Background In European populations, the NPPB rs198389 single nucleotide polymorphism (SNP) is associated with a reduced risk of type 2 diabetes mellitus (T2DM). We investigated the putative associations between NPPB rs198389, the T2DM risk and quantitative metabolic traits in an Algerian population. Methods The association analysis was performed as a T2DM case–control study (with 78 cases and 645 controls) nested into the ISOR population-based study. Results The NPPB rs198389 SNP was not associated with T2DM (odds ratio (OR) [95% confidence interval (CI)] = 0.73 [0.51–1.04], p = 0.08). However, the C allele was associated with lower fasting plasma insulin levels ( p = 0.05) and a lower homeostatic model assessment insulin resistance index ( p = 0.05) in non-diabetic individuals. Conclusion The NPPB rs198389 SNP might modulate fasting insulin levels in an Algerian population. [ABSTRACT FROM AUTHOR]