Effects of knockout of the protein kinase C β gene on glucose transport and glucose homeostasis

The beta-isoform of protein kinase C (PKC) has paradoxically been suggested to be important for both insulin action and insulin resistance as well as for contributing to the pathogenesis of diabetic complications. Presently, we evaluated the effects of knockout of the PKC beta gene on overall glucose homeostasis and insulin regulation of glucose transport. To evaluate subtle differences in glucose homeostasis in vivo, knockout mice were extensively backcrossed in C57BL/6 mice to diminish genetic differences other than the absence of the PKC beta gene. PKC beta(-/-) knockout offspring obtained through this backcrossing had 10% lower blood glucose levels than those observed in PKC beta(+/+) wild-type offspring in both the fasting state and 30 min after ip injection of glucose despite having similar or slightly lower serum insulin levels. Also, compared with commercially obtained C57BL/6-129/SV hybrid control mice, serum glucose levels were similar, and serum insulin levels were similar or slightly lower, in C57BL/6-129/SV hybrid PKC beta knockout mice in fasting and fed states and after ip glucose administration. In keeping with a tendency for slightly lower serum glucose and/or insulin levels in PKC beta knockout mice, insulin-stimulated 2-deoxyglucose (2-DOG) uptake was enhanced by 50-100% in isolated adipocytes; basal and insulin-stimulated epitope-tagged GLUT4 translocations in adipocytes were increased by 41% and 27%, respectively; and basal 2-DOG uptake was mildly increased by 20-25% in soleus muscles incubated in vitro. The reason for increased 2-DOG uptake and/or GLUT4 translocation in these tissues was uncertain, as there were no significant alterations in phosphatidylinositol 3-kinase activity or activation or in levels of GLUT1 or GLUT4 glucose transporters or other PKC isoforms. On the other hand, increases in 2-DOG uptake may have been partly caused by the loss of PKC beta 1, rather than PKC beta 2, as transient expression of PKC beta 1 selectively inhibited insulin-stimulated translocation of epitope-tagged GLUT4 in adipocytes prepared from PKC beta knockout mice. Our findings suggest that 1) PKC beta is not required for insulin-stimulated glucose transport; 2) overall glucose homeostasis in vivo is mildly enhanced by knockout of the PKC beta gene; 3) glucose transport is increased in some tissues in PKC beta knockout mice; and 4) increased glucose transport may be partly due to loss of PKC beta 1, which negatively modulates insulin-stimulated GLUT4 translocation.