Slc2a4, also known as GLUT4, is a gene encoding the primary glucose transporter in adipose and skeletal muscle tissues [2]. Glucose, an essential fuel for contracting muscle, enters the muscle cell via facilitated diffusion through GLUT4, which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction. This process is part of the complex regulation of muscle glucose uptake, and GLUT4 expression is also increased following exercise, contributing to improved insulin action, glucose disposal, and muscle glycogen storage [1].

In human diseases, dysregulation of Slc2a4 has been associated with various conditions. In type 2 diabetes (T2D), miR-335-5p inhibits SLC2A4 expression, hampering the growth of T2D cell models by inhibiting proliferation and elevating apoptosis, suggesting it as a potential therapeutic target [3]. In obesity and insulin resistance, fatty acid induced hypermethylation in the Slc2a4 gene in visceral adipose tissue is associated with decreased Slc2a4 expression [4]. Also, in breast cancer, SLC2A4 was found to be significantly downregulated, and higher mRNA expression was associated with a better prognosis [5]. In a Chinese population, SLC2A4 gene polymorphisms were associated with gestational diabetes mellitus (GDM) risk, and certain genotype combinations were related to lower GDM risk [6].

In conclusion, Slc2a4 plays a crucial role in glucose metabolism in adipose and skeletal muscle tissues, with its dysregulation linked to diseases like T2D, obesity, insulin resistance, breast cancer, and GDM. Understanding the function of Slc2a4 through in vivo studies, such as those implicating its regulation by miRNAs, DNA methylation, and gene polymorphisms, can provide insights into disease mechanisms and potential therapeutic strategies.

References:

1. Richter, Erik A, Hargreaves, Mark. . Exercise, GLUT4, and skeletal muscle glucose uptake. In Physiological reviews, 93, 993-1017. doi:10.1152/physrev.00038.2012. https://pubmed.ncbi.nlm.nih.gov/23899560/

2. Yuan, Yafei, Kong, Fang, Xu, Hanwen, Yan, Nieng, Yan, Chuangye. 2022. Cryo-EM structure of human glucose transporter GLUT4. In Nature communications, 13, 2671. doi:10.1038/s41467-022-30235-5. https://pubmed.ncbi.nlm.nih.gov/35562357/

3. Li, Geng, Zhang, Linghui. 2021. miR-335-5p aggravates type 2 diabetes by inhibiting SLC2A4 expression. In Biochemical and biophysical research communications, 558, 71-78. doi:10.1016/j.bbrc.2021.04.011. https://pubmed.ncbi.nlm.nih.gov/33901926/

4. Britsemmer, Jan H, Krause, Christin, Taege, Natalie, Mann, Oliver, Kirchner, Henriette. 2023. Fatty Acid Induced Hypermethylation in the Slc2a4 Gene in Visceral Adipose Tissue Is Associated to Insulin-Resistance and Obesity. In International journal of molecular sciences, 24, . doi:10.3390/ijms24076417. https://pubmed.ncbi.nlm.nih.gov/37047391/

5. Shi, Zhenyu, Liu, Jiahao, Wang, Fei, Li, Yongqiang. . Integrated analysis of Solute carrier family-2 members reveals SLC2A4 as an independent favorable prognostic biomarker for breast cancer. In Channels (Austin, Tex.), 15, 555-568. doi:10.1080/19336950.2021.1973788. https://pubmed.ncbi.nlm.nih.gov/34488531/

6. Hu, Shimin, Ma, Shujuan, Li, Xun, Chen, Mengshi, Tan, Hongzhuan. 2019. Relationships of SLC2A4, RBP4, PCK1, and PI3K Gene Polymorphisms with Gestational Diabetes Mellitus in a Chinese Population. In BioMed research international, 2019, 7398063. doi:10.1155/2019/7398063. https://pubmed.ncbi.nlm.nih.gov/30805369/