INSULIN SECRETORY RESPONSES AND PHOSPHOLIPID COMPOSITION OF PANCREATIC ISLETS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 涉及胰岛和胰岛素瘤细胞中VIA组磷脂酶A2（iPLA 2）活性的药理学或分子生物学操作的研究表明iPLA 2参与胰岛素分泌。还已经表明，iPLA 2是调节细胞2-溶血磷脂酰胆碱（LPC）水平和花生四烯酸掺入磷脂酰胆碱（PC）的管家酶。我们已经通过同源重组产生了iPLA 2-null小鼠，并报道了它们表现出雄性生育力降低和精子运动缺陷。在这里，我们报告说，胰岛iPLA 2-null小鼠有受损的胰岛素分泌反应D-葡萄糖和毛喉素。电喷雾电离质谱分析表明，来自iPLA 2缺失小鼠的胰岛、脑和其他组织的含花生四烯酸盐的PC种类的丰度与野生型小鼠的几乎相同，并且在来自任何年龄的iPLA 2缺失小鼠的任何组织中均未观察到iPLA 2 mRNA。尽管分离的胰岛的胰岛素分泌异常，但iPLA 2-null和野生型小鼠的空腹和进食血糖浓度在正常情况下基本相同，但iPLA 2-null小鼠在施用多个低剂量的β-细胞毒素链脲佐菌素后比野生型小鼠发展更严重的高血糖症，表明胰岛分泌储备受损。高脂饮食也诱导iPLA 2-null小鼠比野生型小鼠更严重的葡萄糖耐受不良，但PLA 2-null小鼠比喂食高脂饮食的野生型小鼠对外源性胰岛素具有更大的反应性。因此，这些和先前的发现表明，iPLA 2缺失小鼠除了睾丸和巨噬细胞外，还在胰岛中表现出表型异常。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies involving pharmacologic or molecular biologic manipulation of Group VIA phospholipase A2 (iPLA2) activity in pancreatic islets and insulinoma cells suggest that iPLA2 participates in insulin secretion. It has also been suggested that iPLA2 is a housekeeping enzyme that regulates cell 2-lysophosphatidylcholine (LPC) levels and arachidonate incorporation into phosphatidylcholine (PC). We have generated iPLA2-null mice by homologous recombination and have reported that they exhibit reduced male fertility and defective motility of spermatozoa. Here we report that pancreatic islets from iPLA2-null mice have impaired insulin secretory responses to D-glucose and forskolin. Electrospray ionization mass spectrometric analyses indicate that the abundance of arachidonate-containing PC species of islets, brain, and other tissues from iPLA2-null mice is virtually identical to that of wild-type mice, and no iPLA2 mRNA was observed in any tissue from iPLA2-null mice at any age. Despite the insulin secretory abnormalities of isolated islets, fasting and fed blood glucose concentrations of iPLA2-null and wild-type mice are essentially identical under normal circumstances, but iPLA2-null mice develop more severe hyperglycemia than wild-type mice after administration of multiple low doses of the -cell toxin streptozotocin, suggesting an impaired islet secretory reserve. A high fat diet also induces more severe glucose intolerance in iPLA2-null mice than in wild-type mice, but PLA2-null mice have greater responsiveness to exogenous insulin than do wild-type mice fed a high fat diet. These and previous findings thus indicate that iPLA2-null mice exhibit phenotypic abnormalities in pancreatic islets in addition to testes and macrophages.