Recently a glucose dependent transcriptional regulation of

Recently, a glucose-dependent transcriptional regulation of cardiac ANP purchase Calcium Ionophore I mediated by micro-ribonucleic acid-425 was reported in stem cell-derived cardiomyocytes (Arora et al., 2016). Based on this observation, hyperglycemia may be the mechanism underlying decreased plasma concentrations of ANP and its precursor, proANP, observed in obesity and type 2 diabetes. In support of this, ANP secretion decreases after a meal (Arora et al., 2016; Goetze, 2013), but whether glucose per se, or in conjunction with post-prandial hormones (Jujić et al., 2016), regulates the cardiac ANP expression, remains unclear. Importantly, cardiomyocytes express receptors for both glucagon and insulin and increased plasma concentrations of both hormones are well-known features of obesity and type 2 diabetes (Brubaker and Drucker, 2002; Gammeltoft and Van Obberghen, 1986). Hence, the objective of the present study was to examine the cardiac ANP response to insulin, glucagon and glucose. Specifically, we investigated the effects of increased plasma concentrations of insulin and glucagon in human infusion experiments, where plasma glucose was either clamped or increased. Moreover, we measured circulating peptide concentrations in middle-aged individuals with normal and impaired glucose regulation. As physical inactivity is associated with not only decreased muscle mass but also reduced glucose extraction in skeletal muscle (Biensø et al., 2012), we also examined the ANP response to short-term reduced insulin sensitivity by subjecting healthy humans to a strict bed rest regimen. The mature ANP hormone is however considered unstable under most storage conditions. Hence, we quantified plasma concentrations of the midregional part of N-terminal proANP, a peptide that is co-secreted into the circulation in equimolar amounts with mature ANP and thus considered a robust marker of ANP secretion (Davidson et al., 1995; Hall et al., 1995; Nelesen et al., 1995).
Materials and Methods
Results
Discussion The effects of (supine and head-down) bed rest on ANP concentrations have been examined before. In the circulation, however, ANP has a very short half-life and may mainly represent hemodynamic changes including altered renal elimination. Therefore, the overall decrease in ANP concentrations noted in these early studies was ascribed the cardiovascular changes observed during bed rest (Gauquelin et al., 1996, 1995; Maillet et al., 1994). Bed rest, however, also has profound effects on the metabolic homeostasis and the induction of insulin resistance, including decreased activity of key proteins involved in glucose transport, has been well described (Biensø et al., 2012; Stuart et al., 1988). Hence, in the present study we investigated the bed rest-induced proANP response, as proANP is a much more stable marker of cardiac ANP expression and without the same elimination mechanism in circulation. Decreased insulin sensitivity including glucose-mediated hyperinsulinemia was successfully induced and plasma proANP was significantly decreased after bed rest. Nonetheless, we were not able to detect a significant association between indices of insulin sensitivity and plasma proANP or between the decrease in proANP and the magnitude of the induced insulin resistance in the population in question. The bed rest-induced decrease in plasma proANP concentrations may thus reflect other physiological processes than decreased insulin sensitivity such as plasma volume reduction and cardiac atrophy due to reduced myocardial load in the supine position (Perhonen et al., 2001). To further elucidate the link between circulating markers of ANP expression and insulin resistance, we quantified circulating proANP concentrations in middle-aged men and women with prevalent impaired glucose regulation. We found that individuals with impaired glucose tolerance had similar proANP levels as individuals with normal glucose tolerance. In line with this, proANP concentrations did not differ between individuals with isolated impaired fasting glycemia and individuals with isolated impaired glucose tolerance, and the concentrations were not associated with insulin sensitivity. These findings contrast previous cross-sectional population-based studies reporting lower circulating proANP concentrations in obesity, insulin resistance, and diabetes (Then et al., 2013; Wang et al., 2007). Head-on comparisons with these studies are hampered by the broad clinical spectrum of the syndromes of insulin resistance ranging from obesity over type 2 diabetes to extreme insulin resistance. In the present study, the deteriorated insulin sensitivity induced by bed rest was characterized mainly by an increased insulin response to an oral glucose challenge, whereas the prevalent cases of insulin resistance represented normal to prediabetic states of hyperglycemia and not type 2 diabetes (Færch et al., 2008). These differences notwithstanding, the individuals in the present study were non-obese and with early low-grade insulin resistance, whereas the previous population-based studies included significantly more individuals and a wider range of insulin resistance including overt type 2 diabetes. Taken together, it is therefore conceivable that decreased cardiac ANP secretion may represent a later event in disease progression, where the early stages are not affected or perhaps compensated.