Although the development of neuroaxonal dystrophy represents unambiguous and compelling pathology in the sympathetic ganglia of diabetic humans, early studies described axon loss in preganglionic sympathetic communicating (“white”)rami and greater splanchnic [57,64,65] nerves. Loss of preganglionic sympathetic innervation may, together with NAD, result in diminished numbers of normal presynaptic elements innervating principal sympathetic neurons.
Autonomic Axons in Somatic Nerves
Autonomic axons, particularly small unmyelinated axons, may be lost in somatic nerves as part of symmetrical sensorimotor neuropathy [66], which is thought to have an ischemic basis, resulting in local, distally accentuated autonomic symptoms. The loss of autonomic innervation of the vasa nervorum of somatic nerves, thought to affect blood flow to the nerve trunk, may significantly contribute to nerve ischemia described in somatic sensory polyneuropathy [67].
Diabetic Parasympathetic Nervous System
Although significant loss of vagal axons and active axonal degeneration have been described in various studies of diabetic autonomic neuropathy [68,69], the number of patients examined has typically been small. In one case of diabetic gastroparesis, dramatic axon loss in the abdominal vagus nerve was described [70]; however, a similar study failed to identify morphological abnormalities in the gastric wall or abdominal vagus nerve [71]. Immunofluorescence studies of diabetic human penis have shown preferential loss of VIP-containing axons in the corpora cavernosa [72,73].
Miscellaneous
Neuropeptide immunolocalization techniques have described decreased substance P content of human rectal mucosa in diabetic patients compared to nondiabetic controls [74]. The involvement of distal axons innervating diabetic bladder [75], skin, and penile corpora [76] has been proposed. Meissner's and Auerbach's plexuses in patients with diabetic diarrhea have failed to demonstrate reproducible histopathology [77], although one ultrastructural study has claimed the demonstration of marked axonal swellings within intramural ganglia [78]. PET scanning techniques have demonstrated the loss of sympathetic innervation in the distal myocardium in diabetic patients with autonomic neuropathy, although proximal segments were hyperinnervated, perhaps reflecting disorganized axonal sprouting and reinnervation [79].
Experimental Diabetic Autonomic Neuropathy
Animal models of diabetic autonomic neuropathy have been sought to provide insight into the pathogenetic mechanisms of the latter and to develop rational forms of therapy.
Sympathetic Nervous System
An unequivocal neuropathy of the alimentary tract of the streptozotocin (STZ)-diabetic and genetically diabetic BB rat and Chinese hamster has been characterized in detail [80–82]. The regular occurrence of degenerating, regenerating, and pathologically distinctive dystrophic axons has been demonstrated in: (1) preterminal axons and synapses within the prevertebral celiac and superior mesenteric sympathetic ganglia (Figs. 4.8-4.10), and (2) noradrenergic axons contained in ileal mesenteric nerves innervating the distal alimentary tract (Fig. 4.11) in rats with chronic long term STZ-induced diabetes. As in diabetic humans, NAD again developed in the prevertebral superior mesenteric and celiac ganglia but not comparably in the paravertebral superior cervical ganglia. Dystrophic swellings involved postganglionic sympathetic noradrenergic distal ileal paravascular mesenteric nerve axons and their terminals on intramural myenteric and submucosal ganglia; however, the equally lengthy noradrenergic axons which innervate the adjacent mesenteric vasculature consistently failed to develop NAD. The time course over several months of the development of NAD, its anatomical distribution (chiefly alimentary and distal), relationship to axonal length, and its response to islet cell transplantation, short- or long-term insulin therapy, aldose reductase inhibitors, and several other novel therapeutic agents (administered in a preventive or reversal mode) have been reported. A recent study [83] has demonstrated the ability of the neurotrophic substance IGF-I to reverse established neuroaxonal dystrophy in STZ-diabetic rats without correction of the metabolic severity of the diabetic state, which may reflect the known ability of IGF-I to affect axonal regeneration, collateral sprouting, or synaptic plasticity [84].
Fig. 4.8 A dystrophic axon (arrow) in the diabetic rat SMG is located within the satellite cell sheath (magnification 3000×)
Fig. 4.9 Typically, dystrophic axons In diabetic rat SMG contain large numbers of anastomosing tubulovesicular elements (arrow; magnification 10 000×)
Fig. 4.10 Occasional swellings containing coarse tubulovesicular elements (arrowhead) appear to arise from projections from the adjacent perikaryon or principal dendrites, visible in this electron micrograph as a narrow cytoplasmic bridge (arrow; magnification 15 000×)
Fig. 4.11 Dystrophic axons (arrows, a), which may dominate the histologic appearance of the ileal mesenteric nerves of chronically diabetic rats, contain aggregates of tubulovesicular elements, mitochondria, and synaptic vesicles (seen better at higher magnification in b) (magnification: a 1200x; b 5000×)
Investigation of the effect of diabetes on postsynaptic dendritic structure has demonstrated dystrophic dendritic lesions (and involvement of dendritic spines in particular, Fig. 4.10) in diabetic rat prevertebral sympathetic ganglia [80,81].
The effect of diabetes on the STZ-induced diabetic rat gastrointestinal system has been further defined using electrophysiologic, immunohistologic, biochemical, and ultrastructural techniques. Degenerative changes, but not NAD, have also been described in the alimentary tract of eight-week STZ-diabetic rats, involving subpopulations of axons containing VIP [85]and calcitonin-gene-related peptide (CGRP) [86] but not substance P. Measurement of neuropeptides in diabetic rat ileum has demonstrated increased VIP and decreased substance P content [87], although changes may vary with duration of diabetes [88]. In addition, VIP and CGRP in the diabetic gut wall are not released appropriately in response to electrical stimuli [89].
Changes in neuropeptidergic and noradrenergic innervation of the diabetic rodent bowel may underlie changes in gut electrophysiology. Delayed small intestine transit time has been reported in STZ-diabetic rats [90] and in chronically diabetic Chinese hamsters [91]. Other electrophysiologic studies of the alimentary tract in experimental diabetes have also established deficiencies of cholinergic transmission [92] and muscarinic signal transduction [93], prejunctional impairment of ileal sympathetic nerve function, as well as abnormal transmucosal ionic flux apparently mediated by abnormalities in noradrenergic innervation [94].
Extra-alimentary Endorgans
Recent studies have examined the effect of diabetes on innervation of the vasa nervorum [67], heart [95] and cardiac valves, urinary bladder [96], pancreatic islets [97], and the penile corpora [98]. These studies have consistently reported decreased innervation of diabetic endorgans. However, the sympathetic innervation of the iris of long-term diabetic rats is relatively spared [99].
Parasympathetic Nervous System
Unmyelinated and myelinated axons in the vagus nerve of chronically diabetic rats [100] and Chinese hamsters [82] are reported to show axonal atrophy (but not axon loss) and regenerative changes, respectively, which may underlie changes in the variability of cardiac rhythm [100] and altered alimentary motility. Axonal atrophy and degenerative changes have also been reported in parasympathetic innervation of the diabetic rat penis, distal myenteric nerves, and urinary bladder [101,102].
Immunofluorescence studies of STZ-diabetic rat penis have shown preferential loss of VIP-containing axons