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

被引:51
作者
Léon C. [1 ]
Freund M. [1 ]
Latchoumanin O. [2 ]
Farret A. [2 ]
Petit P. [2 ]
Cazenave J.-P. [2 ]
Gachet C. [1 ]
机构
[1] Inst. Natl. de la Sante/Rech. Med., Etablissement Francais Sang-Alsace, Strasbourg, Cedex
[2] Ctr. Pharmacol. Biotechnol. Sante, CNRS UMR, Institut de Biologie
关键词
Glucose homeostasis; Glycemia; Insulin; Knockout mice; P2Y[!sub]1[!/sub;
D O I
10.1007/s11302-005-6209-x
中图分类号
学科分类号
摘要
Pancreatic β cells express several P2 receptors including P2Y1 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 P2Y1 receptor is involved in this process, we performed studies in P2Y1-/- mice. In baseline conditions, P2Y1-/- 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 P2Y1 receptor in the control of glucose metabolism. Dynamic experiments further showed that P2Y1-/- 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 P2Y1 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 P2Y1-/- mice. Altogether, these results show that the P2Y1 receptor plays a physiological role in the maintenance of glucose homeostasis at least in part by regulating insulin secretion. © Springer 2005.
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页码:145 / 151
页数:6
相关论文
共 38 条
[1]  
Ralevic V., Burnstock G., Receptors for purines and pyrimidines, Pharmacol. Rev., 50, 3, pp. 413-492, (1998)
[2]  
Webb T.E., Simon J., Krishek B.J., Et al., Cloning and functional expression of a brain G-protein-coupled ATP receptor, FEBS Lett., 324, 2, pp. 219-225, (1993)
[3]  
Leon C., Hechler B., Vial C., Et al., The P2Y<sub>1</sub> receptor is an ADP receptor antagonized by ATP and expressed in platelets and megakaryoblastic cells, FEBS Lett., 403, 1, pp. 26-30, (1997)
[4]  
Hechler B., Vigne P., Leon C., Et al., ATP derivatives are antagonists of the P2Y<sub>1</sub> receptor: Similarities to the platelet ADP receptor, Mol. Pharmacol., 53, 4, pp. 727-733, (1998)
[5]  
Gachet C., Identification, characterization, and inhibition of the platelet ADP receptors, Int. J. Hematol., 74, 4, pp. 375-381, (2001)
[6]  
Hollopeter G., Jantzen H.M., Vincent D., Et al., Identification of the platelet ADP receptor targeted by antithrombotic drugs, Nature, 409, 6817, pp. 202-207, (2001)
[7]  
Hechler B., Leon C., Vial C., Et al., The P2Y<sub>1</sub> receptor is necessary for adenosine 5'-diphosphate-induced platelet aggregation, Blood, 92, 1, pp. 152-159, (1998)
[8]  
Jin J., Kunapuli S.P., Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation, Proc. Natl. Acad. Sci. USA, 95, 14, pp. 8070-8074, (1998)
[9]  
Leon C., Hechler B., Freund M., Et al., Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y(1) receptor-null mice, J. Clin. Invest, 104, 12, pp. 1731-1737, (1999)
[10]  
Fabre J.E., Nguyen M., Latour A., Et al., Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y<sub>1</sub> -deficient mice, Nat. Med., 5, 10, pp. 1199-1202, (1999)