Dysfunction of the autonomic nervous system is a recognized complication of diabetes.
Neuroaxonal dystrophy (
NAD), a distinctive axonopathy involving distal axons and synapses, represents the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in human and several insulinopenic experimental rodent models. Recent studies have suggested that loss of the neurotrophic effects of
insulin and/or
IGF-I on sympathetic neurons and not
hyperglycemia per se, may underlie the development of sympathetic
NAD. The
streptozotocin (STZ)-diabetic and BB/W rat, the most commonly used experimental rodent models, develop marked
hyperglycemia and concomitant deficiency in both circulating
insulin and
IGF-I. These animals reproducibly develop
NAD in nerve terminals in the prevertebral sympathetic ganglia and the distal portions of noradrenergic ileal mesenteric nerves. The Zucker Diabetic Fatty (ZDF) rat, an animal model of
type 2 diabetes, also develops severe
hyperglycemia comparable to that in the STZ- and BB/W-diabetic rat models, although in the presence of
hyperinsulinemia. In our study, ZDF rats maintained for 6 to 7 months in a severely diabetic state, as assessed by plasma
glucose and
glycated hemoglobin levels, maintained significant
hyperinsulinemia and normal levels of plasma
IGF-I at sacrifice.
NAD did not develop in diabetic ZDF rat sympathetic ganglia and ileal mesenteric nerves as assessed by quantitative ultrastructural techniques, which is in dramatic contrast to neuropathologic findings in comparably hyperglycemic 6-month STZ-diabetic insulinopenic rats. These data combined with our previous results argue very strongly that
hyperglycemia is not the critical and sufficient
element in the pathogenesis of diabetes-induced
NAD, rather that it is the loss of trophic support, most likely of
IGF-I or
insulin, that causes
NAD.