Introduction

The development of potential new therapies for diabetic neuropathy has been sporadic over the last 20 years. In general, the process has been boosted by a prospective aetio-logical mechanism reaching consensus among scientists together with the development of drugs to counteract it. The polyol pathway and aldose reductase inhibitors provide a classical example. As is shown in Fig. 1, interest in the polyol pathway rose dramatically in the 1980s, peaking at around 1990; thereafter there has been a steady decline as clinical findings indicated that the hypothesis was inapplicable to complications, at least as a sole explanation of pathogenesis. Subsequently, no hypothesis has reached such a consensus and the development of potential novel therapeutics has virtually stalled.

This chapter attempts to revitalize the process by proposing two new hypotheses to explain the development of diabetic neuropathy. These are not mutually exclusive; indeed it is instrumental that more than one set of pathogenetic mechanisms coexist and act in concert. If these hypotheses are cogent, then new avenues for development of therapeutics open up.

It has been obvious for many years that, if glucose itself is the damaging agent in the initial aetiology of neuropathy, then there must be some processes that are sensitive to

From: Contemporary Diabetes: Diabetic Neuropathy: Clinical Management, Second Edition Edited by: A. Veves and R. Malik © Humana Press Inc., Totowa, NJ

http://www.ncbi.nlm.nih.gov/PubMed/)."/>
Fig. 1. Publications per year on the sorbitol/polyol pathway as indexed by PubMed (http://www.ncbi.nlm.nih.gov/PubMed/).

glucose and are interpolated between hyperglycemia and the onset of neurodegeneration. We have made an extensive study of the way in which the mitogen-activated protein kinases (MAPKs), and especially p38 MAPK, are activated directly by glucose and indirectly by the osmotic and oxidative stresses that it induces in diabetes (1,2). In this chapter is presented and discussed evidence for involvement of p38 MAPK in functional changes and its inhibition as a therapeutic strategy considered.

The influence of long-term trophic support and its defects in diabetes on the development of neuropathy have been examined (3). It is clear from this that more than one neurotrophic factor is defective in diabetes and reversal of this possibly requires a pleio-typic response characteristic of several factors. It is possible that agents that govern multiple developmental changes may exert just such a broad-based influence. Such a factor is sonic hedgehog (Shh) and this chapter begins with consideration of its potential influence and the novel therapeutic opportunities that it might present (4).

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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