title: GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish.
abstract: Cardiomyopathies-associated metabolic pathologies (e.g., type 2 diabetes and insulin resistance) are a leading cause of mortality. It is known that the association between these pathologies works in both directions, for which heart failure can lead to metabolic derangements such as insulin resistance. This intricate crosstalk exemplifies the importance of a fine coordination between one of the most energy-demanding organs and an equilibrated carbohydrate metabolism. In this light, to assist in the understanding of the role of insulin-regulated glucose transporters (GLUTs) and the development of cardiomyopathies, we have developed a model for glut12 deficiency in zebrafish. GLUT12 is a novel insulin-regulated GLUT expressed in the main insulin-sensitive tissues, such as cardiac muscle, skeletal muscle, and adipose tissue. In this study, we show that glut12 knockdown impacts the development of the embryonic heart resulting in abnormal valve formation. Moreover, glut12-deficient embryos also exhibited poor glycemic control. Glucose measurements showed that these larvae were hyperglycemic and resistant to insulin administration. Transcriptome analysis demonstrated that a number of genes known to be important in cardiac development and function as well as metabolic mediators were dysregulated in these larvae. These results indicate that glut12 is an essential GLUT in the heart where the reduction in glucose uptake due to glut12 deficiency leads to heart failure presumably due to the lack of glucose as energy substrate. In addition, the diabetic phenotype displayed by these larvae after glut12 abrogation highlights the importance of this GLUT during early developmental stages.
authors.affiliation: Institute of BiologyLeiden University, PO Box 9502, 2300 RA Leiden, The NetherlandsZF-screens BVJ.H. Oortweg 19, 2333 CH Leiden, The NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht and Interuniversity3584 CT Utrecht, The Netherlands.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Jiménez-Amilburu
authors.affiliation: Institute of BiologyLeiden University, PO Box 9502, 2300 RA Leiden, The NetherlandsZF-screens BVJ.H. Oortweg 19, 2333 CH Leiden, The NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht and Interuniversity3584 CT Utrecht, The Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: Jong-Raadsen
authors.affiliation: Institute of BiologyLeiden University, PO Box 9502, 2300 RA Leiden, The NetherlandsZF-screens BVJ.H. Oortweg 19, 2333 CH Leiden, The NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht and Interuniversity3584 CT Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakkers
authors.affiliation: Institute of BiologyLeiden University, PO Box 9502, 2300 RA Leiden, The NetherlandsZF-screens BVJ.H. Oortweg 19, 2333 CH Leiden, The NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht and Interuniversity3584 CT Utrecht, The Netherlands marinjuez@zfscreens.com h.p.spaink@biology.leidenuniv.nl.
authors.forename: Herman P
authors.initials: HP
authors.lastname: Spaink
authors.affiliation: Institute of BiologyLeiden University, PO Box 9502, 2300 RA Leiden, The NetherlandsZF-screens BVJ.H. Oortweg 19, 2333 CH Leiden, The NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht and Interuniversity3584 CT Utrecht, The Netherlands marinjuez@zfscreens.com h.p.spaink@biology.leidenuniv.nl.
authors.forename: Rubén
authors.initials: R
authors.lastname: Marín-Juez
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000196:embryology / Q000235:genetics*; D058065:Diabetic Cardiomyopathies / Q000150:complications / Q000196:embryology / Q000235:genetics*; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051246:Glucose Transport Proteins, Facilitative / Q000172:deficiency / Q000235:genetics*; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D010641:Phenotype; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; C000595351:SLC2A12 protein, zebrafish; D029961:Zebrafish Proteins; D008687:Metformin
keywords: diabetes; glut12; heart failure; valve dysgenesis; zebrafish