Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Abstract

A 1 and A2A receptor subtypes modulate metabolism in adult mammals. This study was designed to determine the role of these receptors in regulating plasma levels of insulin, glucose, and lactate in 20 chronically catheterized fetal sheep (Ͼ0.8 term). In normoxic fetuses (Pa O 2 ϳ24 Torr), systemic blockade of A1 receptors with DPCPX (n ϭ 6) increased plasma concentrations of insulin, glucose, and lactate, but antagonism of A 2A receptors with ZM-241385 (n ϭ 5) had no significant effects. Intravascular administration of adenosine (n ϭ 9) reduced insulin concentrations and elevated glucose and lactate levels. DPCPX (n ϭ 6) augmented the glycemic and lactatemic responses of adenosine. In contrast, ZM241385 (n ϭ 5) virtually abolished adenosine-induced hyperglycemia and hyperlactatemia. Isocapnic hypoxia (Pa O 2 ϳ13 Torr) suppressed insulinemia and enhanced glycemia and lactatemia, but only the hyperglycemia was blunted by blockade of A1 (n ϭ 6) or A2A (n ϭ 6) receptors. We conclude that 1) endogenous adenosine via A1 receptors depresses plasma concentrations of insulin, glucose, and lactate; 2) exogenous adenosine via A2A receptors increases glucose and lactate levels, but these responses are dampened by stimulation of A1 receptors; and 3) hypoxia, which increases endogenous adenosine concentrations, induces hyperglycemia that is partly mediated by activation of A1 and A2A receptors. We predict that adenosine, via A1 receptors, facilitates at least 12% of glucose uptake and utilization in normoxic fetuses. fetus; hypoxia; metabolism; growth; placenta ADENOSINE REGULATES GLUCOSE metabolism in mammals through several mechanisms that include inhibiting insulin secretion by islet cells, altering insulin transduction, and facilitating intracellular glucose transport. Interstitial levels of adenosine increase substantially in hypoxia, hypoglycemia, or heightened cellular metabolism that can occur through intense neuronal activity or skeletal muscle contractions. The physiological effects of adenosine are mediated through activation of G protein-liganded cell surface receptors that are subdivided into four adenosine receptor subtypes: A 1 , A 2A , A 2B , and A 3 (45). These receptors are connected to classical second-messenger pathways that modulate intracellular cAMP production, phospholipase C pathway, and mitogen-activated protein kinases (45,46). With regard to cAMP, stimulation of A 1 receptors, via inhibition of adenylyl cyclase, generally inhibits intracellular cAMP synthesis, while activation of A 2A and A 2B receptors has the opposite effects.Glucose promotes A 1 and A 2A expression in rat cardiac fibroblasts, while insulin suppresses the expression of A 1 and A 2B receptors (11). Insulin also facilitates the equilibrative transcellular movement of adenosine through stimulation of nucleoside transporters in human umbilical vein endothelial cells (37). Adenosine, in turn, inhibits insulin release via activation of islet A 1 receptors (21, 51). Stimulation of A 1 receptors also enhances glucose uptake in tissues thr...

Fall in oxygen tension of culture medium stimulates the adenosinergic signalling of a human T cell line

“…However, we noticed that hypoxia increased the anaerobic glycolysis in CEM cells by significantly increasing the lactate production in the culture medium at 9 and 12 h. This is in agreement with previous observations that, after stimulation, the glucose catabolism in immune cells increased [16] and that inhibitors of glycolysis impaired the function of immune cells whereas inhibitors of oxidative phosphorylation did not [17][18][19]. Our results also fit nicely with a recent report that concludes to a role of hypoxiainduced adenosine via A 2A R in high glucose and lactate plasma levels [20].…”

A 2b Adenosine Receptor Regulates Hyperlipidemia and Atherosclerosis

“…Adenosine can regulate inflammation 6–8 , as well as metabolic processes involved in insulin homeostasis 9–10 , glucose metabolism 11–13 , lipolysis 14–15 and cholesterol synthesis 16 . Of all four adenosine receptors, the A 2b AR has the lowest affinity for adenosine 17 .…”

Adenosine, Adenosine Receptors and Their Role in Glucose Homeostasis and Lipid Metabolism

“…The null mice showed also an enhanced second phase of pancreatic insulin secretion (Johansson et al, 2007a). A recent study by Maeda and Koos (2008), suggested that in adult animals endogenous adenosine reduces plasma concentrations of insulin, glucose, and lactate via the selectively inhibiting A 1 AR. These studies demonstrate that in vivo elimination or inhibition of A1AR has an effect on glucose homeostasis and the effect is contingent upon the length of the diet or the level of obesity.…”

“…Studies have shown that exogenous adenosine signaling through A 2a AR increases gluconeogenesis and glucose release (González‐Benítez et al, 2002; Yasuda et al, 2003; Maeda and Koos, 2008). In fetal sheep, A 2a AR activation increases glucose and lactate levels as a result of the increased endogenous adenosine levels under hypoxic conditions (Table 4; Maeda and Koos, 2008). In rat hepatocytes, gluconeogenesis stimulation was also observed by the activation of A 2a AR with a selective agonist (CGS‐21680) in cAMP‐dependent manner (González‐Benítez et al, 2002).…”

“…The anti‐inflammatory role of adenosine has also been associated with protection of the vasculature in a restenosis like model (Yang et al, 2008) and in improving overall myocardial tone (Law et al, 1988; Guo et al, 2001). It is important to mention that in addition to inflammation, adenosine, and adenosine receptors have been associated with regulation of glucose clearance (Han et al, 1998; Maeda and Koos, 2008; Johnston‐Cox et al, 2012a), lipolysis (Ulrich Schwabe, 1974; Johansson et al, 2008), and fatty liver prevention post‐alcohol intake (Peng et al, 2009), or prevention of liver steatosis post high fat diet (Koupenova et al, 2012), regulation of cholesterol synthesis (Koupenova et al, 2012), or fat deposition (Johnston‐Cox et al, 2012a).…”