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Aims Higher levels of brain natriuretic peptide ( BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established. Methods N-terminal of the pro hormone brain natriuretic peptide (NT-pro BNP) was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance ( HOMA- IR), quantitative insulin sensitivity check index ( QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-pro BNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-pro BNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-pro BNP levels on insulin resistance. Results Lower NT-pro BNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors ( P < 0.001 for all four indices). Although the genetic score was strongly related to measured NT-pro BNP levels amongst European Americans ( F statistic = 71.08), we observed no association of genetically determined NT-pro BNP with insulin resistance ( P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-pro BNP). Conclusions In older adults, lower NT-pro BNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study. [ABSTRACT FROM AUTHOR]