Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in the regulation of diverse physiological responses, including glycogen metabolism (Frame & Cohen, 2001). GSK3 is inhibited by insulin and lithium and, like the hormone, Li has been shown to stimulate glucose transport and induce activation of glycogen synthase (GS) (Chen et al. 1998; Orena et al. 2000), leading to the suggestion that GSK3 inactivation may be of importance for the hormonal stimulation of glucose transport. In the present study we have used Li and SB-415286, a maleimide derivative that selectively inhibits GSK3 (Coghlan et al. 2000), to test this proposition in rat L6 myotubes.

Insulin stimulated glucose transport by ~2-fold and induced inactivation of GSK3 by ~50 %. This inhibition in GSK3 led to an increase in GS activity by ~4.2-fold. Like insulin, Li and SB-415286 induced a significant reduction in GSK3 activity (by 73 % and 97 %, respectively) and caused a corresponding stimulation in GS, which was comparable to or greater than that elicited by insulin. L6 cells exposed to Li for 1 h induced a dose-dependent increase in glucose transport which was stimulated maximally to over 2-fold by 50 mM Li. Replacing Li with an equivalent concentration of sucrose did not mimic this effect suggesting that the response was not due to osmotic shock. In contrast, SB-415286 had no detectable effect on glucose transport. The Li-induced increase in glucose uptake was not sensitive to inhibitors of phosphoinositide 3-kinase, the classical mitogen-activated protein (MAP) kinase pathway or the mammalian target of rapamycin, but was suppressed completely by SB-203580, a p38 MAP kinase inhibitor. Li also induced a dose-dependent activation of p38 MAP kinase in L6 cells in a SB-203580 sensitive manner.

Our findings support a role for GSK3 in the chemical inactivation of GS which is sufficient to elicit a decrease in GS activity. We propose, based on the differential effects of Li and SB-415286, that GSK3 is unlikely to contribute towards the hormonal regulation of glucose transport in insulin target tissues, as previously suggested (Orena et al. 2000; Chen et al. 1998). Instead, our data indicate that this stimulation arises through activation of p38 MAP kinase.

This work was supported by the MRC, BBSRC, Diabetes UK and GlaxoSmithKline.