scholarly journals Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ming Yang ◽  
Tamana Darwish ◽  
Pierre Larraufie ◽  
Debra Rimmington ◽  
Irene Cimino ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Glucose Uptake ◽  
Intestinal Cell ◽  
Cell Physiology ◽  
Sequencing Analysis ◽  
Extracellular Acidification ◽  
Type2 Diabetes ◽  
Site Of Action ◽  
Glycolytic Rate ◽  
Hexose Metabolism

AbstractEven though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used intestinal organoids to explore the effects of metformin on intestinal cell physiology. Bulk RNA-sequencing analysis identified changes in hexose metabolism pathways, particularly glycolytic genes. Metformin increased expression of Slc2a1 (GLUT1), decreased expression of Slc2a2 (GLUT2) and Slc5a1 (SGLT1) whilst increasing GLUT-dependent glucose uptake and glycolytic rate as observed by live cell imaging of genetically encoded metabolite sensors and measurement of oxygen consumption and extracellular acidification rates. Metformin caused mitochondrial dysfunction and metformin’s effects on 2D-cultures were phenocopied by treatment with rotenone and antimycin-A, including upregulation of GDF15 expression, previously linked to metformin dependent weight loss. Gene expression changes elicited by metformin were replicated in 3D apical-out organoids and distal small intestines of metformin treated mice. We conclude that metformin affects glucose uptake, glycolysis and GDF-15 secretion, likely downstream of the observed mitochondrial dysfunction. This may explain the effects of metformin on intestinal glucose utilisation and food balance.

scholarly journals Hexose metabolism in pancreatic islets. Inhibition of hexokinase

1984 ◽  
Vol 223 (2) ◽  
pp. 447-453 ◽  
Author(s):  
M H Giroix ◽  
A Sener ◽  
D G Pipeleers ◽  
W J Malaisse
Keyword(s):  
Major Fraction ◽  
Intracellular Space ◽  
Extracellular Glucose ◽  
Low Glucose ◽  
Glucose Phosphorylation ◽  
Metabolic Data ◽  
A Minor ◽  
Glycolytic Rate ◽  
State Content ◽  
Hexose Metabolism

In islet homogenates, hexokinase-like activity (Km 0.05 mM; Vmax. 1.5 pmol/min per islet) accounts for the major fraction of glucose phosphorylation. Yet the rate of glycolysis in intact islets incubated at low glucose concentrations (e.g. 1.7 mM) sufficient to saturate hexokinase only represents a minor fraction of the glycolytic rate observed at higher glucose concentrations. This apparent discrepancy between enzymic and metabolic data may be attributable, in part at least, to inhibition of hexokinase in intact islets. Hexokinase, which is present in both islet and purified B-cell homogenates, is indeed inhibited by glucose 6-phosphate (Ki 0.13 mM) and glucose 1,6-bisphosphate (Ki approx. 0.2 mM), but not by fructose 2,6-bisphosphate. In intact islets, the steady-state content of glucose 6-phosphate (0.26-0.79 pmol/islet) and glucose 1,6-bisphosphate (5-48 fmol/islet) increases, in a biphasic manner, at increasing concentrations of extracellular glucose (up to 27.8 mM). From these measurements and the intracellular space of the islets, it was estimated that the rate of glucose phosphorylation as catalysed by hexokinase represents, in intact islets, no more than 12-24% of its value in islet homogenates.

Sequencing analysis of CpG islands in Bt: SNCA & mitochondrial dysfunction

Mitochondrion ◽  
2015 ◽  
Vol 24 ◽  
pp. S11
Author(s):  
Angelina M. Ditta ◽  
Julie A. Grammatico ◽  
Megan A. Gray ◽  
Sarah J. Jacobson ◽  
Kaitlyn A. Koch ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cpg Islands ◽  
Sequencing Analysis

scholarly journals Insulin activation of lipogenesis in isolated mammary acini from lactating rats fed on a high-fat diet. Evidence that acetyl-CoA carboxylase is a site of action

1987 ◽  
Vol 242 (3) ◽  
pp. 905-911 ◽  
Author(s):  
M R Munday ◽  
D H Williamson
Keyword(s):  
Glucose Uptake ◽  
High Fat Diet ◽  
Acetyl Coa Carboxylase ◽  
High Fat ◽  
Acetyl Coa ◽  
Carboxylase Activity ◽  
Glucose Incorporation ◽  
Site Of Action ◽  
A Site

Feeding lactating rats on high-fat cheese crackers in addition to laboratory chow increased the dietary intake of fat from 2 to 20% of the total weight of food eaten and decreased mammary-gland lipogenesis in vivo by approx. 50%. This lipogenic inhibition was also observed in isolated mammary acini, where it was accompanied by decreased glucose uptake. These inhibitions were completely reversed by incubation with insulin. Insulin had no effect on the rate of glucose transport into acini, nor on pyruvate dehydrogenase activity as estimated by the accumulation of pyruvate and lactate, suggesting that these are not the sites of lipogenic inhibition. Insulin stimulated the incorporation of [1-14C]acetate into lipid in acini from high-fat-fed rats. In the presence of alpha-cyanohydroxycinnamate, a potent inhibitor of mitochondrial pyruvate transport, and with glucose as the sole substrate, neither [1-14C]glucose incorporation into lipid nor glucose uptake were stimulated by insulin. Insulin did stimulate the incorporation of [1-14C]acetate into lipid in the presence of alpha-cyanohydroxycinnamate, and this was accompanied by an increase in glucose uptake by the acini. This indicated that increased glucose uptake was secondary to the stimulation of lipogenesis by insulin, which therefore must occur via activation of a step in the pathway distal to mitochondrial pyruvate transport. Insulin stimulated acetyl-CoA carboxylase activity measured in crude extracts of acini from high-fat-fed rats, restoring it to values close to those of chow-fed controls. The effects of insulin on acetyl-CoA carboxylase activity and lipogenesis were not antagonized by adrenaline or dibutyryl cyclic AMP.

scholarly journals Increased expression of Polδ does not alter the canonical replication program in vivo

2021 ◽  
Vol 6 ◽  
pp. 44
Author(s):  
Róbert Zach ◽  
Antony M. Carr
Keyword(s):  
Cell Biology ◽  
Rare Event ◽  
Replication Initiation ◽  
Cell Physiology ◽  
Moderate Increase ◽  
Sequencing Analysis ◽  
Phase Duration ◽  
Leading Strand ◽  
The Impact

Background: In vitro experiments utilising the reconstituted Saccharomyces cerevisiae eukaryotic replisome indicated that the efficiency of the leading strand replication is impaired by a moderate increase in Polδ concentration. It was hypothesised that the slower rate of the leading strand synthesis characteristic for reactions containing two-fold and four-fold increased concentration of Polδ represented a consequence of a relatively rare event, during which Polδ stochastically outcompeted Polε and, in an inefficient manner, temporarily facilitated extension of the leading strand. Inspired by this observation, we aimed to determine whether similarly increased Polδ levels influence replication dynamics in vivo using the fission yeast Schizosaccharomyces pombe as a model system. Methods: To generate S. pombe strains over-expressing Polδ, we utilised Cre-Lox mediated cassette exchange and integrated one or three extra genomic copies of all four Polδ genes. To estimate expression of respective Polδ genes in Polδ-overexpressing mutants, we measured relative transcript levels of cdc1+, cdc6+ (or cdc6L591G), cdc27+ and cdm1+ by reverse transcription followed by quantitative PCR (RT-qPCR). To assess the impact of Polδ over-expression on cell physiology and replication dynamics, we used standard cell biology techniques and polymerase usage sequencing. Results: We provide an evidence that two-fold and four-fold over-production of Polδ does not significantly alter growth rate, cellular morphology and S-phase duration. Polymerase usage sequencing analysis further indicates that increased Polδ expression does not change activities of Polδ, Polε and Polα at replication initiation sites and across replication termination zones. Additionally, we show that mutants over-expressing Polδ preserve WT-like distribution of replication origin efficiencies. Conclusions: Our experiments do not disprove the existence of opportunistic polymerase switches; however, the data indicate that, if stochastic replacement of Polε for Polδ does occur in vivo, it represents a rare phenomenon that does not significantly influence canonical replication program.

T1924 Mechanisms of Glucose Uptake in Intestinal Cell Lines: Role of GLUT2

2010 ◽  
Vol 138 (5) ◽  
pp. S-607-S-608
Author(s):  
Ye Zheng ◽  
Jeffrey S. Scow ◽  
Judith A. Duenes ◽  
Srivats Madhavan ◽  
Michael G. Sarr
Keyword(s):  
Glucose Uptake ◽  
Cell Lines ◽  
Intestinal Cell ◽  
Intestinal Cell Lines

scholarly journals Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 121
Author(s):  
Federica Rey ◽  
Sara Ottolenghi ◽  
Toniella Giallongo ◽  
Alice Balsari ◽  
Carla Martinelli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Acidification ◽  
Atp Levels ◽  
Transmission Electron ◽  
First Time ◽  
Glycolytic Rate

Existing therapies for Parkinson’s disease (PD) are only symptomatic. As erythropoietin (EPO) is emerging for its benefits in neurodegenerative diseases, here, we test the protective effect driven by EPO in in vitro (SH-SY5Y cells challenged by MPP+) and in vivo (C57BL/6J mice administered with MPTP) PD models. EPO restores cell viability in both protective and restorative layouts, enhancing the dopaminergic recovery. Specifically, EPO rescues the PD-induced damage to mitochondria, as shown by transmission electron microscopy, Mitotracker assay and PINK1 expression. Moreover, EPO promotes a rescue of mitochondrial respiration while markedly enhancing the glycolytic rate, as shown by the augmented extracellular acidification rate, contributing to elevated ATP levels in MPP+-challenged cells. In PD mice, EPO intrastriatal infusion markedly improves the outcome of behavioral tests. This is associated with the rescue of dopaminergic markers and decreased neuroinflammation. This study demonstrates cellular and functional recovery following EPO treatment, likely mediated by the 37 Kda isoform of the EPO-receptor. We report for the first time, that EPO-neuroprotection is exerted through restoring ATP levels by accelerating the glycolytic rate. In conclusion, the redox imbalance and neuroinflammation associated with PD may be successfully treated by EPO.

scholarly journals ARRB1 Regulates Metabolic Reprogramming to Promote Glycolysis in Stem Cell-Like Bladder Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1809
Author(s):  
Kenza Mamouni ◽  
Jeongheun Kim ◽  
Bal L. Lokeshwar ◽  
Georgios Kallifatidis
Keyword(s):  
Bladder Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Metabolic Reprogramming ◽  
Knock Out ◽  
Atp Production ◽  
Protein Levels ◽  
Glycolytic Rate

β-arrestin 1 (ARRB1) is a scaffold protein that regulates signaling downstream of G protein-coupled receptors (GPCRs). In the current work, we investigated the role of ARRB1 in regulating the metabolic preference of cancer stem cell (CSC)-like cells in bladder cancer (BC). We show that ARRB1 is crucial for spheroid formation and tumorigenic potential. Furthermore, we measured mitochondrial respiration, glucose uptake, glycolytic rate, mitochondrial/glycolytic ATP production and fuel oxidation in previously established ARRB1 knock out (KO) cells and corresponding controls. Our results demonstrate that depletion of ARRB1 decreased glycolytic rate and induced metabolic reprogramming towards oxidative phosphorylation. Mechanistically, the depletion of ARRB1 dramatically increased the mitochondrial pyruvate carrier MPC1 protein levels and reduced the glucose transporter GLUT1 protein levels along with glucose uptake. Overexpression of ARRB1 in ARRB1 KO cells reversed the phenotype and resulted in the upregulation of glycolysis. In conclusion, we show that ARRB1 regulates the metabolic preference of BC CSC-like cells and functions as a molecular switch that promotes reprogramming towards glycolysis by negatively regulating MPC1 and positively regulating GLUT1/ glucose uptake. These observations open new therapeutic avenues for targeting the metabolic preferences of cancer stem cell (CSC)-like BC cells.

scholarly journals Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

2020 ◽  
Author(s):  
Ada Admin ◽  
Adam R. Wende ◽  
John C. Schell ◽  
Chae-Myeong Ha ◽  
Mark E. Pepin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Glucose Uptake ◽  
Diabetic Cardiomyopathy ◽  
Transcriptional Repression ◽  
Glucose Transporter ◽  
Glucose Utilization ◽  
Specific Expression ◽  
Transport Chain ◽  
Atp Generation ◽  
Glucose Transporter Glut4

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by <i>O</i>-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct <i>O</i>-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins.<b> </b>These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

scholarly journals Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

2020 ◽  
Author(s):  
Ada Admin ◽  
Adam R. Wende ◽  
John C. Schell ◽  
Chae-Myeong Ha ◽  
Mark E. Pepin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Glucose Uptake ◽  
Diabetic Cardiomyopathy ◽  
Transcriptional Repression ◽  
Glucose Transporter ◽  
Glucose Utilization ◽  
Specific Expression ◽  
Transport Chain ◽  
Atp Generation ◽  
Glucose Transporter Glut4

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by <i>O</i>-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct <i>O</i>-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins.<b> </b>These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

Tu1202 MITOCHONDRIAL DYSFUNCTION ALTERS METABOLISM OF HEPATIC ACYLCARNITINES IN INTESTINAL CELL LINES, HUMAN COLONIC ORGANOIDS, AND IN COLITIS

2020 ◽  
Vol 158 (6) ◽  
pp. S-1017
Author(s):  
Sayaka A. Ogawa ◽  
Sarah A. Smith ◽  
Lillian Chau ◽  
Jie Chen ◽  
Lu G. Tan ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cell Lines ◽  
Intestinal Cell ◽  
Intestinal Cell Lines
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