Diabetes is the most common cause of autonomic neuropathy in humans (294,295). Diabetic autonomic neuropathy has been implicated in dysfunction of the cardiovascular, gastrointestinal, and urogenital systems (295,296).
Animal models have been used extensively in research in the field of diabetes. Studies of rats made diabetic by administration of streptozotocin (STZ) have provided a wealth of evidence for diabetes-induced changes in autonomic nerves throughout the vasculature and visceral organs. In erectile tissue a similar loss of VIP and neurogenic relaxation has been demonstrated in human male diabetics with impotence and in experimental diabetes (264,297). In the rat proximal colon, an initial increase in NA and VIP is followed by a loss of NA and VIP at a later stage in STZ-induced diabetes (298). Similarly, in human skin from patients with diabetes of different duration, an early increase of VIP in autonomic nerve fibers precedes a later depletion (299). In the rat ileum 8 weeks after induction of diabetes, no VIP release can be detected on electrical field stimulation of myen-teric nerves despite the fact that VIP levels in diabetic tissue are more than twice that of controls (300). Thus, an early feature of autonomic nerve damage in diabetes may be a failure in release mechanisms resulting in accumulation of a neu-rotransmitter within the nerve. At a later stage, there is overt degeneration of nerve terminals resulting in loss of neurotransmitter.
Not all autonomic nerves are affected in the same way by diabetes. Thus in rat cerebral vessels, there is a reduction of VIP and 5-HT but not NPY or NA in perivascular nerves in STZ-induced diabetes (301). Similarly, in the proximal colon, intrinsic VIP- and extrinsic NA-containing nerves undergo degeneration in STZ-induced diabetes, while 5-HT-, SP-, and CGRP-containing nerves display altered levels of their neurotransmitters without undergoing degeneration. NPY-containing nerves appear to be unaffected by diabetes in this region (298,302,303). In addition, the same types of nerve may be affected differently by diabetes depending on the target they innervate. Thus, NA-containing nerves supplying the ileum degenerate, whereas those supplying the distal colon appear unaffected by diabetes (304).
A number of theories have been proposed to account for the development of neuropathy in diabetes. These include activation of the polyol pathway, depletion of myoinositol, impaired fatty acid metabolism, a reduction in the blood supply to nerves, and inadequate trophic support by the target (see Refs. 305-308). There is some evidence that all of these factors contribute to diabetic neuropathy, and they are not mutually exclusive. However, they cannot adequately explain why some nerves degenerate in diabetes while others do not. One factor that may be of significance in this is oxidative stress, which is known to occur in diabetes (309,310). The potential importance of oxidative stress is indicated by the fact that clinical studies are already investigating the administration of antioxidants as treatment for diabetic autonomic neuropathy (311).
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