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 insulinregulated 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.

Glucose uptake and lipid metabolism are impaired in epicardial adipose tissue from heart failure patients with or without diabetes

“…It is known that the cause/effect relationship between different pathologies can work in both directions; for example, HF can lead to metabolic derangements, such as insulin resistance (37), and systemic insulin resistance was reported to be a risk factor for the development of HF (24). Moreover, myocardial insulin resistance in advanced dilated cardiomyopathy can lead to the subsequent alteration in the insulinsignaling cascade, impairing both glucose uptake and lipolysis (73), as we observed in our study.…”

Glucose Transporters in Cardiac Metabolism and Hypertrophy

“…However, recent studies demonstrate that GLUT12 functions primarily as a basal and insulin independent glucose transporter in the heart (244). GLUT12 deficiency in zebrafish during early development shows sign of heart failure and diabetic phenotype (93). All those data suggest that GLUT12 plays an essential role for basal glucose uptake especially during development.…”

Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy

“…Of the five most significant CpGs, interestingly, two (cg06642177 and cg07786668) have been associated with myocardial infarction 47. The most significant CpG, cg06642177, is located on chromosome 6 near the SLC2A12 gene,48 associated with insulin sensitivity,48 49 heart failure and diabetes50 in animal models. cg07786668, located on chromosome 16, is located in the ZFHX3 gene.…”