Diabetic polyneuropathies (DPN) are a heterogeneous group of dynamic conditions affecting somatic and autonomic peripheral nerves. It is the most common late complication of diabetes mellitus (1-4) and occurs in both type 1 and type 2 diabetes with a prevalence varying from 10% within 1 year of diagnosis to 50% in patients with diabetes for more than 25 years (5-7). DPN complicating type 1 diabetes occurs
From: Contemporary Diabetes: Diabetic Neuropathy: Clinical Management, Second Edition Edited by: A. Veves and R. Malik © Humana Press Inc., Totowa, NJ
more predictably and tend to progress more rapidly in comparison with DPN in type 2 diabetes (3,8,9).
Despite decades of intense clinical and experimental research into DPN, their underlying pathogenetic factors, their dynamics, and how they correlate with emerging functional and structural abnormalities is still not fully understood (10,11). The current understanding of early metabolic and molecular changes in DPN has heavily relied on acute experiments in the streptozotocin (STZ)-diabetic rat. Such data have then been extrapolated to established DPN in humans and have served as a basis for the development of various therapeutic drugs and the design and execution of clinical trials, thereby ignoring the dynamic of underlying mechanisms and changing spectrum of structural changes. No doubt, the STZ-rat model has served as a good and inexpensive model of hyperglycemia and its effects on peripheral nerve. However, it has several shortcomings and reflects poorly on human DPN in which for instance nerve fiber loss is the cardinal pathology, which is lacking in STZ-rats. STZ-induced diabetes causes a partial P-cell destruction and hyperglycemia. Hence, it is neither a good model of human type 1 insulin- and C-peptide-deficient diabetes nor is it a model of human type 2 hyperinsulinemic and insulin-resistant diabetes (12). Furthermore, it lacks the comorbidities characteristic of human type 2 diabetes such as obesity, hypercholesterolemia, and hyperlipidemia.
Our laboratory has taken a different approach in an attempt to mimic the human disorders by using two models with spontaneous onset of diabetes: The type 1 Bio-Breeding Worcester (BB/Wor)-rat develops acute onset of diabetes at the age of 70-75 days, secondary to an immune-mediated selective destruction of pancreatic P-cell. This results in total insulin and C-peptide deficiencies and requires daily titration of insulin doses for maintenance of an even hyperglycemic level at 20-25 mM glucose (13,14). In the type 2 Bio-Breeding Zucker derived Worcester (BBZDR/Wor)-rat, outbred on the same background as the type 1 model, diabetes occurs at 70-80 days of age and is preceded by obesity. It develops peripheral insulin resistance with hyperinsulinemia, hypercholesterolemia and triglyceridememia (15) and maintains spontaneously hyperglycemic levels equal to those of the type 1 BB/Wor-rat. Hence, these two models mimic more accurately the two major types of human diabetes which develop DPN, and can therefore be used advantageously to explore the pathological and pathogenetic differences (1,16) between type 1 and type 2 DPN.
This review will point out the basic underlying metabolic differences in peripheral nerve between the two models, the progression of functional deficits, structural abnormalities, and their correlations.
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