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In Vitro and In Vivo Studies of a Naturally Occurring Variant of the Human p85 Regulatory Subunit of the Phosphoinositide 3-Kinase

Inhibition of Protein Kinase B and Relationships With Type 2 Diabetes, Insulin Secretion, Glucose Disappearance Constant, and Insulin Sensitivity

¹ Steno Diabetes Center, Copenhagen, Denmark
² Department of Public Health and Caring Sciences/Section of Geriatrics and the
³ Department of Medical Sciences, University of Uppsala, Sweden
⁴ Friedrich Miescher-Institut, Basel, Switzerland

In humans, the Met326Ile missense variant of the p85 regulatory subunit of the phosphoinositide 3-kinase (PI3K) has been associated with either significant reductions in glucose effectiveness and intravenous glucose tolerance in Caucasians or a significantly higher insulin secretory response in 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 subunit of PI3K on the acute insulin response, intravenous glucose tolerance, insulin-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 p85 was not associated with type 2 diabetes or with alterations in insulin secretion, insulin sensitivity, or intravenous glucose tolerance in vivo. Expressed in vitro, the Ile326 and the Met326 variant acted equally as a dominant-negative and prevented (60–70% inhibition) insulin-mediated activation of PKB by inhibiting the phosphorylation of PKB at Thr308. We conclude that the Met326Ile variant of the p85 regulatory subunit of PI3K is likely to be as functionally normal in vivo as in vitro.

Abbreviations: CMV, cytomegalovirus; HA, hemagglutinin; IMGU, insulin-mediated glucose uptake; IVGTT, intravenous glucose tolerance test; K_g, glucose disappearance constant; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; S_g, glucose effectiveness constant; ULSAM, Uppsala Longitudinal Study of Adult Men

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