Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes

Protein kinase C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols (DAGs), which play a central role in signal transductio n and intracellular crosstalk by phosphorylating at serine/threonine residu es an array of substrates, including cell-surface receptors, enzymes, contr actile proteins, transcription factors and other kinases. Individual isozym es vary in their pattern of tissue and subcellular distribution, function a nd Ca2+/phospholipid cofactor requirements, and in diabetes there is widesp read activation of the DAG-PKC pathway in metabolic, cardiovascular and ren al tissues. In liver, muscle and adipose tissue, PKC isozymes have been imp licated both as mediators and inhibitors of insulin action. Activation of D AG-sensitive PKC isoforms, such as PKC-theta and PKC-epsilon, down-regulate s insulin receptor signalling and could be an important biochemical mechani sm linking dysregulated lipid metabolism and insulin resistance in muscle. On the other hand, atypical PKC isozymes, such as PKC-zeta and PKC-lambda, have been identified as downstream targets of PI-3-kinase involved in insul in-stimulated glucose uptake, especially in adipocytes. Glucose-induced de novo synthesis of (palmitate-rich) DAG and sustained iso zyme-selective PKC activation (especially but not exclusively PKC-beta) has been strongly implicated in the pathogenesis of diabetic microangiopathy a nd macroangiopathy through a host of undesirable effects on endothelial fun ction, VSM contractility and growth, angiogenesis, gene transcription tin p art by MAP-kinase activation) and vascular permeability. Interventions that increase DAG metabolism (e.g. vitamin E) and/or inhibit PKC isozymes (e.g. the beta -selective inhibitor LY333 531) ameliorate the biochemical and fu nctional consequences of DAG-PKC activation in experimental diabetes, for e xample improving retinal blood flow and albuminuria in parallel with reduct ions in membrane-associated PKC isozyme activities. Thus, a greater underst anding of the functional diversity and pathophysiological regulation of PKC isozymes is likely to have important clinical and therapeutic benefits.