Impaired glucose-stimulated insulin secretion, enhanced intraperitoneal insulin tolerance, and increased β-cell mass in mice lacking the p110γ isoform of phosphoinositide 3-kinase

Abstract

Phosphoinositide 3-kinase (PI3 kinase) has been implicated in G protein-coupled receptor regulation of pancreatic β-cell growth and glucose-stimulated insulin secretion. The G protein-activated p110γ isoform of PI3 kinase was detected in insulinoma cells, mouse islets, and human islets. In 7- to 10-wk-old mice, knockout of p110γ 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 p110γ -/- mice responded to preinjection 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 p110γ 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 p110γ -/- mice had greater pancreatic insulin content, and an increased β-cell mass due to β-cell hypertrophy. These surprising results suggest that the G protein-coupled p110γ isoform of PI3 kinase is not central to the development or maintenance of sufficient β-cell mass but positively regulates glucose-stimulated insulin secretion.