Objective: To examine mechanisms by which consanguinity might increase the risk of type 2 diabetes (T2D) in a Saudi population. Methodology: 362 adult male participants were recruited, 179 were T2D patients and 183 healthy siblings. T2D severity was assessed in patients by recording age at diagnosis. In healthy subjects, diabetes risk was studied by measuring the body mass index, fasting blood glucose (FBG) level, and waist circumference. Extended pedigrees were constructed to calculate inbreeding coefficients. To account for tribal relatedness degrees reported in the constructed pedigrees, assumed inbreeding coefficients for tribal relatedness were added to the calculated inbreeding coefficients. A total of 23 SNPs associated with a higher risk of T2D were genotyped. Results: A significant inverse association was detected between inbreeding coefficients and age at diagnosis (Spearman's coefficient: -0.186, p = 0.013). In 42 families, we were able to recruit 2 healthy siblings. Pearson's correlation coefficient of FBG between siblings was 0.317 (p = 0.04). The correlation between the siblings' FBG increased with an increasing degree of consanguinity. The effect of consanguinity on the FBG level was further assessed by regression line analysis and by controlling for differences in age, caloric intake, and level of physical activity (β: -0.118, p = 0.024). No significant association between the number of T2D risk alleles and the traits was found. Conclusion: Our findings suggest that consanguinity might increase the risk of T2D by an earlier onset of the disease and by strengthening possible genetic effects on FBG.

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