Analysis of the Zucker Diabetic Fatty (ZDF) Type 2 Diabetic Rat Model Suggests a Neurotrophic Role for Insulin/IGF-I in Diabetic Autonomic Neuropathy

Abstract

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.

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

“…The preclinical studies are conducted on young adult rats, whereas the prevalent human myocardial infarction that is followed by progression to heart failure occurs in late adulthood and often over a background of multiple confounding factors and medications associated with their management. Likewise, ZDF rats present several important features of T2D and complex metabolic derangement, including hyperlipidemia, insulin resistance, and hyperinsulinemia (Schmidt et al, 2003) and neuroendocrine compromises (as shown in our study for BNP and aldosterone). The contribution of HF as a risk factor over a background of T2D-like metabolic derangements, a suspected confounding factor in patients that have encountered cardiorenal adverse effect while treated with RGZ could not be explored in the present experimental setting because of extremely high mortality in ZDF rats subjected to coronary ligation-induced MI.…”

Oxidative injury and neuropathy in diabetes and impaired glucose tolerance

“…However, insulin insensitivity alone is unlikely to explain the DRG neuroaxonal degeneration observed in this study. There is no evidence of neuroaxonal dystrophy in sympathetic ganglia or ileal mesenteric nerves in the ZDF rat, unlike the insulinopenic STZ rat (Schmidt et al, 2003).…”

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

“…ZDF rats develop obesity, initial hyperinsulinemia (insulin resistance), and then pancreatic failure with overt diabetes after 8 -10 weeks (19). Several papers have described neurological features, including slowing of conduction velocity (10,11,20 -22), alterations in sensory testing (10,21), and differences from the long-term STZ model in autonomic ganglia (23). Here, we evaluate the impact of type 2 diabetes on the phenotype and expression patterns of sensory neurons.…”