In vitro and in vivo studies of a naturally occurring variant of the humanp85 alpha regulatory subunit of the phosphoinositide 3-kinase - Inhibitionof protein kinase B and relationships with type 2 diabetes, insulin secretion, glucose disappearance constant, and insulin sensitivity

In humans, the Met326Ile missense variant of the p85 alpha regulatory subun it of the phosphoinositide 3-kinase (PI3K) has been associated with either significant reductions in glucose effectiveness and intravenous glucose tol erance in Caucasians or a significantly higher insulin secretory response i n Pima Indians. In the present study, we genotyped 1,190 Caucasian males to evaluate the impact in vivo of the Met326Ile variant of the p85 alpha subu nit of PI3K on the acute insulin response, intravenous glucose tolerance, i nsulin-mediated glucose uptake, and the prevalence of type 2 diabetes after 20 years of follow-up. We also expressed the variant in vitro to evaluate the impact on insulin-stimulated activation of protein kinase B (PKB), The Met326Ile variant of p85a was not associated with type 2 diabetes or with a lterations in insulin secretion, insulin sensitivity, or intravenous glucos e tolerance in vivo, Expressed in vitro, the Ile326 and the Met326 variant acted equally as a dominant-negative and prevented (60-70% inhibition) insu lin-mediated activation of PKB by inhibiting the phosphorylation of PKB at Thr308, We conclude that the Met326Ile variant of the p85 alpha regulatory subunit of PI3K is likely to be as functionally normal in vivo as in vitro.