Early Alterations in Glucose Homeostasis Associated with a Family History of Diabetes Mellitus: A Systematic Review and Meta-Analysis

Background and Aims: To evaluate whether the family history of diabetes mellitus (FHD+) is associated with markers of glucose homeostasis in healthy adults. Methods: Studies evaluating adults aged 18 to 60 years without a diagnosis of cardiometabolic disease, and reporting the influence of FHD+ (at least one first-degree relative) on fasting and 2 h postload glucose, and fasting insulin were included. The electronic database MEDLINE (via PubMed) was searched in February 2026 for studies published in English. Results are presented as mean differences with 95% confidence intervals, using random-effects models. Sensitivity analyses were performed considering study design, methodological quality, the definition of FHD+, and participants’ age and sex. Results: Twenty-six studies totaling 3122 individuals were included. Fasting glucose [3.48 (1.34–5.63) mg·dL−1; – = 90%], 2 h postload glucose [4.18 (2.27–6.10) mg·dL−1; I2 = 38%], A1c [0.12 (0.04–0.19)%; – = 67%]; fasting insulin [1.72 (0.97–2.48) µU·mL−1; – = 90%], and HOMA–IR [0.55 (0.42–0.69); – = 70%] were higher (p < 0.001) in individuals with an FHD+. Meta-regression analyses showed no significant associations between mean age or BMI and markers of glucose homeostasis. Findings remained robust across sensitivity and subgroup analyses, with reduced heterogeneity for some outcomes. Conclusions: The available evidence suggests that FHD+ may be associated with markers of impaired glucose homeostasis in healthy adults. However, these results should be interpreted with caution and confirmed in higher-quality prospective studies.