Comprehensive Review of the Role of Homocysteine in Insulin Resistance

Homocysteine, a sulfur-containing amino acid, has been increasingly linked to metabolic disturbances, particularly insulin resistance and type 2 diabetes mellitus (T2DM). This review explores the relationship between elevated homocysteine levels and impaired insulin sensitivity by synthesizing evidence from epidemiological, mechanistic, and genetic studies. A structured literature search was conducted using PubMed, Scopus, and Google Scholar, following PRISMA guidelines and guided by the PICOT model. Studies published over the past two decades were screened, and 32 met the inclusion criteria after full-text review. Findings indicate a consistent association between hyperhomocysteinemia and insulin resistance, with proposed mechanisms including oxidative stress, endothelial dysfunction, mitochondrial impairment, and direct inhibition of insulin signaling pathways. Mendelian randomization studies further suggest a potential causal relationship. However, intervention trials using vitamin B supplementation have shown mixed results, and weight loss alone does not appear to lower homocysteine levels. Despite its promising role as a biomarker, the clinical relevance of homocysteine in predicting or treating insulin resistance remains uncertain. Further research is needed to determine its utility in risk stratification and therapeutic intervention. Further research is required to determine its utility in risk stratification and therapeutic intervention, and to support the development of health policy guidelines for its application in real practice.