, Volume 42, Issue 11, pp 1271-1281

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Abstract

The damaging effects of glucose on the cells which contribute to the development of diabetic complications are ill-understood. There are three major hypotheses – the sorbitol pathway, non-enzymatic glycation of proteins and increased oxidative stress – and many examples illustrate inter-connections between the three. It is suggested that these pathways, together with other biochemical anomalies arising from hyperglycaemia, can synergise by sharing the capacity to activate mitogen-activated protein kinases (MAP kinases) and that these enzymes in actual fact form glucose transducers. The more recent hypothesis, namely that activation of a specific isoform of protein kinase C (PKC) underpin damaging changes in retinopathy and neuropathy, can also be related because protein kinase C is an effective activator of mitogen-activated protein kinases. These latter kinases phosphorylate transcription factors, which in turn alter the balance of gene expression. In this way they can alter cellular phenotype, promote division or increase production of extracellular material. In short, mitogen-activated protein kinases have the capacity to trigger all the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy and it is suggested that their pharmacological modulation might provide therapeutic control of these conditions. [Diabetologia (1999) 42: 1271–1281]

Received: 23 June 1999 and in revised form: 21 July 1999