Ferté Laura, Marino Alice, Battault Sylvain, Bultot Laurent, Van Steenbergen Anne, Bol Anne, Cumps Julien, Ginion Audrey, Koepsell Hermann, Dumoutier Laure, Hue Louis, Horman Sandrine, Bertrand Luc, Beauloye Christophe
Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
Center of Molecular Imaging, Radiotherapy and Oncology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
Am J Physiol Heart Circ Physiol. 2021 Feb 1;320(2):H838-H853. doi: 10.1152/ajpheart.00736.2019. Epub 2021 Jan 8.
Although sodium glucose cotransporter 1 (SGLT1) has been identified as one of the major SGLT isoforms expressed in the heart, its exact role remains elusive. Evidence using phlorizin, the most common inhibitor of SGLTs, has suggested its role in glucose transport. However, phlorizin could also affect classical facilitated diffusion via glucose transporters (GLUTs), bringing into question the relevance of SGLT1 in overall cardiac glucose uptake. Accordingly, we assessed the contribution of SGLT1 in cardiac glucose uptake using the SGLT1 knockout mouse model, which lacks exon 1. Glucose uptake was similar in cardiomyocytes isolated from SGLT1-knockout (KO) and control littermate (WT) mice either under basal state, insulin, or hyperglycemia. Similarly, in vivo basal and insulin-stimulated cardiac glucose transport measured by micro-PET scan technology did not differ between WT and KO mice. Micromolar concentrations of phlorizin had no impact on glucose uptake in either isolated WT or KO-derived cardiomyocytes. However, higher concentrations (1 mM) completely inhibited insulin-stimulated glucose transport without affecting insulin signaling nor GLUT4 translocation independently from cardiomyocyte genotype. Interestingly, we discovered that mouse and human hearts expressed a shorter transcript, leading to SGLT1 protein lacking transmembrane domains and residues involved in glucose and sodium bindings. In conclusion, cardiac SGLT1 does not contribute to overall glucose uptake, probably due to the expression of transcript variant. The inhibitory effect of phlorizin on cardiac glucose uptake is SGLT1-independent and can be explained by GLUT transporter inhibition. These data open new perspectives in understanding the role of SGLT1 in the heart. Ever since the discovery of its expression in the heart, SGLT1 has been considered as similar as the intestine and a potential contributor to cardiac glucose transport. For the first time, we have demonstrated that a transcript variant is present in the heart that has no significant impact on cardiac glucose handling.
尽管钠葡萄糖协同转运蛋白1（SGLT1）已被确定为心脏中表达的主要SGLT亚型之一，但其确切作用仍不清楚。使用根皮素（最常见的SGLT抑制剂）的证据表明了其在葡萄糖转运中的作用。然而，根皮素也可能通过葡萄糖转运蛋白（GLUTs）影响经典的易化扩散，这使得SGLT1在心脏整体葡萄糖摄取中的相关性受到质疑。因此，我们使用缺乏外显子1的SGLT1基因敲除小鼠模型评估了SGLT1在心脏葡萄糖摄取中的作用。在基础状态、胰岛素或高血糖条件下，从SGLT1基因敲除（KO）小鼠和对照同窝仔（WT）小鼠分离的心肌细胞中的葡萄糖摄取相似。同样，通过微型PET扫描技术测量的体内基础和胰岛素刺激的心脏葡萄糖转运在WT和KO小鼠之间没有差异。微摩尔浓度的根皮素对分离的WT或KO来源的心肌细胞中的葡萄糖摄取没有影响。然而，更高浓度（1 mM）完全抑制了胰岛素刺激的葡萄糖转运，而不影响胰岛素信号传导，也不独立于心肌细胞基因型影响GLUT4易位。有趣的是，我们发现小鼠和人类心脏表达了一种较短的转录本，导致SGLT1蛋白缺乏跨膜结构域以及参与葡萄糖和钠结合的残基。总之，心脏SGLT1对整体葡萄糖摄取没有贡献，可能是由于转录本变体的表达。根皮素对心脏葡萄糖摄取的抑制作用不依赖于SGLT1，可以通过GLUT转运蛋白抑制来解释。这些数据为理解SGLT1在心脏中的作用开辟了新的视角。自从在心脏中发现其表达以来，SGLT1一直被认为与肠道中的情况相似，是心脏葡萄糖转运的潜在贡献者。我们首次证明，心脏中存在一种转录本变体，对心脏葡萄糖处理没有显著影响。
