A1 receptor deficiency causes increased insulin and glucagon secretion in mice

Adenosine influences metabolism and the adenosine receptor antagonist caffeine decreases the risk of type 2 diabetes. In this study the metabolic role of one adenosine receptor subtype, the adenosine A1R, was evaluated in mice lacking this receptor [A1R (−/−)]. The HbA1c levels and body weight were not significantly different between wild type [A1R (+/+)] and A1R (−/−) mice (3–4 months) fed normal lab chow. At rest, plasma levels of glucose, insulin and glucagon were similar in both genotypes. Following glucose injection, glucose tolerance was not appreciably altered in A1R (−/−) mice. Glucose injection induced sustained increases in plasma insulin and glucagon levels in A1R (−/−) mice, whereas A1R (+/+) control mice reacted with the expected transient increase in insulin and decrease in glucagon levels. Pancreas perfusion experiments showed that A1R (−/−) mice had a slightly higher basal insulin secretion than A1R (+/+) mice. The first phase insulin secretion (initiated with 16.7 mM glucose) was of the same magnitude in both genotypes, but the second phase was significantly enhanced in the A1R (−/−) pancreata compared with A1R (+/+). Insulin- and contraction-mediated glucose uptake in skeletal muscle were not significantly different between in A1R (−/−) and A1R (+/+) mice. All adenosine receptors were expressed at mRNA level in skeletal muscle in A1R (+/+) mice and the mRNA A2AR, A2BR and A3R levels were similar in A1R (−/−) and A1R (+/+) mice. In conclusion, the A1R minimally affects muscle glucose uptake, but is important in regulating pancreatic islet function.