Experimental Rat Models of Types 1 and 2 Diabetes Differ in Sympathetic Neuroaxonal Dystrophy

Abstract

Dysfunction of the autonomic nervous system is a recognized complication of diabetes, ranging in severity from relatively minor sweating and pupillomotor abnormality to debilitating interference with cardiovascular, genitourinary, and alimentary dysfunction. Neuroaxonal dystrophy (NAD), a distinctive distal axonopathy involving terminal axons and synapses, represents the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in man and several insulinopenic experimental rodent models. Although the pathogenesis of diabetic sympathetic NAD is unknown, recent studies have suggested that loss of the neurotrophic effects of insulin and/or insulin-like growth factor-I (IGF-I) on sympathetic neurons rather than hyperglycemia per se, may be critical to its development. Therefore, in our current investigation we have compared the sympathetic neuropathology developing after 8 months of diabetes in the streptozotocin (STZ)-induced diabetic rat and BB/ Wor rat, both models of hypoinsulinemic type 1 diabetes, with the BBZDR/Wor rat, a hyperglycemic and hyperinsulinemic type 2 diabetes model. Both STZ- and BB/Wor-diabetic rats reproducibly developed NAD in nerve terminals in the prevertebral superior mesenteric sympathetic ganglia (SMG) and ileal mesenteric nerves. The BBZDR/Wor-diabetic rat, in comparison, failed to develop superior mesenteric ganglionic NAD in excess of that of age-matched controls. Similarly, NAD which developed in axons of ileal mesenteric nerves of BBZDR/Wor rats was substantially less frequent than in BB/Wor- and STZ-rats. These data, considered in the light of the results of previous experiments, argue that hyperglycemia alone is not sufficient to produce sympathetic ganglionic NAD, but rather that it may be the diabetes-induced superimposed loss of trophic support, likely of IGF-I, insulin, or C-peptide, that ultimately causes NAD.

Quantification of sweat gland innervation

“…The pathophysiology of the thickened nerve fibers (figure 5) is not known, but could suggest a predegenerative process similar to that seen in epidermal nerve fibers in humans with swelling 26,27 or neuroaxonal dystrophy seen in autonomic ganglia in rodent experimental models of diabetic neuropathy. 28,29 This observation may be the morphologic correlate of the increase in sweat droplet size and decrease in droplet number seen in silicone impressions of patients with diabetic neuropathy. 30 Further studies are required to clarify these clinical observations and morphologic findings.…”

Animal Models of Peripheral Neuropathies

“…Prevalence of autonomic nervous system involvement in types 1 and 2 diabetes is as high as 90% [64][65][66]. Evaluations of autonomic function in animal models of diabetes have relied on the typical induced or genetic models of rat and mouse diabetes [67][68][69][70][71]. A common pathological feature of both human diabetic autonomic neuropathy and experimental diabetic autonomic neuropathy is the presence of neuroaxonal dystrophy in the autonomic ganglia [72,73].…”

Diabetes-related alterations in the enteric nervous system and its microenvironment

“…Now, we want to know whether the diabetesinduced alterations in the microvasculature of the retina, renal glomerulus and nerves are accompanied by changes in the capillaries supplying the MP and whether such changes can result in an impairment of the strict control of capillary permeability, which then gives rise to the gut region-specific nitrergic neuropathy demonstrated in the MP of rats with STZ-induced diabetes [22] . Although the metabolic and cellular mechanisms leading to severe macro-and microvascular diseases may differ between type 1 and type 2 diabetes, both share a decreased NO bioavailability and altered vascular permeability [150] . A deficit in bioavailable NO could result from an impairment of the eNOS function or the inactivation of NO by oxidative stress.…”