Although sodium-glucose co-transporter 1 (SGLT1) has been identified as one of the major SGLT isoforms expressed in the heart, its exact role remains elusive. Evidences using phlorizin, the most common inhibitor of SGLTs, 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 knock-out mouse model, which lacks exon 1. Glucose uptake was similar in cardiomyocytes isolated from SGLT1 knock-out (^Dex1KO) 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 ^Dex1KO mice. Micromolar concentrations of phlorizin had no impact on glucose uptake in either isolated WT or ^Dex1KO-derived cardiomyocytes. However, higher concentrations (1mM) completely inhibited insulin-stimulated glucose transport without affecting insulin signaling nor GLUT4 translocation, independently from cardiomyocyte genotype. Interestingly, we discover that mouse and human hearts expressed a shorter slc5a1 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 slc5a1 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.

中文翻译：

---

了解 SGLT1 在心脏葡萄糖摄取中的贡献的新见解：小鼠和人类中截短形式的证据


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，但其确切作用仍然难以捉摸。使用根皮苷（最常见的 SGLT 抑制剂）的证据表明其在葡萄糖转运中的作用。然而，根皮苷也可能影响通过葡萄糖转运蛋白 (GLUT) 的经典易化扩散，从而使 SGLT1 在心脏总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 敲除小鼠模型评估了 SGLT1 在心脏葡萄糖摄取中的贡献。从 SGLT1 敲除 ( ^{D ex1} KO) 和对照同窝 (WT) 小鼠分离的心肌细胞中，葡萄糖摄取相似，无论是在基础状态、胰岛素还是高血糖下。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^{D ex1} KO 小鼠之间没有差异。微摩尔浓度的根皮苷对分离的 WT 或^{D ex1} KO 衍生心肌细胞中的葡萄糖摄取没有影响。然而，较高浓度 (1mM) 完全抑制胰岛素刺激的葡萄糖转运，而不影响胰岛素信号传导或 GLUT4 易位，与心肌细胞基因型无关。有趣的是，我们发现小鼠和人类心脏表达较短的 slc5a1 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 对总体葡萄糖摄取没有贡献，可能是由于 slc5a1 转录变体的表达所致。 根皮苷对心脏葡萄糖摄取的抑制作用不依赖于 SGLT1，并且可以通过抑制 GLUT 转运蛋白来解释。这些数据为理解 SGLT1 在心脏中的作用开辟了新的视角。