• Association between GLUT4 Gene Variants and Hemoglobin A1c Levels in Type 2 Diabetes Patients
  • Seyed Mohammad Kasra Esfahani,1 Armin Motevalli Jooybari,2 Kimia Sadat Esfahani,3 Hiva Danesh,4,*
    1. Department of Medical Laboratory Sciences, TeMS.C., Islamic Azad University, Tehran, Iran
    2. Department of Medical Laboratory Sciences, TeMS.C., Islamic Azad University, Tehran, Iran
    3. Department of Medical Laboratory Sciences, TeMS.C., Islamic Azad University, Tehran, Iran
    4. Department of Medical Laboratory Sciences, TeMS.C., Islamic Azad University, Tehran, Iran


  • Introduction: Type 2 diabetes (T2D) is a growing global health concern, with its prevalence rising at an alarming rate worldwide. It results from a complex interaction of genetic, epigenetic, and environmental factors. In recent years, increasing attention has been given to epigenetic mechanisms, such as DNA methylation and histone modifications, which are known to play crucial roles in both the onset and progression of T2D. One of the key genes involved in glucose homeostasis is GLUT4, encoded by the SLC2A4 gene. This glucose transporter is essential for insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Alterations in GLUT4 expression—caused by either genetic polymorphisms or epigenetic dysregulation—can impair glucose transport and contribute to hyperglycemia. Given the central role of GLUT4 in glycemic control, such changes may directly affect hemoglobin A1c (HbA1c) levels, a widely used clinical biomarker that reflects average blood glucose over the preceding 2–3 months. This study aimed to explore the potential association between GLUT4 gene polymorphisms and epigenetic regulation—including histone acetylation—and their impact on HbA1c levels in type 2 diabetes patients.
  • Methods: A systematic search was performed in PubMed, Scopus, and Google Scholar (2010–2025) using keywords related to GLUT4, SNPs, HbA1c, and epigenetic regulation. Original human studies evaluating the association between GLUT4 polymorphisms or epigenetic mechanisms and HbA1c levels in type 2 diabetes patients were included. After screening and eligibility assessment, 20 relevant articles were selected for qualitative synthesis.
  • Results: Maintaining glucose homeostasis relies on tightly regulated hepatic glucose output and glucose uptake by insulin-responsive tissues such as skeletal muscle and adipose tissue. Upon insulin stimulation, signaling cascades involving AKT and PRKCZ facilitate the translocation of GLUT4 to the plasma membrane, enhancing cellular glucose uptake. GLUT4, encoded by the SLC2A4 gene, is central to this mechanism. Notably, SNPs such as rs5418 and rs2654185 have been linked to elevated HbA1c levels, a key clinical biomarker of long-term glycemic control. In a Japanese cohort, individuals carrying the G allele of rs5418 and A allele of rs2654185 exhibited significantly higher HbA1c values. Haplotype analyses further demonstrated that the GA haplotype correlated with increased HbA1c, whereas the AC haplotype was associated with lower levels. These findings underscore the genetic contribution of SLC2A4 variants to glycemic regulation. In addition, experimental data suggest that combined insulin and selenium treatment enhances glucose control via upregulation of PI3K and GLUT4 expression in skeletal muscle. Beyond genetic factors, epigenetic regulation plays a key role. HDAC5 suppresses MEF2-mediated expression of metabolic genes such as PPARGC1A and GLUT4. Its inhibition increases glucose uptake and improves metabolic flexibility. However, interference with intracellular calcium signaling or CamK2 activity may attenuate this response, indicating complex crosstalk between histone acetylation and DNA methylation. Future research should further elucidate the interaction between H3 acetylation and methylation in regulating metabolic genes in skeletal muscle.
  • Conclusion: In conclusion, type 2 diabetes results from a complex interplay of genetic, epigenetic, and environmental factors that critically affect glucose homeostasis. The findings presented here highlight specific genetic variants in the GLUT4 gene, particularly the SNPs rs5418 and rs2654185, which show significant associations with altered HbA1c levels and may contribute to impaired glycemic regulation. Furthermore, epigenetic mechanisms such as histone acetylation—partially regulated by the histone deacetylase HDAC5—play a pivotal role in modulating the expression of key metabolic genes, including GLUT4. The intricate interaction between histone modifications and DNA methylation emphasizes the necessity for further studies to clarify their combined effects on metabolic gene regulation in skeletal muscle. These insights provide a foundation for developing targeted therapeutic strategies aimed at improving glucose control and managing the progression of type 2 diabetes.
  • Keywords: Type 2 Diabetes, GLUT4, HbA1c, SNP, Histone acetylation, DNA methylation