We aimed to investigate whether the variant rs5068 within the NPPA locus, previously shown to be associated with ANP levels in plasma, also is associated with incident diabetes. The use of genetic variants should decrease the risk of confounding and reverse causality. Several studies, including our own, have suggested a possible role of natriuretic peptides in etiology of diabetes, however these prospective associations might have been subject to confounding and reverse causality,,. The key finding of this large prospective study is that the carriers of at least one copy of G allele of rs5068, an SNP that was previously shown to be associated with MR-ANP levels in plasma, had lower likelihood of incident diabetes at a follow up of,14 years. Since gene variants are inherited randomly and are not subject to confounding, our data suggest a causal role of the ANP metabolism in diabetes development. The minor allele of rs5068 is associated with higher levels of circulating ANP, as well as with lower BP,. A recent study explored associations between NP system polymorphisms and cardiovascular outcome in a general population with coronary artery disease, demonstrating associations between the rare allele of rs5068 and lower likelihood of hypertension, but also higher circulating NP levels. There is also evidence of association between rs5068 and cardiometabolic protection observed by Cannone and associates, which suggests that this particular single nucleotide polymorphism or genetic loci in linkage disequilibrium might have a protective role via metabolic actions of natriuretic peptides. Cannone and associates managed recently to replicate these findings in a Mediterranean population where carriers of the G allele of rs5068 had lower BP, BMI, and prevalence of hypertension and metabolic syndrome, but found no correlation between rs5068 and T2D after adjusting for BMI. However, since the sample size in this study is relatively small, it warrants replication in larger cohorts. Surprisingly, in our study, the carriers of the minor allele of rs5068 had somewhat higher BMI compared to AA and AG carriers, but we believe that this is due to the small number of minor allele carriers, and this discrepancy was attenuated when using a model where AG+GG alleles were pooled into one variable. Therefore, we do not believe that the actions of rs5068 are mediated by lower BMI. Genetic Rosiridin studies in both animals and humans have established the role of ANP in hypertension, and there is an increasing number of studies suggesting that ANP is involved in glucose metabolism and plays a role in clustering of diabetes and hypertension. The mechanism of Echinacoside action of ANP is not completely understood, but experimental data suggest that low levels of ANP promote future development of insulin resistance and diabetes 
via activation of the renin-angiotensin system which in turn increases oxidative stress and inflammatory response, causes cross-talk between insulin and angiotensin signalling systems, and disturb glucose transporting. ANP infusion has been shown to increase circulating levels of insulin in humans by 50%, and there is evidence of inhibition of glucagon secretion via direct effects on pancreatic b-cells.