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Article: Natural history of three late-diagnosed classic Galactosemia patients.

Quelhas, Dulce / Kingma, Sandra D K / Jonckheere, An I / Smeets-Peels, Claudia S / Gomes, Daniel Costa / Duro, José / Oliveira, Anabela / Matthijs, Gert / Steinbusch, Laura K M / Jaeken, Jaak / Rivera, Isabel / Rubio-Gozalbo, Estela

Molecular genetics and metabolism reports

2024 Volume 38, Page(s) 101057

Abstract: The authors report the natural history of three patients with late-diagnosed Classic Galactosemia (CG) (at 16, 19 and 28 years). This was due to a combination of factors: absence of neonatal screening, absence of some typical acute neonatal symptoms, and ...

Abstract	The authors report the natural history of three patients with late-diagnosed Classic Galactosemia (CG) (at 16, 19 and 28 years). This was due to a combination of factors: absence of neonatal screening, absence of some typical acute neonatal symptoms, and negative galactosemia screening. This report underlines the value of neonatal screening and the importance of further diagnostic testing in case of late-onset manifestations.
Language	English
Publishing date	2024-01-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2821908-9
ISSN	2214-4269
ISSN	2214-4269
DOI	10.1016/j.ymgmr.2024.101057
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Article ; Online: Extending inherited metabolic disorder diagnostics with biomarker interaction visualizations.

Slenter, Denise N / Hemel, Irene M G M / Evelo, Chris T / Bierau, Jörgen / Willighagen, Egon L / Steinbusch, Laura K M

Orphanet journal of rare diseases

2023 Volume 18, Issue 1, Page(s) 95

Abstract: Background: Inherited Metabolic Disorders (IMDs) are rare diseases where one impaired protein leads to a cascade of changes in the adjacent chemical conversions. IMDs often present with non-specific symptoms, a lack of a clear genotype-phenotype ... ...

Abstract	Background: Inherited Metabolic Disorders (IMDs) are rare diseases where one impaired protein leads to a cascade of changes in the adjacent chemical conversions. IMDs often present with non-specific symptoms, a lack of a clear genotype-phenotype correlation, and de novo mutations, complicating diagnosis. Furthermore, products of one metabolic conversion can be the substrate of another pathway obscuring biomarker identification and causing overlapping biomarkers for different disorders. Visualization of the connections between metabolic biomarkers and the enzymes involved might aid in the diagnostic process. The goal of this study was to provide a proof-of-concept framework for integrating knowledge of metabolic interactions with real-life patient data before scaling up this approach. This framework was tested on two groups of well-studied and related metabolic pathways (the urea cycle and pyrimidine de-novo synthesis). The lessons learned from our approach will help to scale up the framework and support the diagnosis of other less-understood IMDs. Methods: Our framework integrates literature and expert knowledge into machine-readable pathway models, including relevant urine biomarkers and their interactions. The clinical data of 16 previously diagnosed patients with various pyrimidine and urea cycle disorders were visualized on the top 3 relevant pathways. Two expert laboratory scientists evaluated the resulting visualizations to derive a diagnosis. Results: The proof-of-concept platform resulted in varying numbers of relevant biomarkers (five to 48), pathways, and pathway interactions for each patient. The two experts reached the same conclusions for all samples with our proposed framework as with the current metabolic diagnostic pipeline. For nine patient samples, the diagnosis was made without knowledge about clinical symptoms or sex. For the remaining seven cases, four interpretations pointed in the direction of a subset of disorders, while three cases were found to be undiagnosable with the available data. Diagnosing these patients would require additional testing besides biochemical analysis. Conclusion: The presented framework shows how metabolic interaction knowledge can be integrated with clinical data in one visualization, which can be relevant for future analysis of difficult patient cases and untargeted metabolomics data. Several challenges were identified during the development of this framework, which should be resolved before this approach can be scaled up and implemented to support the diagnosis of other (less understood) IMDs. The framework could be extended with other OMICS data (e.g. genomics, transcriptomics), and phenotypic data, as well as linked to other knowledge captured as Linked Open Data.
MeSH term(s)	Humans ; Metabolic Diseases/diagnosis ; Biomarkers ; Genomics ; Metabolomics/methods ; Pyrimidines
Chemical Substances	Biomarkers ; Pyrimidines
Language	English
Publishing date	2023-04-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2225857-7
ISSN	1750-1172 ; 1750-1172
ISSN (online)	1750-1172
ISSN	1750-1172
DOI	10.1186/s13023-023-02683-9
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Article ; Online: Novel mRNA therapy restores GALT protein and enzyme activity in a zebrafish model of classic galactosemia.

Delnoy, Britt / Haskovic, Minela / Vanoevelen, Jo / Steinbusch, Laura K M / Vos, Esther Naomi / Knoops, Kèvin / Zimmermann, Luc J I / Noga, Marek / Lefeber, Dirk J / Martini, Paolo G V / Coelho, Ana I / Rubio-Gozalbo, Maria Estela

Journal of inherited metabolic disease

2022 Volume 45, Issue 4, Page(s) 748–758

Abstract: Messenger RNA (mRNA) has emerged as a novel therapeutic approach for inborn errors of metabolism. Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a severe deficiency of galactose-1-phosphate:uridylyltransferase (GALT) ... ...

Abstract	Messenger RNA (mRNA) has emerged as a novel therapeutic approach for inborn errors of metabolism. Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a severe deficiency of galactose-1-phosphate:uridylyltransferase (GALT) activity leading to neonatal illness and chronic impairments affecting the brain and female gonads. In this proof of concept study, we used our zebrafish model for CG to evaluate the potential of human GALT mRNA (hGALT mRNA) packaged in two different lipid nanoparticles to restore GALT expression and activity at early stages of development. Both one cell-stage and intravenous single-dose injections resulted in hGALT protein expression and enzyme activity in the CG zebrafish (galt knockout) at 5 days post fertilization (dpf). Moreover, the levels of galactose-1-phosphate (Gal-1-P) and galactonate, metabolites that accumulate because of the deficiency, showed a decreasing trend. LNP-packaged mRNA was effectively translated and processed in the CG zebrafish without signs of toxicity. This study shows that mRNA therapy restores GALT protein and enzyme activity in the CG zebrafish model, and that the zebrafish is a suitable system to test this approach. Further studies are warranted to assess whether repeated injections safely mitigate the chronic impairments of this disease.
MeSH term(s)	Animals ; Female ; Galactose/metabolism ; Galactosemias/diagnosis ; Galactosemias/genetics ; Galactosemias/therapy ; Humans ; Infant, Newborn ; Liposomes ; Nanoparticles ; Nucleotidyltransferases ; RNA, Messenger/genetics ; UTP-Hexose-1-Phosphate Uridylyltransferase/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism
Chemical Substances	Lipid Nanoparticles ; Liposomes ; RNA, Messenger ; Nucleotidyltransferases (EC 2.7.7.-) ; UTP-Hexose-1-Phosphate Uridylyltransferase (EC 2.7.7.10) ; Galactose (X2RN3Q8DNE)
Language	English
Publishing date	2022-05-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	438341-2
ISSN	1573-2665 ; 0141-8955
ISSN (online)	1573-2665
ISSN	0141-8955
DOI	10.1002/jimd.12512
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Article ; Online: Targeted urine metabolomics with a graphical reporting tool for rapid diagnosis of inborn errors of metabolism.

Steinbusch, Laura K M / Wang, Ping / Waterval, Huub W A H / Stassen, Fons A P M / Coene, Karlien L M / Engelke, Udo F H / Habets, Daphna D J / Bierau, Jörgen / Körver-Keularts, Irene M L W

Journal of inherited metabolic disease

2021 Volume 44, Issue 5, Page(s) 1113–1123

Abstract: The current diagnostic work-up of inborn errors of metabolism (IEM) is rapidly moving toward integrative analytical approaches. We aimed to develop an innovative, targeted urine metabolomics (TUM) screening procedure to accelerate the diagnosis of ... ...

Abstract	The current diagnostic work-up of inborn errors of metabolism (IEM) is rapidly moving toward integrative analytical approaches. We aimed to develop an innovative, targeted urine metabolomics (TUM) screening procedure to accelerate the diagnosis of patients with IEM. Urinary samples, spiked with three stable isotope-labeled internal standards, were analyzed for 258 diagnostic metabolites with an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) configuration run in positive and negative ESI modes. The software automatically annotated peaks, corrected for peak overloading, and reported peak quality and shifting. Robustness and reproducibility were satisfactory for most metabolites. Z-scores were calculated against four age-group-matched control cohorts. Disease phenotypes were scored based on database metabolite matching. Graphical reports comprised a needle plot, annotating abnormal metabolites, and a heatmap showing the prioritized disease phenotypes. In the clinical validation, we analyzed samples of 289 patients covering 78 OMIM phenotypes from 12 of the 15 society for the study of inborn errors of metabolism (SSIEM) disease groups. The disease groups include disorders in the metabolism of amino acids, fatty acids, ketones, purines and pyrimidines, carbohydrates, porphyrias, neurotransmitters, vitamins, cofactors, and creatine. The reporting tool easily and correctly diagnosed most samples. Even subtle aberrant metabolite patterns as seen in mild multiple acyl-CoA dehydrogenase deficiency (GAII) and maple syrup urine disease (MSUD) were correctly called without difficulty. Others, like creatine transporter deficiency, are illustrative of IEM that remain difficult to diagnose. We present TUM as a powerful diagnostic screening tool that merges most urinary diagnostic assays expediting the diagnostics for patients suspected of an IEM.
MeSH term(s)	Biomarkers/urine ; Chromatography, High Pressure Liquid/methods ; Humans ; Metabolism, Inborn Errors/diagnosis ; Metabolism, Inborn Errors/urine ; Metabolome ; Metabolomics/methods ; Reproducibility of Results ; Tandem Mass Spectrometry/methods ; Urinalysis/methods
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-05-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	438341-2
ISSN	1573-2665 ; 0141-8955
ISSN (online)	1573-2665
ISSN	0141-8955
DOI	10.1002/jimd.12385
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Article ; Online: Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models.

Haskovic, Minela / Coelho, Ana I / Bierau, Jörgen / Vanoevelen, Jo M / Steinbusch, Laura K M / Zimmermann, Luc J I / Villamor-Martinez, Eduardo / Berry, Gerard T / Rubio-Gozalbo, M Estela

Journal of inherited metabolic disease

2020 Volume 43, Issue 3, Page(s) 392–408

Abstract: Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the ... ...

Abstract	Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.
MeSH term(s)	Animals ; Disease Models, Animal ; Galactokinase/genetics ; Galactokinase/metabolism ; Galactose/metabolism ; Galactosemias/genetics ; Galactosemias/metabolism ; Galactosemias/physiopathology ; Galactosemias/therapy ; Genotype ; Humans ; Oxidative Stress ; Phenotype ; UDPglucose 4-Epimerase/genetics ; UDPglucose 4-Epimerase/metabolism ; UTP-Hexose-1-Phosphate Uridylyltransferase/genetics ; UTP-Hexose-1-Phosphate Uridylyltransferase/metabolism
Chemical Substances	Galactokinase (EC 2.7.1.6) ; UTP-Hexose-1-Phosphate Uridylyltransferase (EC 2.7.7.10) ; UDPglucose 4-Epimerase (EC 5.1.3.2) ; Galactose (X2RN3Q8DNE)
Language	English
Publishing date	2020-01-14
Publishing country	United States
Document type	Journal Article ; Systematic Review
ZDB-ID	438341-2
ISSN	1573-2665 ; 0141-8955
ISSN (online)	1573-2665
ISSN	0141-8955
DOI	10.1002/jimd.12202
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Article ; Online: Sex-Specific Control of Fat Mass and Counterregulation by Hypothalamic Glucokinase.

Steinbusch, Laura K M / Picard, Alexandre / Bonnet, Marion S / Basco, Davide / Labouèbe, Gwenaël / Thorens, Bernard

Diabetes

2016 Volume 65, Issue 10, Page(s) 2920–2931

Abstract: Glucokinase (Gck) is a critical regulator of glucose-induced insulin secretion by pancreatic β-cells. It has been suggested to also play an important role in glucose signaling in neurons of the ventromedial hypothalamic nucleus (VMN), a brain nucleus ... ...

Abstract	Glucokinase (Gck) is a critical regulator of glucose-induced insulin secretion by pancreatic β-cells. It has been suggested to also play an important role in glucose signaling in neurons of the ventromedial hypothalamic nucleus (VMN), a brain nucleus involved in the control of glucose homeostasis and feeding. To test the role of Gck in VMN glucose sensing and physiological regulation, we studied mice with genetic inactivation of the Gck gene in Sf1 neurons of the VMN (Sf1Gck(-/-) mice). Compared with control littermates, Sf1Gck(-/-) mice displayed increased white fat mass and adipocyte size, reduced lean mass, impaired hypoglycemia-induced glucagon secretion, and a lack of parasympathetic and sympathetic nerve activation by neuroglucopenia. However, these phenotypes were observed only in female mice. To determine whether Gck was required for glucose sensing by Sf1 neurons, we performed whole-cell patch clamp analysis of brain slices from control and Sf1Gck(-/-) mice. Absence of Gck expression did not prevent the glucose responsiveness of glucose-excited or glucose-inhibited Sf1 neurons in either sex. Thus Gck in the VMN plays a sex-specific role in the glucose-dependent control of autonomic nervous activity; this is, however, unrelated to the control of the firing activity of classical glucose-responsive neurons.
MeSH term(s)	Adipocytes/cytology ; Adipocytes/drug effects ; Adipocytes/metabolism ; Animals ; Female ; Glucagon/metabolism ; Glucokinase/genetics ; Glucokinase/metabolism ; Glucose/pharmacology ; Homeostasis/drug effects ; Hypothalamus/cytology ; Hypothalamus/enzymology ; Hypothalamus/metabolism ; Male ; Mice ; Mice, Mutant Strains ; Neurons/cytology ; Neurons/drug effects ; Neurons/metabolism ; Patch-Clamp Techniques ; Ventromedial Hypothalamic Nucleus/cytology ; Ventromedial Hypothalamic Nucleus/enzymology ; Ventromedial Hypothalamic Nucleus/metabolism
Chemical Substances	Glucagon (9007-92-5) ; Glucokinase (EC 2.7.1.2) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db15-1514
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Article ; Online: CD36 as a target to prevent cardiac lipotoxicity and insulin resistance.

Glatz, Jan F C / Angin, Yeliz / Steinbusch, Laura K M / Schwenk, Robert W / Luiken, Joost J F P

Prostaglandins, leukotrienes, and essential fatty acids

2013 Volume 88, Issue 1, Page(s) 71–77

Abstract: The fatty acid transporter and scavenger receptor CD36 is increasingly being implicated in the pathogenesis of insulin resistance and its progression towards type 2 diabetes and associated cardiovascular complications. The redistribution of CD36 from ... ...

Abstract	The fatty acid transporter and scavenger receptor CD36 is increasingly being implicated in the pathogenesis of insulin resistance and its progression towards type 2 diabetes and associated cardiovascular complications. The redistribution of CD36 from intracellular stores to the plasma membrane is one of the earliest changes occurring in the heart during diet induced obesity and insulin resistance. This elicits an increased rate of fatty acid uptake and enhanced incorporation into triacylglycerol stores and lipid intermediates to subsequently interfere with insulin-induced GLUT4 recruitment (i.e., insulin resistance). In the present paper we discuss the potential of CD36 to serve as a target to rectify abnormal myocardial fatty acid uptake rates in cardiac lipotoxic diseases. Two approaches are described: (i) immunochemical inhibition of CD36 present at the sarcolemma and (ii) interference with the subcellular recycling of CD36. Using in vitro model systems of high-fat diet induced insulin resistance, the results indicate the feasibility of using CD36 as a target for adaptation of cardiac metabolic substrate utilization. In conclusion, CD36 deserves further attention as a promising therapeutic target to redirect fatty acid fluxes in the body.
MeSH term(s)	Animals ; Biological Transport/drug effects ; CD36 Antigens/chemistry ; CD36 Antigens/metabolism ; Diabetic Cardiomyopathies/metabolism ; Diabetic Cardiomyopathies/prevention & control ; Heart/drug effects ; Humans ; Insulin Resistance ; Lipid Metabolism/drug effects ; Lipotropic Agents/pharmacology ; Lipotropic Agents/therapeutic use ; Membrane Transport Modulators/pharmacology ; Membrane Transport Modulators/therapeutic use ; Molecular Targeted Therapy ; Myocardium/metabolism
Chemical Substances	CD36 Antigens ; Lipotropic Agents ; Membrane Transport Modulators
Language	English
Publishing date	2013-01
Publishing country	Scotland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	286714-x
ISSN	1532-2823 ; 0952-3278
ISSN (online)	1532-2823
ISSN	0952-3278
DOI	10.1016/j.plefa.2012.04.009
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Article ; Online: Palmitate-Induced Vacuolar-Type H

Liu, Yilin / Steinbusch, Laura K M / Nabben, Miranda / Kapsokalyvas, Dimitris / van Zandvoort, Marc / Schönleitner, Patrick / Antoons, Gudrun / Simons, Peter J / Coumans, Will A / Geomini, Amber / Chanda, Dipanjan / Glatz, Jan F C / Neumann, Dietbert / Luiken, Joost J F P

Diabetes

2017 Volume 66, Issue 6, Page(s) 1521–1534

Abstract: Dietary fat overconsumption leads to myocardial lipid accumulation through mechanisms that are incompletely resolved. Previously, we identified increased translocation of the fatty acid transporter CD36 from its endosomal storage compartment to the ... ...

Abstract	Dietary fat overconsumption leads to myocardial lipid accumulation through mechanisms that are incompletely resolved. Previously, we identified increased translocation of the fatty acid transporter CD36 from its endosomal storage compartment to the sarcolemma as the primary mechanism of excessive myocellular lipid import. Here, we show that increased CD36 translocation is caused by alkalinization of endosomes resulting from inhibition of proton pumping activity of vacuolar-type H
MeSH term(s)	Animals ; Blotting, Western ; CD36 Antigens/metabolism ; Carbon Radioisotopes ; Cells, Cultured ; Deoxyglucose/metabolism ; Diet, High-Fat ; Endosomes/drug effects ; Endosomes/metabolism ; Glucose/metabolism ; Heart/drug effects ; Humans ; Hydrogen-Ion Concentration ; Induced Pluripotent Stem Cells ; Insulin Resistance ; Male ; Myocardial Contraction/drug effects ; Myocardium/metabolism ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myosin Heavy Chains/genetics ; Palmitates/pharmacology ; RNA, Messenger/metabolism ; Rats ; Rats, Inbred Lew ; Triglycerides/metabolism ; Tritium ; Troponin T/genetics ; Vacuolar Proton-Translocating ATPases/antagonists & inhibitors
Chemical Substances	CD36 Antigens ; Carbon Radioisotopes ; Palmitates ; RNA, Messenger ; Triglycerides ; Troponin T ; Tritium (10028-17-8) ; Deoxyglucose (9G2MP84A8W) ; Vacuolar Proton-Translocating ATPases (EC 3.6.1.-) ; Myosin Heavy Chains (EC 3.6.4.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2017-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db16-0727
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Article ; Online: Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes.

Steinbusch, Laura K M / Schwenk, Robert W / Ouwens, D Margriet / Diamant, Michaela / Glatz, Jan F C / Luiken, Joost J F P

Cellular and molecular life sciences : CMLS

2011 Volume 68, Issue 15, Page(s) 2525–2538

Abstract: Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored ... ...

Abstract	Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy.
MeSH term(s)	Animals ; CD36 Antigens/metabolism ; Fatty Acids/metabolism ; Glucose/metabolism ; Glucose Transporter Type 4/metabolism ; Humans ; Intracellular Space/metabolism ; Models, Biological ; Myocytes, Cardiac/metabolism ; Protein Transport
Chemical Substances	CD36 Antigens ; Fatty Acids ; Glucose Transporter Type 4 ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2011-05-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-011-0690-x
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Article ; Online: Overexpression of AMP-activated protein kinase or protein kinase D prevents lipid-induced insulin resistance in cardiomyocytes.

Steinbusch, Laura K M / Dirkx, Ellen / Hoebers, Nicole T H / Roelants, Veronique / Foretz, Marc / Viollet, Benoit / Diamant, Michaela / van Eys, Guillaume / Ouwens, D Margriet / Bertrand, Luc / Glatz, Jan F C / Luiken, Joost J F P

Journal of molecular and cellular cardiology

2013 Volume 55, Page(s) 165–173

Abstract: During lipid oversupply, the heart becomes insulin resistant, as exemplified by defective insulin-stimulated glucose uptake, and will develop diastolic dysfunction. In the healthy heart, not only insulin, but also increased contractile activity ... ...

Abstract	During lipid oversupply, the heart becomes insulin resistant, as exemplified by defective insulin-stimulated glucose uptake, and will develop diastolic dysfunction. In the healthy heart, not only insulin, but also increased contractile activity stimulates glucose uptake. Upon increased contraction both AMP-activated protein kinase (AMPK) and protein kinase D (PKD) are activated, and mediate the stimulation of glucose uptake into cardiomyocytes. Therefore, each of these kinases is a potential therapeutic target in the diabetic heart because they may serve to bypass defective insulin-stimulated glucose uptake. To test the preventive potential of these kinases against loss of insulin-stimulated glucose uptake, AMPK or PKD were adenovirally overexpressed in primary cultures of insulin resistant cardiomyocytes for assaying substrate uptake, insulin responsiveness and lipid accumulation. To induce insulin resistance and lipid loading, rat primary cardiomyocytes were cultured in the presence of high insulin (100 nM; HI) or high palmitate (palmitate/BSA: 3/1; HP). HI and HP each reduced insulin responsiveness, and increased basal palmitate uptake and lipid storage. Overexpression of each of the kinases prevented loss of insulin-stimulated glucose uptake. Overexpression of AMPK also prevented loss of insulin signaling in HI- and HP-cultured cardiomyocytes, but did not prevent lipid accumulation. In contrast, overexpression of PKD prevented lipid accumulation, but not loss of insulin signaling in HI- and HP-cultured cardiomyocytes. In conclusion, AMPK and PKD prevent loss of insulin-stimulated glucose uptake into cardiomyocytes cultured under insulin resistance-inducing conditions through different mechanisms. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".
MeSH term(s)	AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Animals ; Gene Expression ; Glucose/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Insulin/metabolism ; Insulin Resistance/genetics ; Lipid Metabolism ; Male ; Myocytes, Cardiac/metabolism ; Palmitates/metabolism ; Protein Kinase C/genetics ; Protein Kinase C/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Signal Transduction
Chemical Substances	Insulin ; Palmitates ; protein kinase D (EC 2.7.10.-) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Protein Kinase C (EC 2.7.11.13) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2013-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2012.11.005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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