Autonomic neuropathy in experimental models of diabetes mellitus

Autonomic neuropathy complicates diabetes by increasing patient morbidity and mortality. Surprisingly, considering its importance, development and exploitation of animal models has lagged behind the wealth of information collected for somatic symmetrical sensory neuropathy. Nonetheless, animal studies have resulted in a variety of insights into the pathogenesis, neuropathology, and pathophysiology of diabetic autonomic neuropathy (DAN) with significant and, in some cases, remarkable correspondence between rodent models and human disease. Particularly in the study of alimentary dysfunction, findings in intrinsic intramural ganglia, interstitial cells of Cajal and the extrinsic parasympathetic and sympathetic ganglia serving the bowel vie for recognition as the chief mechanism. A body of work focused on neuropathologic findings in experimental animals and human subjects has demonstrated that axonal and dendritic pathology in sympathetic ganglia with relative neuron preservation represents one of the neuropathologic hallmarks of DAN but it is unlikely to represent the entire story. There is a surprising selectivity of the diabetic process for subpopulations of neurons and nerve terminals within intramural, parasympathetic, and sympathetic ganglia and innervation of end organs, afflicting some while sparing others, and differing between vascular and other targets within individual end organs. Rather than resulting from a simple deficit in one limb of an effector pathway, autonomic dysfunction may proceed from the inability to integrate portions of several complex pathways. The selectivity of the diabetic process appears to confound a simple global explanation (e.g., ischemia) of DAN. Although the search for a single unifying pathogenetic hypothesis continues, it is possible that autonomic neuropathy will have multiple pathogenetic mechanisms whose interplay may require therapies consisting of a cocktail of drugs. The role of multiple neurotrophic substances, antioxidants (general or pathway specific), inhibitors of formation of advanced glycosylation end products and drugs affecting the polyol pathway may be complex and therapeutic elements may have both salutary and untoward effects. This review has attempted to present the background and current findings and hypotheses, focusing on autonomic elements including and beyond the typical parasympathetic and sympathetic nervous systems to include visceral sensory and enteric nervous systems.