GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish

TY - JOUR

T1 - GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish

AU - Jiménez-Amilburu, Vanesa

AU - Jong-Raadsen, Susanne

AU - Bakkers, Jeroen

AU - Spaink, Herman P

AU - Marín-Juez, Rubén

N1 - © 2015 Society for Endocrinology.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Genetically Modified

KW - Diabetes Mellitus, Type 2

KW - Diabetic Cardiomyopathies

KW - Disease Models, Animal

KW - Embryo, Nonmammalian

KW - Gene Expression Regulation, Developmental

KW - Glucose Transport Proteins, Facilitative

KW - Heart Failure

KW - Insulin

KW - Metformin

KW - Phenotype

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1530/JOE-14-0539

DO - 10.1530/JOE-14-0539

M3 - Article

C2 - 25326603

SN - 0022-0795

VL - 224

SP - 1

EP - 15

JO - Journal of Endocrinology

JF - Journal of Endocrinology

IS - 1

ER -