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J. Biol. Chem., Vol. 281, Issue 30, 20958-20973, July 28, 2006

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Insulin Secretory Responses and Phospholipid Composition of Pancreatic Islets from Mice That Do Not Express Group VIA Phospholipase A₂ and Effects of Metabolic Stress on Glucose Homeostasis^*

From the Mass Spectrometry Facility and Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110

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.

Received for publication, January 4, 2006 , and in revised form, April 17, 2006.

^* This work was supported by United States Public Health Service Grants R37-DK34388, P01-HL57278, P41-RR00954, P60-DK20579, R01-69455, and P30-DK56341. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental figures.

¹ To whom correspondence should be addressed: Washington University School of Medicine, Campus Box 8127, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8190; Fax: 314-362-7641; E-mail: jturk{at}wustl.edu.

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