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 in the corpora cavernosa [73] and selective degeneration of nitrergic nerves [103].
Pathogenetic Mechanisms
The terminal aspects of autonomic axons appear to be preferentially targeted in diabetes. Ganglionic neuroaxonal dystrophy may represent an abnormal outcome of synaptic turnover, which may normally sub-serve synaptic plasticity, or the synaptic detachment/reattachment process that follows postganglionic sympathetic axotomy [104]. Other possible pathogenetic mechanisms have been previously described in detail [105].
Pathobiochemistry and Pathophysiology
D. Ziegler
Introduction
It was as early as in 1864 when Marchal de Calvi established that neurologic symptoms reflect the consequence rather than the cause of diabetes mellitus [106], However, one of the most intriguing questions in clinical research in diabetes during the past decades was whether long-term near-normoglycemia may retard or improve the chronic diabetic complications, including diabetic neuropathy [107,108]. The recent publications of the two largest and longest studies in the history of diabetes research, the Diabetes Control and Complications Trial (DCCT), conducted in type 1 diabetic patients, and the United Kingdom Prospective Diabetes Study (UKPDS), performed in type 2 diabetic patients, have been interpreted as providing evidence of the benefit of intensive diabetes therapy on the development and progression of the chronic diabetic complications [109–111]. However, while in both studies the effects of improved glycemic control on the microvascular endpoints were unanimously considered as being favorable [107,112], the effects on macrovascular endpoints in the UKPDS have also been interpreted as showing a clinically important benefit on macrovascular endpoints only in patients treated with metformin, but not those treated with sulfonylureas or insulin. Because metformin provided blood glucose levels similar to those of sulfonylureas or insulin, the benefit from metformin appeared to be independent of its blood-glucose-lowering effect [113]. Moreover, in both studies microvascular or macrovascular rather than neuropathic endpoints were used as the primary outcome measures.
Numerous previous short-term studies have shown that neuropathic symptoms or abnormal nerve function tests occurring during periods of metabolic derangement can be ameliorated within several days or weeks following improvement of blood glucose control [114–122]. However, possible long-term effects have been difficult to study due to the following problems: (1) the progression of diabetic polyneuropathy is relatively slow, so that expected changes may take place over several years, (2) the various nerve fiber populations might be affected at different rates, (3) minor changes may not be detected due to a low reproducibility of some methods, (4) glycemic control or the risk factor profile may fluctuate over time, and (5) even with the modern intensive diabetes therapy regimens, long-term near-normoglycemia is difficult to achieve in some patients. These problems may in part account for the conflicting findings in the earlier reports, with some showing improvement of peripheral nerve function [123–125], while others have failed to demonstrate any changes [126,127].
Rapidly Reversible Nerve Dysfunction After Correction of Metabolic Derangement
Untreated, newly diagnosed type 1 diabetic patients show slight
