and pTCP ?95%. Methods and Materials: Quantitative dynamic 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography was performed to measure regional MRglc at the primary lesion before and 2 weeks after preoperative chemoradiotherapy in an initial group of 13 patients with locally advanced NSCLC. A simplified kinetic method was developed subsequently from the initial dynamic study and used in the subsequent 16 patients. The preoperative radiotherapy programs consisted of (1) a split course of 42 Gy in 28 fractions within a period of 28 days using a twice-daily treatment schedule for Stage IIIA(N2) NSCLC (n=18) and (2) standard once-daily radiation schedule of 45-63 Gy in 25-35 fractions during a 5-7-week period (n=11). The preoperative chemotherapy regimens included two cycles of cisplatin, vinblastine, and 5-fluorouracil (n=24), cisplatin and etoposide (n=2), and cisplatin, Taxol, and 5-fluorouracil (n=3). Patients free of tumor progression after preoperative chemoradiotherapy underwent surgery. The degree of residual MRglc measured 2 weeks after preoperative chemoradiotherapy and 2 weeks before surgeemoradiotherapy and 2 weeks before surgery was correlated with the pathologic tumor response. The relationship between MRglc and pTCP was modeled using logistic regression. Results: Of 32 patients entered into the study, 29 (16 men and 13 women; 30 lesions) were evaluated for the correlation between residual MRglc and pathologic tumor response. Three patients did not participate in the second study because of a steady decline in general condition. The median age was 60 years (range 42-78). One of the 29 patients had two separate lesions, and MRglc was measured in each separately. The tumor histologic types included squamous cell carcinoma (n=9), adenocarcinoma (n=13), large cell carcinoma (n=6), and poorly differentiated carcinoma (n=2). The extent of the primary and nodal disease was as follows: Stage IIB (T3N0M0), Pancoast tumor (n=2); Stage IIIA, T2-T3N2M0 (n=18); Stage IIIB: T1-T3N3M0 (n=5) and T4N0M0 (n=2); a second lesion, T1 (n=1); and localized stump recurrence (n=2). A pathologically complete response was obtained in 14 (47%) of the 30 lesions. The remaining 16 lesions had residual cancer. The mean baseline value of the maximal MRglc was 0.333 ± 0.087 ?mol/min/g (n=16), and it was reduced to 0.0957 ± 0.059 ?mol/min/g 2 weeks after chemoradiotherapy (p=0.011). The correlation between residual MRglc and pTCP was made using an increment value of 0.02 ?mol/min/g between the maximal and minimal values of MRglc. A pathologically complete response was obtained in 6 of 6 patients with residual MRglc of ?0.050 ?mol/min/g, 3 of 4 with ?0.070, 4 of 7 with ?0.090, 0 of 4 with ?0.110, 1 of 3 with ?0.130, and 0 of 6 with ?0.130 ?mol/min/g. The fitted logistic model showed that residual MRglc corresponding to pTCP 50% and pTCP ?95% was 0.076 and ?0.040 ?mol/min/g, respectively. Conclusion: The correlation between the gradient of residual MRglc after chemoradiotherapy and pTCP is an inverse dose-response relationship. Residual MRglc of 0.076 and ?0.040 ?mol/min/g, representing pTCP 50% and pTCP ?95%, respectively, may be useful surrogate markers for the tumor response to radiotherapy or chemoradiotherapy in lung cancer

331

Metabolism of glucose in brain of patients with Parkinson's disease  

International Nuclear Information System (INIS)

We examined 11C accumulation by positron emission computed tomography in the region of interest (ROI) in the brain of 8 patients with Parkinson's disease and 5 normal controls when administered with 11C-glucose (per os). 11C-glucose was prepared from 11CO2 by photosynthesis. 1) No significant difference was observed in the 11C accumulation in the striatum and cerebral cortex (frontal cortex, temporal cortex and occipital cortex) in 4 patients with Parkinson's disease between continuous medication and 7--10 day interruption of medication. 2) No difference was observed in the 11C accumulation in the striatum and cerebral cortex between 8 patients with Parkinson's disease and 5 normal controls. (author)

332

Root Border Cells Take Up and Release Glucose?C  

Digital Repository Infrastructure Vision for European Research (DRIVER)

• Background and Aims Border cells are released from the root tips of many plant species, and can remain viable in the rhizosphere for 1 week. Whether border cells are capable of controlled glucose exchange with their environment was investigated.

Stubbs, V. E. C.; Standing, D.; Knox, O. G. G.; Killham, K.; Bengough, A. G.; Griffiths, B.

2004-01-01

333

Alterations in glucose metabolism by cyclosporine in rat brain slices link to oxidative stress: interactions with mTOR inhibitors.  

Science.gov (United States)

Co-administration of the calcineurin inhibitor cyclosporine and the mTOR inhibitors sirolimus or everolimus increases the efficacy of immunosuppression after organ transplantation. However, clinical studies showed enhancement of cyclosporine toxicity. To characterize the biochemical mechanisms involved, we assessed the time-dependent effects of cyclosporine in combination with mTOR inhibitors on energy production (ex vivo (31)P-MRS), glucose metabolism (ex vivo (13)C-MRS), and reactive oxygen species (ROS) formation (using the fluorescent agent 2',7'-dichlorofluorescein diacetate) in perfused rat brain slices. Cyclosporine alone inhibited energy production (ATP: 75+/-9%), the Krebs cycle (4-(13)C-glutamate from 1-(13)C-glucose: 61+/-27%), and oxidative phosphorylation (NAD(+): 62+/-25%) after 4 h of perfusion. After 10 h, activation of anaerobic glycolysis (3-(13)C-lactate: 140+/-17%) compensated for inhibition of mitochondrial energy production and lowered the intracellular pH. ROS formation was increased after 4 h (285+/-55% of untreated control), but not after 10 h. mTOR inhibitors alone inhibited lactate production. When combined with cyclosporine, sirolimus enhanced cyclosporine-induced inhibition of energy metabolism (ATP: 64+/-9%) and ROS formation (367+/-46%). Most importantly, sirolimus inhibited cytosolic glycolysis and therefore compensation for cyclosporine-induced ATP reduction after 10 h. In contrast to sirolimus, everolimus antagonized cyclosporine-induced inhibition of mitochondrial energy metabolism (ATP: 91+/-7%) and ROS formation (170+/-49%). The antioxidant tocopherol antagonized all cyclosporine effects on cell metabolism. Cyclosporine time-dependently inhibited mitochondrial metabolism and increased ROS, followed by compensation involving anaerobic glycolysis. Everolimus antagonized cyclosporine-induced mitochondrial dysfunction, whereas sirolimus inhibited compensatory anaerobic glycolysis, thus enhancing cyclosporine's negative effects. ROS play the key role in mediating the negative effects of cyclosporine on cell energy metabolism. PMID:15339861

Christians, Uwe; Gottschalk, Sven; Miljus, Jelena; Hainz, Carsten; Benet, Leslie Z; Leibfritz, Dieter; Serkova, Natalie

2004-10-01

334

Brain metabolism is significantly impaired at blood glucose below 6 mM and brain glucose beneath 1 mM in patients with severe traumatic brain injury.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

ABSTRACT: INTRODUCTION: The optimal blood glucose target following severe traumatic brain injury (TBI) must be defined. Cerebral microdialysis was used to investigate the influence of arterial blood and brain glucose on cerebral glucose, lactate, pyruvate, glutamate, and calculated indices of downstream metabolism. METHODS: In twenty TBI patients, microdialysis catheters inserted in the edematous frontal lobe were dialyzed at 1 mul/ min, collecting samples at 60 minute intervals. Occult metab...

Meierhans, R.; Bechir, M.; Ludwig, S.; Sommerfeld, J.; Brandi, G.; Haberthur, C.; Stocker, R.; Stover, J. F.

2010-01-01

335

Changes in mitochondrial carriers exhibit stress-specific signatures in INS-1E?-cells exposed to glucose versus fatty acids  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Chronic exposure of ?-cells to metabolic stresses impairs their function and potentially induces apoptosis. Mitochondria play a central role in coupling glucose metabolism to insulin secretion. However, little is known on mitochondrial responses to specific stresses; i.e. low versus high glucose, saturated versus unsaturated fatty acids, or oxidative stress. INS-1E cells were exposed for 3 days to 5.6 mM glucose, 25 mM glucose, 0.4 mM palmitate, and 0.4 mM oleate. Culture at standard 11.1 mM...

Brun, Thierry; Scarcia, Pasquale; Li, Ning; Gaudet, Pascale; Duhamel, Dominique; Palmieri, Ferdinando; Maechler, Pierre

2013-01-01

336

Radiorespirometric analysis of glucose metabolism in the rat during feeding with 3'-methyl-4-(dimethylamino) azobenzene  

International Nuclear Information System (INIS)

We estimated the enzyme activities on the hexose monophosphate oxidative pathway of glucose metabolism at an early stage during feeding with 3'-methyl-4-(dimethylamino) azobenzene (3'-Me-DAB) in the first paper of this series. In the present paper, the importance of this non-glycolytic pathway of glucose metabolism in preneoplastic liver in azodye fed rat was studied by radiorespirometry using [1 - 14C] glucose and [6 - 14C] glucose. In addition to radioisotope analysis, the level of activity of glucose-6-phosphate dehydrogenase was measured in rat liver after various periods of feeding with 3'-Me-DAB. In radiorespirometry using [1 - 14C] glucose, the peak time was delayed up to the 2nd week, but was early by the 4th week and was the same as the control at the 5th week and thereafter. On the other hand, the peak height and the yield value both changed in almost the same way. That is to say, they were lower than those of the control until the 2nd week, began to increase from the 3rd week, reached a maximum at the 4th week, and remained at the control level at the 5th week and thereafter. Moreover, the yield value ratio of respiratory 14CO2 from [1 - 14C] glucose to that from [6 - 14C] glucose increased from 1.3 to 1.52 at the 3rd to 4th week after feeding with 3'-Me-DAB. The activity of glucose-6-phosphate dehydrogenase increased as early as the 2nd week after the start of feeding with 3'-Me-Dek after the start of feeding with 3'-Me-DAB, reaching a maximum at the 4th week. Thereafter, the activity remained high with a slight decrease from the maximum by the 6th week. (author)

337

Effect of green tea on blood glucose levels and serum proteomic patterns in diabetic (db/db) mice and on glucose metabolism in healthy humans  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Abstract Background Green tea is widely consumed in Asian countries and is becoming increasingly popular in Western countries. Epidemiologically, it has been suggested that green tea consumption prevents type 2 diabetes. The present study was aimed at providing evidence of improvement in glucose metabolism in diabetic mice and healthy humans upon green tea consumption. Results Green tea promoted glucose metabolism in healthy human volunteers at 1.5 g/body in ora...

Wu Jin-Bin; Terasawa Miki; Ishizuka Mitsuyo; Tsuneki Hiroshi; Sasaoka Toshiyasu; Kimura Ikuko

2004-01-01

338

Chemosensitizing and cytotoxic effects of 2-deoxy-D-glucose on breast cancer cells  

Directory of Open Access Journals (Sweden)

Full Text Available Background: Accelerated glucose uptake for anerobic glycolysis is one of the major metabolic changes found in malignant cells. This property has been exploited for imaging malignancies and as a possible anticancer therapy. The nonmetabolizable glucose analog 2-deoxyglucose (2?DG interferes with glucose metabolism leading to breast cancer cell death. Aims: To determine whether 2DG can synergize with chemotherapeutic agents commonly used in breast cancer treatment and identify cellular characteristics associated with sensitivity to 2DG. Materials and Methods: SkBr3 breast cancer cells were incubated with varying concentrations of 5-fluorouracil (5FU, doxorubicin, cisplatin, cyclophosphamide, or herceptin with or without 2DG. Cell viability was measured using the MTT (3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay. Results: Combining 2DG with doxorubicin, 5?FU, cyclophosphamide, and herceptin resulted in enhanced cell death compared with each agent alone, while in combination with cisplatin, the amount of cell death was additive. Mouse embryo fibroblasts (MEF mutated for p53 (-/- were 30% more sensitive to the cytotoxic effects of 2DG than the parental cell lines. Cells mutated for Bax/Bac, genes involved in protection from apoptosis, are slightly more sensitive than the parental cell lines. Conclusions: These results indicate that 2DG acts synergistically with specific chemotherapeutic agents in causing cell death and the class of chemicals most sensitive appear to be those which cause DNA damage.

Zhang Fanjie

2009-09-01

339

Regulators of glucose and lipid metabolism in skeletal muscle and serum : implications for obesity and type 2 diabetes  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Type 2 diabetes mellitus (T2DM) has become a growing worldwide problem of public health importance. Insulin resistance is commonly associated with obesity and a key factor mediating the progression to T2DM. The failure of insulin-sensitive peripheral tissues to respond to insulin results in an increase in serum glucose levels that leads to an impaired homeostatic state. Skeletal muscle plays a crucial role in maintaining glucose metabolism. Impairments in both glucose and lipid metabolism ari...

Mashili, Fredirick

2012-01-01

340

The regulation of cerebral glucose uptake and metabolism in normal and diabetic man  

International Nuclear Information System (INIS)

The effects of changes in serum insulin and glucose on brain glucose metabolism using PET technology were investigated. Eight normal, right-handed, male subjects were studied on three separate occasions at least one week apart. In each subject a PET scan was performed under three different metabolic circumstances: basal conditions after an overnight fast, euglycemic clamp, and hypoglycemic clamp in which the plasma glucose was maintained at 55 mg/dl. Exogenous insulin was infused at the same rate in the euglycemic and hypoglycemic clamp studies. In the latter study, the concomitant glucose infusion rate was reduced to allow the plasma glucose concentration to fall to the desired level of mild hypoglycemia. During each study, dynamic positron emission tomography was used to characterize cerebral uptake and distribution of the Fluorine-18 2-deoxyglucose radiotracer as a function of time. Analysis of the brain uptake curve and tracer input function provided rate constants for transport and phosphorylation in accord with a 3 compartmental model (Sokoloff, 1979). Dynamic scans were performed on each study occasion allowing individual rate constants to be studied. In addition to the brain uptake curves, plasma glucose, F-18 2DG levels and counterregulatory hormone values were determined from frequent arterialized venous blood samples

 
 
 
 
341

Chronic unpredictable stress regulates visceral adipocyte-mediated glucose metabolism and inflammatory circuits in male rats.  

Science.gov (United States)

Chronic psychological stress is a prominent risk factor involved in the pathogenesis of many complex diseases, including major depression, obesity, and type II diabetes. Visceral adipose tissue is a key endocrine organ involved in the regulation of insulin action and an important component in the development of insulin resistance. Here, we examined for the first time the changes on visceral adipose tissue physiology and on adipocyte-associated insulin sensitivity and function after chronic unpredictable stress in rats. Male rats were subjected to chronic unpredictable stress for 35 days. Total body and visceral fat was measured. Cytokines and activated intracellular kinase levels were determined using high-throughput multiplex assays. Adipocyte function was assessed via tritiated glucose uptake assay. Stressed rats showed no weight gain, and their fat/lean mass ratio increased dramatically compared to control animals. Stressed rats had significantly higher mesenteric fat content and epididymal fat pad weight and demonstrated reduced serum glucose clearing capacity following glucose challenge. Alterations in fat depot size were mainly due to changes in adipocyte numbers and not size. High-throughput molecular screening in adipocytes isolated from stressed rats revealed activation of intracellular inflammatory, glucose metabolism, and MAPK networks compared to controls, as well as significantly reduced glucose uptake capacity in response to insulin stimulation. Our study identifies the adipocyte as a key regulator of the effects of chronic stress on insulin resistance, and glucose metabolism, with important ramifications in the pathophysiology of several stress-related disease states. PMID:24819750

Karagiannides, Iordanes; Golovatscka, Viktoriya; Bakirtzi, Kyriaki; Sideri, Aristea; Salas, Martha; Stavrakis, Dimitris; Polytarchou, Christos; Iliopoulos, Dimitrios; Pothoulakis, Charalabos; Bradesi, Sylvie

2014-01-01

342

Insulin resistance for glucose metabolism in disused soleus muscle of mice  

Science.gov (United States)

Results of this study on mice provide the first direct evidence of insulin resistance for glucose metabolism in skeletal muscle that has undergone a previous period of reduced muscle usage. This lack of responsiveness to insulin developed in one day and in the presence of hypoinsulinemia. Future studies will utilize the model of hindlimb immobilization to determine the causes of these changes.

Seider, M. J.; Nicholson, W. F.; Booth, F. W.

1981-01-01

343

Brain Size and Cerebral Glucose Metabolic Rate in Nonspecific Retardation and Down Syndrome.  

Science.gov (United States)

Brain size and cerebral glucose metabolic rate were determined for 10 individuals with mild mental retardation (MR), 7 individuals with Down syndrome (DS), and 10 matched controls. MR and DS groups both had brain volumes of about 80% compared to controls, with variance greatest within the MR group. (SLD)

Haier, Richard J.; And Others

1995-01-01

344

UP-REGULATION OF SUCROSE SYNTHASE AND UDP-GLUCOSE PYROPHOSPHORYLASE IMPACTS PLANT GROWTH AND METABOLISM  

Science.gov (United States)

The effects of over expressing cotton (Gossypium hyrisutum) sucrose synthase (SuSy) and Acetobacter xylinum UDP-glucose pyrophosphorylase (UGPase) genes on plant growth and metabolism were evaluated in tobacco (Nicotiana tabacum cv. Xanthi). T1 transgenic tobacco plants expressing either gene under...

345

Alpha-melanocyte-stimulating hormone is a peripheral, integrative regulator of glucose and fat metabolism.  

Science.gov (United States)

Melanocortins are known to affect feeding and probably insulin activity through the central nervous system. It was also recently shown that peripheral alpha-melanocyte-stimulating hormone (alpha-MSH) administration can reduce weight gain in both genetic and diet-induced obese mice. As obesity is often associated with disregulation of glucose and insulin, we investigated the nature of glucose homeostasis in the obese pro-opiomelanocortin (POMC) knockout mouse. Here we report that though they are obese, mice deficient in POMC (and, thereby, deficient in alpha-MSH) are euglycemic throughout their lives. While these mice are euinsulinemic, they are hypersensitive to exogenous insulin. This defect can be reversed through administration of alpha-MSH. We demonstrate that the actions of alpha-MSH in the periphery, known from our work to include lipid metabolism effects, are also involved in glucose homeostasis. These findings substantiate a pivotal role of the POMC gene products in integrating metabolism. PMID:12851327

Brennan, Miles B; Costa, Jessica Lynn; Forbes, Stacy; Reed, Peggy; Bui, Stephanie; Hochgeschwender, Ute

2003-06-01

346

Glucose metabolism transporters and epilepsy: only GLUT1 has an established role.  

Science.gov (United States)

The availability of glucose, and its glycolytic product lactate, for cerebral energy metabolism is regulated by specific brain transporters. Inadequate energy delivery leads to neurologic impairment. Haploinsufficiency of the glucose transporter GLUT1 causes a characteristic early onset encephalopathy, and has recently emerged as an important cause of a variety of childhood or later-onset generalized epilepsies and paroxysmal exercise-induced dyskinesia. We explored whether mutations in the genes encoding the other major glucose (GLUT3) or lactate (MCT1/2/3/4) transporters involved in cerebral energy metabolism also cause generalized epilepsies. A cohort of 119 cases with myoclonic astatic epilepsy or early onset absence epilepsy was screened for nucleotide variants in these five candidate genes. No epilepsy-causing mutations were identified, indicating that of the major energetic fuel transporters in the brain, only GLUT1 is clearly associated with generalized epilepsy. PMID:24483274

Hildebrand, Michael S; Damiano, John A; Mullen, Saul A; Bellows, Susannah T; Oliver, Karen L; Dahl, Hans-Henrik M; Scheffer, Ingrid E; Berkovic, Samuel F

2014-02-01

347

Clinical significance of determination of serum leptin, insulin levels and blood sugar in pregnant women with glucose metabolism disturbances  

International Nuclear Information System (INIS)

Objective: To investigate the changes of serum leptin, insulin levels and blood sugar contents in pregnant women with gestational glucose metabolism disturbances. Methods: Fasting and 3h after oral 50g glucose serum levels of leptin were measured with RIA in 36 pregnant women with glucose metabolism disturbances (gestational diabetes mellitus or gestational impaired glucose tolerance) and 34 controls. Also, fasting serum insulin levels (with CLIA) and blood sugar contents 1h after oral 50 glucose (with glucose oxidase method) were determined in all these subjects. Results: 1. Serum levels of leptin in pregnant women with glucose metabolism disturbances were 14.9 ± 4.3 ?g/L (vs controls 9.8 ± 1.7 ?g/L, P<0.01). 2. The serum levels of insulin and 1 h post - 50g glucose blood sugar contents in pregnant women with glucose metabolism disturbances were 12.9±4.3mU/L and 11.0±1.4mmol/L respectively, which were both significantly positively correlated with the serum leptin levels (r=0.835, r=0.758 respectively) (vs levels in controls: 8.45±3.0mU/L and 7.84±1.3mmol/L). Conclusion: Elevation of fasting serum levels of leptin was demonstrated in pregnant women with glucose metabolism disturbances and the level of leptin was positively correlated with that of insulin and blood sugar. (authors)

348

Ovarian tumor-initiating cells display a flexible metabolism.  

Science.gov (United States)

An altered metabolism during ovarian cancer progression allows for increased macromolecular synthesis and unrestrained growth. However, the metabolic phenotype of cancer stem or tumor-initiating cells, small tumor cell populations that are able to recapitulate the original tumor, has not been well characterized. In the present study, we compared the metabolic phenotype of the stem cell enriched cell variant, MOSE-LFFLv (TIC), derived from mouse ovarian surface epithelial (MOSE) cells, to their parental (MOSE-L) and benign precursor (MOSE-E) cells. TICs exhibit a decrease in glucose and fatty acid oxidation with a concomitant increase in lactate secretion. In contrast to MOSE-L cells, TICs can increase their rate of glycolysis to overcome the inhibition of ATP synthase by oligomycin and can increase their oxygen consumption rate to maintain proton motive force when uncoupled, similar to the benign MOSE-E cells. TICs have an increased survival rate under limiting conditions as well as an increased survival rate when treated with AICAR, but exhibit a higher sensitivity to metformin than MOSE-E and MOSE-L cells. Together, our data show that TICs have a distinct metabolic profile that may render them flexible to adapt to the specific conditions of their microenvironment. By better understanding their metabolic phenotype and external environmental conditions that support their survival, treatment interventions can be designed to extend current therapy regimens to eradicate TICs. PMID:25172556

Anderson, Angela S; Roberts, Paul C; Frisard, Madlyn I; Hulver, Matthew W; Schmelz, Eva M

2014-10-15

349

High glucose concentrations attenuate hypoxia-inducible factor-1{alpha} expression and signaling in non-tumor cells  

Energy Technology Data Exchange (ETDEWEB)

Hypoxia-inducible factor (HIF) is the major transcription factor mediating adaption to hypoxia e.g. by enhancing glycolysis. In tumor cells, high glucose concentrations are known to increase HIF-1{alpha} expression even under normoxia, presumably by enhancing the concentration of tricarboxylic acid cycle intermediates, while reactions of non-tumor cells are not well defined. Therefore, we analyzed cellular responses to different glucose concentrations in respect to HIF activation comparing tumor to non-tumor cells. Using cells derived from non-tumor origin, we show that HIF-1{alpha} accumulation was higher under low compared to high glucose concentrations. Low glucose allowed mRNA expression of HIF-1 target genes like adrenomedullin. Transfection of C{sub 2}C{sub 12} cells with a HIF-1{alpha} oxygen-dependent degradation domaine-GFP fusion protein revealed that prolyl hydroxylase (PHD) activity is impaired at low glucose concentrations, thus stabilizing the fusion protein. Mechanistic considerations suggested that neither O{sub 2} redistribution nor an altered redox state explains impaired PHD activity in the absence of glucose. In order to affect PHD activity, glucose needs to be metabolized. Amino acids present in the medium also diminished HIF-1{alpha} expression, while the addition of fatty acids did not. This suggests that glucose or amino acid metabolism increases oxoglutarate concentrations, which enhances PHD activity in non-tumor cells. Tumor cells deprived of glutamine showed HIF-1{alpha} accumulation in the absence of glucose, proposing that enhanced glutaminolysis observed in many tumors enables these cells to compensate reduced oxoglutarate production in the absence of glucose.

Dehne, Nathalie, E-mail: dehne@biochem.uni-frankfurt.de [Institute of Biochemistry I/ZAFES (Germany); Hintereder, Gudrun, E-mail: Gudrun.Hintereder@kgu.de [Zentrallabor, Goethe-University, 60590 Frankfurt am Main (Germany); Bruene, Bernhard, E-mail: bruene@pathobiochemie1.de [Institute of Biochemistry I/ZAFES (Germany)

2010-04-15

350

High glucose concentrations attenuate hypoxia-inducible factor-1? expression and signaling in non-tumor cells  

International Nuclear Information System (INIS)

Hypoxia-inducible factor (HIF) is the major transcription factor mediating adaption to hypoxia e.g. by enhancing glycolysis. In tumor cells, high glucose concentrations are known to increase HIF-1? expression even under normoxia, presumably by enhancing the concentration of tricarboxylic acid cycle intermediates, while reactions of non-tumor cells are not well defined. Therefore, we analyzed cellular responses to different glucose concentrations in respect to HIF activation comparing tumor to non-tumor cells. Using cells derived from non-tumor origin, we show that HIF-1? accumulation was higher under low compared to high glucose concentrations. Low glucose allowed mRNA expression of HIF-1 target genes like adrenomedullin. Transfection of C2C12 cells with a HIF-1? oxygen-dependent degradation domaine-GFP fusion protein revealed that prolyl hydroxylase (PHD) activity is impaired at low glucose concentrations, thus stabilizing the fusion protein. Mechanistic considerations suggested that neither O2 redistribution nor an altered redox state explains impaired PHD activity in the absence of glucose. In order to affect PHD activity, glucose needs to be metabolized. Amino acids present in the medium also diminished HIF-1? expression, while the addition of fatty acids did not. This suggests that glucose or amino acid metabolism increases oxoglutarate concentrations, which enhances PHD activity in non-tumor cells. Tumor cells deprived of glutamine showed HIF-1? accumulation in the absence of glucose, proposing that enhanced glutaminolysis observed in many tumors enables these cells to compensate reduced oxoglutarate production in the absence of glucose.

351

In study by the Broad Institute and Massachusetts General, new clues about cancer cell metabolism emerge  

Science.gov (United States)

For almost a century, researchers have known that cancer cells have peculiar appetites, devouring glucose in ways that normal cells do not. But glucose uptake may tell only part of cancer’s metabolic story. Researchers from the Broad Institute and Massachusetts General Hospital looked across 60 well-studied cancer cell lines, analyzing which of more than 200 metabolites were consumed or released by the fastest dividing cells. Their research yields the first large-scale atlas of cancer metabolism and points to a key role for the smallest amino acid, glycine, in cancer cell proliferation. Their results appear in the May 25 issue of the journal Science.

352

Glucose and maltose metabolism in MIG1-disrupted and MAL-constitutive strains of Saccharomyces cerevisiae  

DEFF Research Database (Denmark)

The alleviation of glucose control of maltose metabolism brought about by MIG1 disruption was compared to that by MAL overexpression in a haploid Saccharomyces cerevisiae strain. The sugar consumption profiles during cultivation of the wild type, single transformants and a double transformant in a mixed glucose-maltose medium revealed that the MAL-constitutive strains were more alleviated than the single MIG1-disrupted transformant. While all transformants exhibited higher maximum specific growth rates (0.24-0.25 h(-1)) in glucose-maltose mixtures than the wild type strain (0.20 h(-1)), the MAL-constitutive transformants grew even faster (0.27-0.30 h(-1)) in pure glucose medium than the wild type strain (0.24 h(-1)).

Klein, Christopher; Olsson, Lisbeth

1997-01-01

353

Endocrine and metabolic mechanisms linking postpartum glucose with early embryonic and foetal development in dairy cows.  

Science.gov (United States)

Milk and milk solids production per cow is increasing annually in dairy systems. Peak milk production is in early lactation when the uterus and ovary are recovering from the previous pregnancy. The competing processes of milk production and restoration of reproductive function can be at odds, particularly if unique homeorhetic mechanisms that typify early lactation become imbalanced and cows experience metabolic disease. Homeorhesis leads to an increase in the synthesis of glucose that is irreversibly lost to milk lactose. Irreversible loss of glucose during lactation can invoke an endocrine and metabolic state that impinges upon postpartum uterine health, oestrous cyclicity and subsequent establishment of pregnancy. The first 30 days postpartum may be most critical in terms of the impact that metabolites and metabolic hormones have on reproduction. Depressed immune function caused in part by the postpartum metabolic profile leads to a failure in uterine involution and uterine disease. Oestrous cyclicity (interval to first ovulation and subsequent periodicity) is affected by the same hormones and metabolites that control postpartum immune function. Slower growth of the embryo or foetus perhaps explained by the unique metabolic profile during lactation may predispose cows to pregnancy loss. Understanding homeorhetic mechanisms that involve glucose and collectively affect postpartum uterine health, oestrous cyclicity and the establishment of pregnancy should lead to methods to improve postpartum fertility in dairy cows. PMID:24679333

Lucy, M C; Butler, S T; Garverick, H A

2014-05-01

354

Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients  

DEFF Research Database (Denmark)

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS (n=14), MCS (n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers (n=29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 October 2014; doi:10.1038/jcbfm.2014.169.

Stender, Johan; Kupers, Ron

2014-01-01

355

Prevalence Of Metabolic Syndrome In An Urban Population: Tehran Lipid And Glucose Study  

Directory of Open Access Journals (Sweden)

Full Text Available The aim of the present investigation was to determine the prevalence of metabolic syndrome."nMaterials and Methods: Metabolic syndrome was defined by the presence of three or more of the following components: abdominal obesity, hypertriglyceridemia, low HDL-C, high blood pressure, and high fasting glucose."nResults: In this study, 10368 of the adults (4397 men and 5971 women aged 20 years and over, participated in Tehran Lipid and Glucose study. The unadjusted prevalence of metabolic syndrome in the study population was 30.1% (CI 95%: 29.2-31.0, and age-standardized prevalence was 33.7% (CI 95%: 32.8-34.6. The prevalence increased with age in both sexes. Metabolic syndrome was more commonly seen in women than men (42% vs. 24%, p< 0.001. Low HDL-C was the most common metabolic abnormality in both sexes. Except for high FPG, all abnormalities were more common in women than in men (p< 0.001. Most of those with metabolic syndrome had 3 components of the syndrome (58%, 33% had four, and 9% had five"ncomponents."nConclusion: This first report on metabolic syndrome from Iran shows a high"nprevalence of this disorder, imposing serious impacts on health care system. Efforts"non promoting healthy diets, physical activity, and blood pressure control must be"nundertaken.

Azizi F

2003-10-01

356

Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.  

Science.gov (United States)

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPK?. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors. PMID:21576264

Zaugg, Kathrin; Yao, Yi; Reilly, Patrick T; Kannan, Karuppiah; Kiarash, Reza; Mason, Jacqueline; Huang, Ping; Sawyer, Suzanne K; Fuerth, Benjamin; Faubert, Brandon; Kalliomäki, Tuula; Elia, Andrew; Luo, Xunyi; Nadeem, Vincent; Bungard, David; Yalavarthi, Sireesha; Growney, Joseph D; Wakeham, Andrew; Moolani, Yasmin; Silvester, Jennifer; Ten, Annick You; Bakker, Walbert; Tsuchihara, Katsuya; Berger, Shelley L; Hill, Richard P; Jones, Russell G; Tsao, Ming; Robinson, Murray O; Thompson, Craig B; Pan, Guohua; Mak, Tak W

2011-05-15

357

Deoxyglucose method for the estimation of local myocardial glucose metabolism with positron computed tomography  

International Nuclear Information System (INIS)

The deoxyglucose method originally developed for measurements of the local cerebral metabolic rate for glucose has been investigated in terms of its application to studies of the heart with positron computed tomography (PCT) and FDG. Studies were performed in dogs to measure the tissue kinetics of FDG with PCT and by direct arterial-venous sampling. The operational equation developed in our laboratory as an extension of the Sokoloff model was used to analyze the data. The FDG method accurately predicted the true MMRGlc even when the glucose metabolic rate was normal but myocardial blood flow (MBF) was elevated 5 times the control value or when metabolism was reduced to 10% of normal and MBF increased 5 times normal. Improvements in PCT resolution are required to improve the accuracy of the estimates of the rate constants and the MMRGlc

358

Deoxyglucose method for the estimation of local myocardial glucose metabolism with positron computed tomography  

Energy Technology Data Exchange (ETDEWEB)

The deoxyglucose method originally developed for measurements of the local cerebral metabolic rate for glucose has been investigated in terms of its application to studies of the heart with positron computed tomography (PCT) and FDG. Studies were performed in dogs to measure the tissue kinetics of FDG with PCT and by direct arterial-venous sampling. The operational equation developed in our laboratory as an extension of the Sokoloff model was used to analyze the data. The FDG method accurately predicted the true MMRGlc even when the glucose metabolic rate was normal but myocardial blood flow (MBF) was elevated 5 times the control value or when metabolism was reduced to 10% of normal and MBF increased 5 times normal. Improvements in PCT resolution are required to improve the accuracy of the estimates of the rate constants and the MMRGlc.

Ratib, O.; Phelps, M.E.; Huang, S.C.; Henze, E.; Selin, C.E.; Schelbert, H.R.

1981-01-01

359

Effect of ?-radiation on the ratio of [18F]2-fluoro-2-deoxy- D-glucose to glucose utilization in human glioblastoma cells in vitro  

International Nuclear Information System (INIS)

The glucose consumption in tumours in vitro as reflected by uptake of [18F]2-fluoro-2-deoxy-D-glucose (18FDG) using positron emission tomography (PET) is currently under investigation as a measure of tumour response to radiotherapy. The calculation of cerebral metabolic rate of glucose from 18FDG-PET data requires a proportionality factor referred to as the lumped constant. In the present in vitro study, the utilizations of 18FDG and glucose have been measured in a human glioblastoma cell line (86HG-39) as a function of ?-radiation dose with various post-irradiation times and of different fractionation modes. The ratio of utilization of 18FDG to that of glucose (RF/G), assumed to correspond to the lumped constant, was observed to increase 12 and 24 h after single fraction ?-exposure by factors ranging from 1.2 to 1.5 compared with the non-irradiated controls. It decreased after multiple fraction ?-exposure (4 x 2 Gy) by a factor of 0.7 compared with the single fraction schedule (1 x 8 Gy). The results suggest that the affinities of glucose transporters or hexokinase enzyme or both for 18FDG and glucose could be influenced by ?-irradiation in this tumour cell line in vitro. Apparent changes of the glucose consumption determined with PET in human tumours following radiotherapy may, therefore, not be solely due to changes in cellular metabolism or cell number but may also be due to changes iumber but may also be due to changes in RF/G. (author)

360

Glucose metabolism in small subcortical structures in Parkinson's disease  

DEFF Research Database (Denmark)

Evidence from experimental animal models of Parkinson's disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high-resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei.

Borghammer, Per; Hansen, SØren B

2012-01-01