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This version published online on July 1, 2004
Endocrinology, doi:10.1210/en.2004-0028
A more recent version of this article appeared on September 1, 2004
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Submitted on January 12, 2004
Accepted on June 22, 2004

Impaired glucose-stimulated insulin secretion, enhanced IP insulin tolerance and increased {beta}-cell mass in mice lacking the p110{gamma} isoform of PI3-kinase

P. E. MacDonald*, J. W. Joseph, D. Yau, J. Diao, Z. Asghar, F. Dai, G. Y. Oudit, M. M. Patel, P. H. Backx, and M. B. Wheeler

University of Toronto, Departments of Physiology and Medicine, Toronto, Canada; Lund University, Department of Molecular and Cellular Physiology, Lund, Sweden; University Health Network Richard Lewar/Heart and Stroke Centre of Excellence, Toronto, Canada

* To whom correspondence should be addressed. E-mail: patrick.macdonald{at}mphy.lu.se.

Phosphoinositide 3-kinase (PI3 kinase) has been implicated in G protein-coupled receptor regulation of pancreatic {beta}-cell growth and glucose-stimulated insulin secretion. The G protein activated p110{gamma} isoform of PI3 kinase was detected in insulinoma cells, mouse islets and human islets. In 7-10 week old mice, knockout of p110{gamma} reduced the plasma insulin response to IP glucose injection and impaired first and second phase glucose-stimulated insulin secretion from pancreata perfused ex vivo. The p110{gamma} -/- mice responded to pre-injection with the glucagon-like peptide-1 receptor agonist exendin 4, such that plasma glucose and insulin responses to IP glucose injection were not different from wild types. Mice lacking p110{gamma} were not diabetic and were only slightly glucose intolerant (IP glucose injection) compared with wild types, in part due to enhanced responsiveness to insulin as determined by an IP insulin tolerance test. Despite severely reduced insulin secretion in these animals, the p110{gamma} -/- mice had greater pancreatic insulin content, and an increased {beta}-cell mass due to {beta}-cell hypertrophy. These surprising results suggest that the G protein-coupled p110{gamma} isoform of PI3 kinase is not central to the development or maintenance of sufficient {beta}-cell mass, but positively regulates glucose-stimulated insulin secretion.




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