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Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase.
Hunter RW, Hughey CC, Lantier L, Sundelin EI, Peggie M, Zeqiraj E, Sicheri F, Jessen N, Wasserman DH, Sakamoto K
(2018) Nat Med 24: 1395-1406
MeSH Terms: Adenosine Monophosphate, Aminoimidazole Carboxamide, Animals, Base Sequence, Chickens, Disease Models, Animal, Fructose-Bisphosphatase, Glucose, Glucose Intolerance, Homeostasis, Humans, Hypoglycemia, Liver, Metformin, Mice, Inbred C57BL, Mutation, Obesity, Prodrugs, Ribonucleotides
Show Abstract · Added March 26, 2019
Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Using two-site binding models to analyze microscale thermophoresis data.
Tso SC, Chen Q, Vishnivetskiy SA, Gurevich VV, Iverson TM, Brautigam CA
(2018) Anal Biochem 540-541: 64-75
MeSH Terms: Adenosine Monophosphate, Algorithms, Animals, Aptamers, Nucleotide, Binding Sites, Cattle, Kinetics, Models, Molecular, Monte Carlo Method, Mutagenesis, Site-Directed, Phytic Acid, Protein Binding, Recombinant Proteins, beta-Arrestin 2
Show Abstract · Added March 14, 2018
The emergence of microscale thermophoresis (MST) as a technique for determining the dissociation constants for bimolecular interactions has enabled these quantities to be measured in systems that were previously difficult or impracticable. However, most models for analyses of these data featured the assumption of a simple 1:1 binding interaction. The only model widely used for multiple binding sites was the Hill equation. Here, we describe two new MST analytic models that assume a 1:2 binding scheme: the first features two microscopic binding constants (K(1) and K(2)), while the other assumes symmetry in the bivalent molecule, culminating in a model with a single macroscopic dissociation constant (K) and a single factor (α) that accounts for apparent cooperativity in the binding. We also discuss the general applicability of the Hill equation for MST data. The performances of the algorithms on both real and simulated data are assessed, and implementation of the algorithms in the MST analysis program PALMIST is discussed.
Copyright © 2017 Elsevier Inc. All rights reserved.
0 Communities
2 Members
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14 MeSH Terms
Racial differences in resistance to P2Y12 receptor antagonists in type 2 diabetic subjects.
Cleator JH, Duvernay MT, Holinstat M, Colowick NE, Hudson WJ, Song Y, Harrell FE, Hamm HE
(2014) J Pharmacol Exp Ther 351: 33-43
MeSH Terms: Adenosine Monophosphate, Adult, African Americans, Blood Platelets, Diabetes Mellitus, Type 2, Drug Resistance, European Continental Ancestry Group, Female, Humans, Male, Purinergic P2Y Receptor Antagonists
Show Abstract · Added January 20, 2015
Although resistance to the P2Y12 antagonist clopidogrel is linked to altered drug metabolism, some studies suggest that these pharmacokinetic abnormalities only partially account for drug resistance. To circumvent pharmacokinetic complications and target P2Y12 receptor function we applied the direct P2Y12 antagonist 2-methylthio-AMP (2-methylthioadenosine 5'-monophosphate triethylammonium salt) to purified platelets ex vivo. Platelets were purified from healthy and type 2 diabetes mellitus (T2DM) patients and stimulated with thrombin or the selective protease-activated receptor agonists, protease-activated receptor 1-activating peptide (PAR1-AP), or PAR4-AP. Platelet activation as measured by αIIbβ3 activation, and P-selectin expression was monitored in 141 subjects. Our results demonstrate that, compared with healthy subjects, platelets from diabetic patients are resistant to inhibition by 2-methylthio-AMP, demonstrating P2Y12 pharmacodynamic defects among diabetic patients. Inhibition of thrombin-mediated αIIbβ3 activation by 2-methylthio-AMP was lower in diabetic platelets versus healthy platelets. Subgroup analysis revealed a racial difference in the resistance to 2-methylthio-AMP. We found no resistance in platelets from diabetic African Americans; they were inhibited by 2-methylthio-AMP equally as well as platelets from healthy African Americans. In contrast, platelets from Caucasian patients with diabetes were resistant to P2Y12 antagonism compared with healthy Caucasians. Multivariable analysis demonstrated that other variables, such as obesity, age, or gender, could not account for the differential resistance to 2-methylthio-AMP among races. These results suggest that in addition to altered drug metabolism, P2Y12 receptor function itself is altered in the Caucasian diabetic population. The racial difference in platelet function in T2DM is a novel finding, which may lead to differences in treatment as well as new targets for antiplatelet therapy.
Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
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1 Members
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11 MeSH Terms
Hepatic energy state is regulated by glucagon receptor signaling in mice.
Berglund ED, Lee-Young RS, Lustig DG, Lynes SE, Donahue EP, Camacho RC, Meredith ME, Magnuson MA, Charron MJ, Wasserman DH
(2009) J Clin Invest 119: 2412-22
MeSH Terms: Adenosine Diphosphate, Adenosine Monophosphate, Adenosine Triphosphate, Animals, Energy Metabolism, Glucagon, Liver, Male, Mice, Mice, Inbred C57BL, Phosphoenolpyruvate Carboxykinase (GTP), Receptors, Glucagon, Signal Transduction
Show Abstract · Added March 18, 2013
The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor- null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism.
3 Communities
1 Members
0 Resources
13 MeSH Terms
Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells.
Ryzhov S, Zaynagetdinov R, Goldstein AE, Novitskiy SV, Dikov MM, Blackburn MR, Biaggioni I, Feoktistov I
(2008) J Immunol 180: 7212-20
MeSH Terms: Adenosine, Adenosine A2 Receptor Antagonists, Adenosine Monophosphate, Animals, Bone Marrow Cells, Cell Degranulation, Cell Line, Cells, Cultured, Extracellular Signal-Regulated MAP Kinases, Humans, Interleukin-13, Mast Cells, Mice, Mice, Inbred C57BL, Purines, Receptor, Adenosine A2B, Signal Transduction, Vascular Endothelial Growth Factor A, Xanthines, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added December 10, 2013
Pharmacological studies suggest that A(2B) adenosine receptors mediate proinflammatory effects of adenosine in human mast cells in part by up-regulating production of Th2 cytokines and angiogenic factors. This concept has been recently challenged by the finding that mast cells cultured from bone marrow-derived mast cells (BMMCs) of A(2B) knockout mice display an enhanced degranulation in response to FcepsilonRI stimulation. This finding was interpreted as evidence of anti-inflammatory functions of A(2B) receptors and it was suggested that antagonists with inverse agonist activity could promote activation of mast cells. In this report, we demonstrate that genetic ablation of the A(2B) receptor protein has two distinct effects on BMMCs, one is the previously reported enhancement of Ag-induced degranulation, which is unrelated to adenosine signaling; the other is the loss of adenosine signaling via this receptor subtype that up-regulates IL-13 and vascular endothelial growth factor secretion. Genetic ablation of A(2B) receptors had no effect on A(3) adenosine receptor-dependent potentiation of Ag-induced degranulation in mouse BMMCs, but abrogated A(2B) adenosine receptor-dependent stimulation of IL-13 and vascular endothelial growth factor secretion. Adenosine receptor antagonists MRS1706 and DPCPX with known inverse agonist activity at the A(2B) subtype inhibited IL-13 secretion induced by the adenosine analog NECA, but did not mimic the enhanced Ag-induced degranulation observed in A(2B) knockout BMMCs. Thus, our study confirmed the proinflammatory role of adenosine signaling via A(2B) receptors and the anti-inflammatory actions of A(2B) antagonists in mouse BMMCs.
0 Communities
3 Members
0 Resources
20 MeSH Terms
LKB1 and the regulation of malonyl-CoA and fatty acid oxidation in muscle.
Thomson DM, Brown JD, Fillmore N, Condon BM, Kim HJ, Barrow JR, Winder WW
(2007) Am J Physiol Endocrinol Metab 293: E1572-9
MeSH Terms: AMP-Activated Protein Kinases, Acetyl-CoA Carboxylase, Adenosine Monophosphate, Aminoimidazole Carboxamide, Animals, Body Weight, Electric Stimulation, Fatty Acids, Female, Heart, Hypoglycemic Agents, Male, Malonyl Coenzyme A, Mice, Mice, Inbred Strains, Mice, Knockout, Multienzyme Complexes, Muscle Contraction, Muscle, Skeletal, Myocardium, Oxidation-Reduction, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, Recombinant Proteins, Ribonucleotides
Show Abstract · Added October 23, 2017
5'-AMP-activated protein kinase (AMPK), by way of its inhibition of acetyl-CoA carboxylase (ACC), plays an important role in regulating malonyl-CoA levels and the rate of fatty acid oxidation in skeletal and cardiac muscle. In these tissues, LKB1 is the major AMPK kinase and is therefore critical for AMPK activation. The purpose of this study was to determine how the lack of muscle LKB1 would affect malonyl-CoA levels and/or fatty-acid oxidation. Comparing wild-type (WT) and skeletal/cardiac muscle-specific LKB1 knockout (KO) mice, we found that the 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR)-stimulated decrease in malonyl-CoA levels in WT heart and quadriceps muscles was entirely dependent on the presence of LKB1, as was the AICAR-induced increase in fatty-acid oxidation in EDL muscles in vitro, since these responses were not observed in KO mice. Likewise, the decrease in malonyl-CoA levels after muscle contraction was attenuated in KO gastrocnemius muscles, suggesting that LKB1 plays an important role in promoting the inhibition of ACC, likely by activation of AMPK. However, since ACC phosphorylation still increased and malonyl-CoA levels decreased in KO muscles (albeit not to the levels observed in WT mice), whereas AMPK phosphorylation was entirely unresponsive, LKB1/AMPK signaling cannot be considered the sole mechanism for inhibiting ACC during and after muscle activity. Regardless, our results suggest that LKB1 is an important regulator of malonyl-CoA levels and fatty acid oxidation in skeletal muscle.
0 Communities
1 Members
0 Resources
26 MeSH Terms
Gene induction during differentiation of human pulmonary type II cells in vitro.
Wade KC, Guttentag SH, Gonzales LW, Maschhoff KL, Gonzales J, Kolla V, Singhal S, Ballard PL
(2006) Am J Respir Cell Mol Biol 34: 727-37
MeSH Terms: 8-Bromo Cyclic Adenosine Monophosphate, Cell Differentiation, Cells, Cultured, Dexamethasone, Epithelial Cells, Fatty Acid Synthases, Fetal Proteins, Fetus, Gene Expression Profiling, Gene Expression Regulation, Developmental, Glycerol Kinase, Humans, Infant, Infant, Newborn, Lipoprotein Lipase, Lung, Lysosome-Associated Membrane Glycoproteins, Phospholipids, RNA, Messenger, Subcellular Fractions, Time Factors, Transcriptional Activation, Transferases (Other Substituted Phosphate Groups)
Show Abstract · Added January 20, 2015
Mature alveolar type II cells that produce pulmonary surfactant are essential for adaptation to extrauterine life. We profiled gene expression in human fetal lung epithelial cells cultured in serum-free medium containing dexamethasone and cyclic AMP, a treatment that induces differentiation of type II cells. Microarray analysis identified 388 genes that were induced > 1.5-fold by 72 h of hormone treatment. Induced genes represented all categories of molecular function and subcellular location, with increased frequency in the categories of ionic channel, cell adhesion, surface film, lysosome, extracellular matrix, and basement membrane. In time-course experiments, self-organizing map analysis identified a cluster of 17 genes that were slowly but highly induced (5- to approximately 190-fold) and represented four functional categories: surfactant-related (SFTPC, SFTPA, PGC, SFTPB, LAMP3, LPL), regulatory (WIF2, IGF2, IL1RL1, NR4A2, HIF3A), metabolic (MAOA, ADH1B, SEPP1), and transport (SCNN1A, CLDN18, AQP4). Induction of both mRNA and protein for these genes, which included nine newly identified regulated genes, was confirmed, and cellular localization was determined in both fetal and postnatal tissue. Induction of lysosomal-associated membrane protein 3 required both hormones, and expression was localized to limiting membranes of lamellar bodies. Hormone-induced differentiation of human type II cells is associated with genome-wide increased expression of genes with diverse functions.
0 Communities
1 Members
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23 MeSH Terms
Energy state of the liver during short-term and exhaustive exercise in C57BL/6J mice.
Camacho RC, Donahue EP, James FD, Berglund ED, Wasserman DH
(2006) Am J Physiol Endocrinol Metab 290: E405-8
MeSH Terms: Adenosine Diphosphate, Adenosine Monophosphate, Adenosine Triphosphate, Animals, Energy Metabolism, Glucagon, Liver, Male, Mice, Mice, Inbred C57BL, Muscle, Skeletal, Phosphorylation, Physical Exertion, Protein Kinases
Show Abstract · Added March 5, 2013
A portal venous 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion that results in hepatic 5-aminoimidazole-4-carboxamide-1-beta-D-ribosyl-5-monophosphate (ZMP) concentrations of approximately 4 micromol/g liver increases hepatic glycogenolysis and glucose output. ZMP is an AMP analog that mimics the regulatory actions of this nucleotide. The aim of this study was to measure hepatic AMP concentrations in response to increasing energy requirements to test the hypothesis that AMP achieves concentrations during exercise, consistent with a role in stimulation of hepatic glucose metabolism. Male C57BL/6J mice (27.4+/- 0.4 g) were subjected to 35 min of rest [sedentary (SED), n=8], underwent short-term (ST, 35 min) moderate (20 m/min, 5% grade) exercise (n=8), or underwent treadmill exercise under similar conditions but until exhaustion (EXH, n=8). Hepatic AMP concentrations were 0.82+/- 0.05, 1.17+/- 0.11, and 2.52+/- 0.16 micromol/g liver in SED, ST, and EXH mice, respectively (P< 0.05). Hepatic energy charge was 0.66+/- 0.01, 0.58+/- 0.02, and 0.33+/- 0.22 in SED, ST, and EXH mice, respectively (P< 0.05). Hepatic glycogen was 11.6+/- 1.0, 8.8+/- 2.2, and 0.0+/- 0.1 mg/g liver in SED, ST, and EXH mice, respectively (P< 0.05). Hepatic AMPK (Thr(172)) phosphorylation was 1.00+/- 0.14, 1.96+/- 0.16, and 7.44+/- 0.63 arbitrary units in SED, ST, and EXH mice, respectively (P< 0.05). Thus exercise increases hepatic AMP concentrations. These data suggest that the liver is highly sensitive to metabolic demands, as evidenced by dramatic changes in cellular energy indicators (AMP) and sensors thereof (AMP-activated protein kinase). In conclusion, AMP is sensitively regulated, consistent with it having an important role in hepatic metabolism.
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14 MeSH Terms
Developmental regulation of claudin localization by fetal alveolar epithelial cells.
Daugherty BL, Mateescu M, Patel AS, Wade K, Kimura S, Gonzales LW, Guttentag S, Ballard PL, Koval M
(2004) Am J Physiol Lung Cell Mol Physiol 287: L1266-73
MeSH Terms: 1-Methyl-3-isobutylxanthine, 8-Bromo Cyclic Adenosine Monophosphate, Dexamethasone, Endocytosis, Fetus, Gene Expression Regulation, Developmental, Humans, Lung, Membrane Proteins, Sodium Chloride, Tight Junctions
Show Abstract · Added January 20, 2015
Tight junction proteins in the claudin family regulate epithelial barrier function. We examined claudin expression by human fetal lung (HFL) alveolar epithelial cells cultured in medium containing dexamethasone, 8-bromo-cAMP, and isobutylmethylxanthanine (DCI), which promotes alveolar epithelial cell differentiation to a type II phenotype. At the protein level, HFL cells expressed claudin-1, claudin-3, claudin-4, claudin-5, claudin-7, and claudin-18, where levels of expression varied with culture conditions. DCI-treated differentiated HFL cells cultured on permeable supports formed tight transepithelial barriers, with transepithelial resistance (TER) >1,700 ohm/cm(2). In contrast, HFL cells cultured in control medium without DCI did not form tight barriers (TER <250 ohm/cm(2)). Consistent with this difference in barrier function, claudins expressed by HFL cells cultured in DCI medium were tightly localized to the plasma membrane; however, claudins expressed by HFL cells cultured in control medium accumulated in an intracellular compartment and showed discontinuities in claudin plasma membrane localization. In contrast to claudins, localization of other tight junction proteins, zonula occludens (ZO)-1, ZO-2, and occludin, was not sensitive to HFL cell phenotype. Intracellular claudins expressed by undifferentiated HFL cells were localized to a compartment containing early endosome antigen-1, and treatment of HFL cells with the endocytosis inhibitor monodansylcadaverine increased barrier function. This suggests that during differentiation to a type II cell phenotype, fetal alveolar epithelial cells use differential claudin expression and localization to the plasma membrane to help regulate tight junction permeability.
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1 Members
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11 MeSH Terms
Maintenance of differentiated function of the surfactant system in human fetal lung type II epithelial cells cultured on plastic.
Gonzales LW, Angampalli S, Guttentag SH, Beers MF, Feinstein SI, Matlapudi A, Ballard PL
(2001) Pediatr Pathol Mol Med 20: 387-412
MeSH Terms: 1-Methyl-3-isobutylxanthine, 8-Bromo Cyclic Adenosine Monophosphate, Animals, Cell Culture Techniques, Cell Differentiation, Cells, Cultured, Collagenases, Coloring Agents, Culture Media, Serum-Free, Cyclic AMP, DNA, Complementary, Dexamethasone, Epithelial Cells, Glucocorticoids, Glycoproteins, Humans, Immunoblotting, Immunohistochemistry, Lung, Microscopy, Electron, Oxazines, Phosphatidylcholines, Phosphodiesterase Inhibitors, Phospholipids, Plastics, Precipitin Tests, Proteolipids, Pulmonary Surfactant-Associated Protein A, Pulmonary Surfactant-Associated Protein D, Pulmonary Surfactant-Associated Proteins, Pulmonary Surfactants, RNA, Messenger, Surface-Active Agents, Time Factors, Transfection, Trypsin
Show Abstract · Added January 20, 2015
We report a simplified culture system for human fetal lung type II cells that maintains surfactant expression. Type II cells isolated from explant cultures of hormone-treated lungs (18-22 wk gestation) by collagenase + trypsin digestion were cultured on plastic for 4 days in serum-free medium containing dexamethasone (Dex, 10 nM) + 8-bromo-cAMP (0.1 mM + isobutylmethylxanthine (0.1 mM) or were untreated (control). Surfactant protein (SP) mRNAs decreased markedly in control cells between days 1 and 4 of culture, but mRNA levels were high in treated cells on day) 4 (SP-A, SP-B, SP-C, SP-D; 600%, 100%, 85%, 130% of day 0 content, respectively). Dex or cAMP alone increased SP-B, SP-C, and SP-D mRNAs and together had additive effects. The greatest increase in SP-A mRNA occurred with cAMP alone. Treated cells processed pro-SP-B and pro-SP-C proteins to mature forms and had a higher rate of phosphatidylcholine (PC) synthesis (2-fold) and higher saturation of PC (approximately 34% versus 27%) than controls. Only treated cells maintained secretagogue-responsive phospholipid synthesis. By electron microscopy, the treated cells retained lamellar bodies and extensive microvilli. We conclude that Dex and cAMP additively stimulate expression of surfactant components in isolated fetal type II cells, providing a simplified culture system for investigation of surfactant-related, and perhaps other, type II cell functions.
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36 MeSH Terms