Introduction

It is well-established that diabetic neuropathy as well as other complications of diabetes are consequences of chronic hyperglycemia. However, the mechanism is still unclear. Several models have been proposed to account for the deleterious effects of hyperglycemia on nerve tissue. They include the polyol pathway (1,2), nonenzymatic glycation (3,4), protein kinase-C (PKC) (5,6), and overproduction of reactive oxygen species by the mitochondrial respiratory chain (7). Pharmacological analyses has yielded much information on the pathogenesis of the disease. More recently, genetic analyses, particularly transgenic (TG) and gene knockout (KO) mouse models provided confirmatory as well as novel information.

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

A major drawback of using chemical inhibitors to determine the function of an enzyme is that the drugs seldom inhibit the target enzyme alone without affecting other enzymes, and their availability and stability in target tissues are difficult to ascertain. Gene KO removes only the enzyme encoded by the gene, and the enzyme activity in all tissues is absent, avoiding the problem of drug specificity and availability. However, while the window of action of drugs can be selected as desired, the effect of gene KO might occur throughout the entire life span of the animal, sometimes affecting embryonic development. There is also the possibility that during development, there might be activation of genes to compensate for the lack of an enzyme activity. Thus, there is always a concern that the effects of gene KO on a disease might be the consequences of developmental abnormalities rather than the result of a lack of enzyme activity. Therefore, it is important that the gene KO mice do not exhibit any pathology before the induction of the disease.

Overexpression of genes in TG mice is another approach to determine the role of the genes in the pathogenesis of the disease. This is particularly useful when the mice express low level of the gene product, and consequently they do not develop the disease or develop only a mild form of the disease. A good example is that of mice with a low level of aldose reductase (AR) in their lens and they do not develop cataracts. TG mice that overexpress AR in their lens become susceptible to develop diabetic cataract, demonstrating the role of AR in this disease (8). Another advantage of the TG approach is that human genes can be expressed in mice, producing authentic human enzymes for drug inhibition studies. However, there are also drawbacks in TG experiments. One is similar to gene ablation, wherein the transgenes might exert their effects during embryonic development. The other is that the transgenes are often expressed in other locations besides the target tissues because the expression of the transgene is heavily influenced by the neighboring sequences at the site of integration. It is difficult to determine if expression of the transgene in nontarget tissues would affect the development of the disease.

With these caveats in mind, the TG and KO studies that have been conducted in recent years to investigate the pathogenesis of diabetic neuropathy will be reviewed. Currently, only the studies on the polyol pathway, nonenzymatic glycation, poly(ADP-ribose) polymerase (PARP), and neurofilaments have been reported. Although PKC-0II has been implicated to be involved in this disease, and PKC-P gene KO mice are available (9), the use of these KO mice to study the development of diabetic neuropathy has not yet been reported.

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