Introduction: The multifunctional glycoprotein Fetuin-A, encoded by the alpha-2-Heremans-Schmid glycoprotein (AHSG) gene, is highly implicated in insulin resistance and Type 2 Diabetes Mellitus (T2DM). As a hepatokine, Fetuin-A regulates systemic inflammation, lipid metabolism, and insulin receptor signaling. Genetic variants of the AHSG gene alter plasma Fetuin-A concentrations, thereby modulating an individual's susceptibility to metabolic syndrome and T2DM. This review provides an in-depth analysis of the genetic link between circulating Fetuin-A levels and T2DM risk, with a specific focus on the Indian population. Methodology: The Scopus, PubMed, and Web of Science databases, alongside the Google Scholar search engine, were queried to retrieve relevant literature. Search terms included: “Fetuin-A and T2DM,” “Fetuin-A gene variants and T2DM,” “Fetuin-A gene variants and circulating Fetuin-A,” “circulating Fetuin-A and T2DM,” “AHSG gene variants and T2DM,” and “genetic link between Fetuin-A and T2DM in Indian Population.” The review included genome-wide association studies (GWAS), original research, case-control studies, and case-cohort studies. Eligibility was restricted to full-text articles published in English up to the end of February 2026. Results: A total of 493 articles were initially retrieved; of these, 13 met the inclusion criteria for this systematic narrative review. The analysis revealed that the most frequently studied AHSG variants—rs4917, rs4918, rs248, rs256, rs2518136, rs2248690, rs6809265, rs2070633, and rs2070635—have been evaluated across diverse ethnic populations. Conclusion: The AHSG Thr256Ser (rs4918) single nucleotide polymorphism (SNP) is associated with T2DM in South Indian populations. Specifically, the mutant GG genotype of rs4918 appears to correlate with reduced circulating Fetuin-A levels. Conversely, elevated systemic Fetuin-A is strongly associated with insulin resistance and incident T2DM, suggesting that circulating Fetuin-A may serve as a viable predictive biomarker for the development of diabetes.
Khan et al. (Thu,) studied this question.