Increased Insulin Sensitivity in Mice Lacking p85β Subunit of Phosphoinositide 3-Kinase

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-01, Vol.99 (1), p.419-424
• Main Authors: Ueki, Kohjiro, Yballe, Claudine M., Brachmann, Saskia M., Vicent, David, Watt, John M., Kahn, C. Ronald, Cantley, Lewis C.
• Format: Article
• Language: English
• Subjects: Antibodies; Biological Sciences; Dimers; Insulin; insulin receptor substrate-2; Insulin resistance; Liver; Mice; Muscles; p85^a gene; Phosphatidylinositols; Phosphorylation; Protein isoforms
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.012581799

On the basis of ex vivo studies using insulin-responsive cells, activation of a Class IA phosphoinositide 3-kinase (PI3K) seems to be required for a wide variety of cellular responses downstream of insulin. The Class IA PI3K enzymes are heterodimers of catalytic and regulatory subunits. In mammals, insulin-responsive tissues express both the p85α and p85β isoforms of the regulatory subunit. Surprisingly, recent studies have revealed that disruption of the p85α gene in the mouse (p85α-/- mice) results in hypoglycemia with decreased plasma insulin, and the p85α+/- mice exhibit significantly increased insulin sensitivity. These results suggest either that p85α negatively regulates insulin signaling, or that p85β, which mediates the major fraction of Class IA PI3K signaling in the absence of p85α, is more efficient than p85α in mediating insulin responses. To address this question, we have generated mice in which the p85β gene is deleted (p85β-/- mice). As with the p85α-/- mice, the p85β-/- mice showed hypoinsulinemia, hypoglycemia, and improved insulin sensitivity. At the molecular level, PI3K activity associated with phosphotyrosine complexes was preserved despite a 20-30% reduction in the total protein level of the regulatory subunits. Moreover, insulin-induced activation of AKT was significantly up-regulated in muscle from the p85β-/- mice. In addition, insulin-dependent tyrosine phosphorylation of insulin receptor substrate-2 was enhanced in the p85β-/- mice, a phenotype not observed in the p85α-/- mice. These results indicate that in addition to their roles in recruiting the catalytic subunit of PI3K to the insulin receptor substrate proteins, both p85α and p85β play negative roles in insulin signaling.