LY-83583 stimulates glucose transporter-1-mediated glucose transport independent of changes in cGMP levels

Exposure of Clone 9 cells, a nontransformed rat liver cell line expressing only the Glut1 glucose transporter isoform, to the guanylyl cyclase inhibit or LY-83583 was found to stimulate the rate of glucose transport (similar t o 7- to 8-fold in 1 h). A similar response to LY-83583 was found in NIH 3T3 fibroblasts, 3T3-L1 pre-adipocytes, and C2C12 myoblasts. Neither the rate of glucose transport in cells under control conditions nor the effect of LY -83583 on glucose transport was altered by 10, 50, or 100 mu M 8-bromo-cGMP or by addition of cGMP phosphodiesterase inhibitors, zaprinast, or dipyrid amole suggesting that glucose transport and the response to LY-83583 is ind ependent of cGMP levels. In addition, the effect of LY-83583 on glucose tra nsport was not mediated by inhibition of oxidative phosphorylation, since e xposure to the agent resulted in no increase in lactate production. Incubat ion of Clone 9 cells in the presence of the phospholipase C inhibitor U7312 2, however, attenuated the glucose transport response to LY-83583. Moreover , exposure to LY-83583 resulted in a rise in cell diacylglycerol content, a nd preincubation with U73122 significantly diminished this rise as well as the glucose transport response to LY-83583. The stimulatory effect of LY-83 583 on glucose transport was significantly blocked by thapsigargin. Down-re gulation of protein kinase C activity, resulting from 24 h pre-incubation i n the presence of 160 nM phorbol-12-myristate 13-acetate, did not attenuate the glucose transport response to LY-83583. It is concluded that the stimu lation of glucose transport in response to LY-83583 is independent of chang es in cGMP levels, is not mediated by inhibition of oxidative phosphorylati on, and is mediated, at least in part, through stimulation of the phospholi pase C pathway. (C) 1999 Elsevier Science B.V. All rights reserved.