The P2Y1 receptor is involved in the maintenance of glucose homeostasis and in insulin secretion in mice

Pancreatic beta cells express several P2 receptors including P2Y(1) and the modulation of insulin secretion by extracellular nucleotides has suggested that these receptors may contribute to the regulation of glucose homeostasis. To determine whether the P2Y(1) receptor is involved in this process, we performed studies in P2Y(1)-/- mice. In baseline conditions, P2Y(1)-/- mice exhibited a 15 increase in glycemia and a 40 increase in insulinemia, associated with a 10 increase in body weight, pointing to a role of the P2Y(1) receptor in the control of glucose metabolism. Dynamic experiments further showed that P2Y(1)-/- mice exhibited a tendency to glucose intolerance. These features were associated with a decrease in the plasma levels of free fatty acid and triglycerides. When fed a lipids and sucrose enriched diet for 15 weeks, the two genotypes no longer displayed any significant differences. To determine whether the P2Y(1) receptor was directly involved in the control of insulin secretion, experiments were carried out in isolated Langerhans islets. In the presence of high concentrations of glucose, insulin secretion was significantly greater in islets from P2Y(1)-/- mice. Altogether, these results show that the P2Y(1) receptor plays a physiological role in the maintenance of glucose homeostasis at least in part by regulating insulin secretion.