Protein kinase C (PKC) comprises a superfamily of
isoenzymes, many of which are activated by
1,2-diacylglycerol (DAG) in the presence of
phosphatidylserine. In order to be capable of DAG activation, PKC must first undergo a series of phosphorylation at three conserved sites. PKC
isoforms phosphorylate a wide variety of intracellular target
proteins and have multiple functions in signal transduction-mediated cellular regulation. An elevation in DAG levels and an increase in composite PKC activity and/or certain
isoforms occurs in several nonneural tissues from diabetic animals, including the vasculature. The ability of
isoform-specific PKC inhibitors to antagonize diabetes-induced abnormalities has implicated altered
PKC beta activity in the onset of several
diabetic complications, In contrast to many other tissues, DAG levels fall in diabetic nerve and a consistent pattern of change in PKC activity has not been observed. Treatments that alter PKC activity affect nerve Na+, K+-
ATPase activity, but the mechanism involved is not well understood, Inhibition of
PKC beta in diabetic rats appears to correct reduced nerve blood flow and decreased nerve conduction velocity. These and other findings indicate that changes in the neurovasculature exert adverse effects during the pathogenesis of
diabetic neuropathy. Still unresolved is a clear-cut role for PKC in the development of abnormalities in neural cell metabolism. Further progress will depend on a more complete understanding of the functions of individual PKC
isoforms in nerve. Future investigation could focus profitably on biochemical processes in nerve cells that modulate PKC activity and that are altered in diabetes, such as
vascular endothelial growth factor levels and production of
reactive oxygen species arising from oxidative stress.