Gene-Diet Interactions in Type 2 Diabetes: A Systematic Review of Observational Studies and Clinical Trials.

Type 2 diabetes (T2D) is a multifactorial disorder arising from complex interactions between genetic susceptibility and environmental exposures, including diet. This systematic review aimed to synthesize and critically evaluate evidence on gene-diet interactions in T2D-related phenotypes among adults without diagnosed T2D at baseline. The review was conducted according to PRISMA guidelines and registered in PROSPERO (CRD420251175793). PubMed and Embase were systematically searched for eligible studies published up to November 2025. Observational studies and intervention trials examining interactions between dietary exposures and genetic variants, haplotypes, or genetic risk scores (GRSs) in relation to incident T2D, insulin resistance, glycemic traits, or β-cell function were included. Risk of bias was assessed using study design-specific tools. A total of 61 reports representing 27 unique studies met the eligibility criteria, comprising 30 reports of randomized trials and 31 reports of non-randomized studies. Across studies, 55 Single Nucleotide Polymorphisms (SNPs) in 40 genes were examined, while 11 studies evaluated GRSs. The most frequently studied loci included TCF7L2, ADIPOQ, FTO, IRS1, GIPR and PPM1K. Reported interactions involved dietary patterns, macronutrient composition, dietary fat quality, fiber/whole-grain intake and specific foods, influencing incident T2D, insulin-related traits and glycemic outcomes. However, findings were heterogeneous, frequently inconsistent, and often lacked independent replication. Most randomized and non-randomized studies were judged at high or serious risk of bias. Genetic variation may contribute to interindividual differences in metabolic responses to diet, although robust and reproducible gene-diet interactions remain limited. Larger, well-powered, standardized studies across diverse populations are needed to establish clinically meaningful applications of Precision Nutrition (PN) in T2D prevention.