This account makes it clear that one group of glucose transducers—the MAPKs—has been identified. There can be little doubt of their involvement in early stages of the registration of damaging effects of glucose to neurones and Schwann cells. This probably extends to other cell types and may contribute to vasculopathy, retinopathy, and nephropathy. In so far as p38 MAPK might be pivotal, it is clear that aldose reductase inhibitors that are as effective as fidarestat can remove that source of cellular damage. This might be seen to negate the relevance of p38 because of the lack of clinical efficacy of the aldose reductase inhibitors tested to date. However, it is clear that early intervention is paramount and it is also likely that the level of inhibition may need to be greater than has yet been achieved clinically.
It will be interesting to see the development of Shh analogues and to determine whether these affect activation of MAPKs. If the two approaches to the consequences of glucose intoxication are complimentary then we will have a clear gateway to what some of us consider to be inevitable—multiple therapeutic approaches. This will add interest as well as difficulty to clinical trials.
Was this article helpful?