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    • In the present study we also investigated

    2018-11-01

    In the present study we also investigated plasma pro-ANP in acute hyperinsulinemic settings but found that peptide concentrations were unaffected by acute euglycemic hyperinsulinemia before and after bed rest. Early studies investigated circulating concentrations of the mature ANP hormone iunder hyperinsulinemic conditions but reached divergent conclusions in individuals with normal glucose regulation (Clark et al., 1993; Gans et al., 1996; Miller et al., 1993; Nannipieri et al., 2002; Ohno et al., 2001; Trevisan et al., 1990) as well as in individuals with type 2 diabetes Several factors may account for these discordant findings, including different methodology and demographics of the included study subjects, the lack of stability of mature ANP and the high variability among assays quantifying ANP (Clerico et al., 2000). One previous study however quantified circulating proANP concentrations in obese men and reported decreased concentrations of proANP after euglycemic and hyperglycemic hyperinsulinemia, respectively (Pivovarova et al., 2012). In CM-272 to this latter study, the population investigated in the present study were young individuals with a BMI in the low range of what is classified as normal weight. Differential natriuretic peptide clearance in obese and normal weight adults mediated by an increased expression of NPRC, the gene encoding the natriuretic peptide clearance receptor, has been indicated in previous studies (Kovacova et al., 2016) and it is thus possible that also a differential secretion of ANP exists between obese individuals and their normal weight counterparts. Even though the lack of a statistically significant effect does not equal the lack of true biological effect (particularly in small populations such as ours), the changes in plasma proANP concentrations during the two HIECs were extremely small, thus supporting a lack of effect of euglycemic hyperinsulinemia in the present population. Our findings thus discourage the notion of ANP expression being regulated directly or indirectly by plasma insulin in lean individuals but this notion cannot necessarily be extended to an overweight and obese population. Apart from hyperinsulinemia, early stages of insulin resistance are characterized by hyperglycemia as well as a defective suppression of glucagon secretion (Ahrén, 2009; Færch et al., 2016). Therefore, we also investigated the proANP response to manipulations of insulin, glucose, and glucagon in healthy young men. During isolated hyperglucagonemia, i.e., increased plasma glucagon in the presence of somatostatin-induced suppression of other hormones, proANP concentrations remained unaffected, indicating that glucagon per se is not involved in the regulation of cardiac ANP secretion. Surprisingly, a modest decrease in plasma proANP was observed during infusions of glucagon and saline per se. Seeing that the infusion of glucagon alone was accompanied by a glucagon-induced release of glucose (peaking at 6·8mmol/l), which in turn stimulated pronounced insulin release (Hansen et al., 2015), it cannot be rejected that the combination of hyperglucagonemia and hyperinsulinemia may downregulate cardiac ANP expression. Of note, however, the magnitude of the observed decrease in plasma proANP was very modest and may thus not be biologically significant. Therefore, further studies are needed before this notion is convincingly supported. Although our experimental setup was not aimed at investigating the effects of blood glucose, our data do not support the notion of glucose per se being involved in the regulation of ANP secretion, as has recently been suggested (Arora et al., 2016). First, marked hyperglycemia (peaking at 12.5mmol/l), as was observed in isolated hyperglucagonemia due to blockage of endogenous insulin release, did not affect plasma proANP, whereas proANP concentrations decreased during the infusions of saline and glucagon where normoglycemic conditions were present. Second, the middle-aged individuals with a prediabetic state of hyperglycemia, represented by either increased blood glucose in the fasting state or, after an oral glucose challenge, did not exhibit significantly decreased plasma proANP.