Introduction

Diabetic distal symmetric sensorimotor polyneuropathy affects at least 50% of patients with diabetes, and is the leading cause of foot amputation (1). The pathogenesis of peripheral diabetic neuropathy (PDN) is studied better than the pathogenesis of autonomic neuropathy. However, two largest clinical trials in subjects with type 1 and type 2 diabetes, i.e., diabetes control and complication trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), indicate that intensive therapy and improved blood glucose control reduce incidence and slow progression of both complications, thus implicating hyperglycemia as a leading causative factor (1,2). In particular, the DCCT has shown that the incidence of neuropathy in type 1 diabetes can be reduced by more than 50% with intensive therapy and optimal glycemic control (3). Intensive therapy in the DCCT caused a significant risk reduction of developing autonomic nerve abnormalities at 5 years only

From: Contemporary Diabetes: Diabetic Neuropathy: Clinical Management, Second Edition Edited by: A. Veves and R. Malik © Humana Press Inc., Totowa, NJ

in the primary prevention group (4 vs 9%) (4). A number of mechanisms have been proposed to link chronic hyperglycemia to diabetes-induced deficits in motor and sensory nerve conduction velocities (MNCV and SNCV) and other manifestations of PDN. The vascular concept of PDN implies that diabetes-induced endothelial dysfunction with resulting decrease in nerve blood flow (NBF) and endoneurial hypoxia has a key role in functional and morphological changes in the diabetic nerve (5). Endothelial changes in vasa nervorum have been attributed to multiple mechanisms including increased aldose reductase (AR) activity, nonenzymatic glycation and glycoxidation, activation of protein kinase C (PKC), oxidative-nitrosative stress, changes in arachidonic acid, and prostaglandin metabolism (5). Recently, they have also been attributed to decreased expression of the vanilloid receptor 1 in vasa nervorum (6), increased production of angiotensin (AT) II, and activation of the ATI-receptor (7), activation of poly(ADP-ribose) polymerase (PARP)-1 (8), nuclear factor (NF)-kB (9), and cyclooxygenase-2 (COX-2) (10), and others. The neurochemical concept of PDN suggests the importance of similar mechanisms in the neural elements of peripheral nervous system (PNS), i.e., Schwann cells and neurons. Other pathobiochemical mechanisms in PNS have also been invoked.

Those include:

1. Metabolic abnormalities, such as downregulation of Na+/K+ ATP-ase activity (11), "pseudo-hypoxia," i.e., increase in free cytosolic NADH/NAD+ ratio attributed to increased conversion of sorbitol to fructose by sorbitol dehydrogenase (SDH) (12), changes in fatty acid and phospholipid metabolism (13), and recently, 12/15-lipoxygenase (12/15-LO) activation (14);

2. Impaired neurotrophic support (15,16);

3. Changes in signal transduction (17); and

4. Dorsal root ganglion (DRG) and Schwann cell mitochondrial dysfunction and premature apoptosis (18,19).

The present review of the findings obtained in the last 5 years has two major objectives, i.e., (1) to evaluate new experimental evidence that supports or disproves previously formulated concepts of the pathogenesis of PDN and (2) to characterize newly discovered mechanisms.

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