Increased insulin sensitivity i subunit of phosphoinositide

On the basis of ex vivo studies using insulin-responsive cells, d( activation of a Class IA phosphoinositide 3-kinase (P13K) seems to pi be required for a wide variety of cellular responses downstream of st insulin. The Class IA P13K enzymes are heterodimers of catalytic and ai regulatory subunits. In mammals, insulin-responsive tissues ex- o0 press both the p85a and p8513 isoforms of the regulatory subunit. ul Surprisingly, recent studies have revealed that disruption of the p; p85a gene in the mouse (p85a-/- mice) results in hypoglycemia bi with decreased plasma insulin, and the p85a'+- mice exhibit significantly increased insulin sensitivity. These results suggest re either that p85a negatively regulates insulin signaling, or that ac p85P, which mediates the major fraction of Class IA P13K signaling pi in the absence of p85a, is more efficient than p85a in mediating Ir insulin responses. To address this question, we have generated vi mice in which the p8513 gene is deleted (p8581-'- mice). As with the b' p85a-/- mice, the p8513-/- mice showed hypoinsulinemia, hypo- a( glycemia, and improved insulin sensitivity. At the molecular level, e2 P13K activity associated with phosphotyrosine complexes was P1 preserved despite a 20-30% reduction in the total protein level of e) the regulatory subunits. Moreover, insulin-induced activation of PI AKT was significantly up-regulated in muscle from the p85p3-- cl mice. In addition, insulin-dependent tyrosine phosphorylation of P' insulin receptor substrate-2 was enhanced in the p85,18-- mice, a 1phenotype not observed in the p85a-'- mice. These results indi- th cate that in addition to their roles in recruiting the catalytic subunit Vi of P13K to the insulin receptor substrate proteins, both p85a and o0 p8513 play negative roles in insulin signaling. (2 ot Insulin activates Class IA phosphoinositide 3-kinase (PI3K) to (