The endocrine heart - metabolic actions of atrial natriuretic peptide

Sammanfattning: Abstract The natriuretic peptides (NPs), namely atrial natriuretic peptide (ANP) and bran natriuretic peptide (BNP), which are secreted from cardiomyocytes in response to cardiac wall stress, play a significant role in the regulation of blood pressure, intravascular volume, and cardiac remodeling. Recently, NPs emerged as hormones with metabolic actions such as inhibition of the renin-angiotensin system and inhibition of inflammation, together with lipolysis and adipose tissue browning. Further, cross-sectional studies showed that NPs are reduced in subjects with obesity and insulin resistance, proposing a role of NPs in metabolic disease such as diabetes. In paper I, a prospective study examining the relationship between baseline levels of atrial ANP and BNP, and incident diabetes, we showed that low baseline levels of ANP, but not BNP, predict development of diabetes at follow up 16 years later, in a model adjusted for clinical diabetes risk factors. The individuals in the lowest quartiles of ANP were at greatest risk of developing diabetes at follow-up. In paper II, we sought to explore whether the above-mentioned association is causal by exploring the association between a common genetic variant, rs5068 (previously shown to be associated with higher levels of ANP), and incident diabetes at follow up 14 years later. The study showed that carriers of at least on copy of the G allele of rs5068 had lower likelihood of incident diabetes within 14 years. Since earlier studies demonstrated that ANP inhibits fibroblast growth and slows down proliferative remodeling of the myocardium, paper III aimed to assess the prevalence of left ventricular hypertrophy in a population free from diabetes, by genotype of rs5068. The study demonstrated that the minor allele of rs5068, (previously shown to be associated with higher levels of ANP), was associated with lower prevalence of left ventricular hypertrophy and lower left ventricular mass. Finally, in paper IV, we studied possible mechanistic explanations of ANPs beneficial role in diabetes development. The study demonstrated prospectively that low ANP levels at baseline were associated with higher risk of insulin resistance at follow up 16 years later, which might serve as a mechanistic explanation for the diabetes development, since insulin resistance often precedes diabetes. Further, this study demonstrated that increase in ANP levels was associated with increase in glucose dependent insulinotropic peptide (GIP) post glucose challenge secretion. Since GIP acts as a blood glucose stabilizer, it is possible that ANP’s beneficial effects on diabetes development are incretin dependent.