Non-obese diabetic mice rapidly develop dramatic sympathetic neuritic dystrophy: a new experimental model of diabetic autonomic neuropathy.

To address the pathogenesis of diabetic autonomic neuropathy, we have examined the sympathetic nervous system in non-obese diabetic (NOD) and streptozotocin (STZ)-induced diabetic mice, two models of type 1 diabetes, and the db/db mouse, a model of type 2 diabetes. After only 3 to 5 weeks of diabetes, NOD mice developed markedly swollen axons and dendrites ("neuritic dystrophy") in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), similar to the pathology described in diabetic STZ- and BBW-rat and man. Comparable changes failed to develop in the superior cervical ganglia of the NOD mouse or in the SMG-CG of non-diabetic NOD siblings.

Inhibition of sorbitol dehydrogenase exacerbates autonomic neuropathy in rats with streptozotocin-induced diabetes.

We have developed an animal model of diabetic autonomic neuropathy that is characterized by neuroaxonal dystrophy (NAD) involving ileal mesenteric nerves and prevertebral sympathetic superior mesenteric ganglia (SMG) in chronic streptozotocin (STZ)-diabetic rats. Studies with the sorbitol dehydrogenase inhibitor SDI-158, which interrupts the conversion of sorbitol to fructose (and reactions dependent on the second step of the sorbitol pathway), have shown a dramatically increased frequency of NAD in ileal mesenteric nerves and SMG of SDI-treated versus untreated diabetics. Although lesions developed prematurely and in greater numbers in SDI-treated diabetics, their distinctive ultrastructural appearance was identical to that previously reported in long-term untreated diabetics.

Effect of IGF-I and neurotrophin-3 on gracile neuroaxonal dystrophy in diabetic and aging rats.

Neuroaxonal dystrophy (NAD), a distinctive axonopathy characterized by dramatic swelling of preterminal axons and nerve terminals by the accumulation of a variety of subcellular organelles, develops in the central projections of sensory neurons to medullary gracile nuclei in aged animals and man, and in a number of diseases and experimental conditions. Although its pathogenesis is unknown, proposed mechanisms include abnormalities of axonal regeneration, collateral sprouting and synaptic plasticity which may reflect alteration in neurotrophic support. In the current study, we have demonstrated quantitatively that aging causes the expected marked increase in the frequency of gracile NAD; however, substantial numbers of dystrophic axons develop between 6 and 10 months of age, earlier than expected.

Insulin-like growth factor I reverses experimental diabetic autonomic neuropathy.

Recent studies have suggested a role for neurotrophic substances in the pathogenesis and treatment of diabetic neuropathy. In this study, the effect of insulin-like growth factor I (IGF-I) on diabetic sympathetic autonomic neuropathy was examined in an experimental streptozotocin-induced diabetic rat model. Two months of IGF-I treatment of chronically diabetic rats with established neuroaxonal dystrophy (the neuropathological hallmark of the disease) involving the superior mesenteric ganglion and ileal mesenteric nerves resulted in nearly complete normalization of the frequency of neuroaxonal dystrophy in both sites without altering the severity of diabetes.

Effect of sorbitol dehydrogenase inhibition on experimental diabetic autonomic neuropathy.

The polyol pathway and its dependent biochemical pathways are thought to play a role in the pathogenesis of diabetic neuropathy. We have developed an animal model of diabetic autonomic neuropathy characterized by neuroaxonal dystrophy involving ileal mesenteric nerves and prevertebral sympathetic superior mesenteric ganglia (SMG) in chronic streptozocin-diabetic rats. Our previous studies have shown a salutary effect of aldose reductase inhibitors on experimental autonomic neuropathy, suggesting a role for the polyol pathway in its pathogenesis.