SIGNALING PATHWAY INVOLVED IN THE ACTIVATION OF HEART 6-PHOSPHOFRUCTO-2-KINASE BY INSULIN

Incubation of isolated rat cardiomyocytes with insulin increased 2-deo xyglucose uptake, glycogen synthesis, and fructose 2,6-bisphosphate co ntent. Half-maximal effects were obtained with 1-2 nM insulin. The ins ulin-induced increase in fructose 2,6-bisphosphate content was precede d by a 2-3-fold activation of 6-phosphofructo-2-kinase, which was inde pendent of glucose transport. Insulin activated phosphatidylinositol 3 -kinase and p70 ribosomal S6 kinase (p70 S6 kinase), but had no signif icant effect on mitogen-activated protein kinase, although phorbol 12- myristate 13-acetate activated the latter, The effect of insulin on fr uctose 2,6-bisphosphate, 6-phosphofructo-2-kinase, and phosphatidylino sitol 3-kinase was blocked by wortmannin. However, rapamycin, which in hibited p70 S6 kinase activation, and PD 98059, an inhibitor of the mi togen-activated protein kinase pathway, had no effect on the insulin-i nduced activation of 6-phosphofructo-2-kinase. Heart 6-phosphofructo-2 -kinase can therefore be regarded as a glycolytic target of insulin. I ts activation by insulin might be mediated by phosphatidylinositol 3-k inase.