Editorial [Hot Topic: Diabetic Neuropathy (Guest Editor: Eva L. Feldman)]

Diabetes and obesity have reached epidemic levels in the Western world. In the United States, 20 million people have diabetes, and this number is increasing annually. The morbidity of diabetes is secondary to the macrovascular and microvascular complications that develop in a patient's lifetime. This edition of Current Drug Targets is focused on the most common microvascular complication of diabetes, neuropathy. More than half of all patients with diabetes develop neuropathy, a progressive loss of peripheral and autonomic nerve function. Diabetic neuropathy is the most common cause of foot ulcers and nontraumatic amputations in the United States; in his or her lifetime, a patient with diabetes and neuropathy has a greater than 15% likelihood of undergoing an amputation. Patients with neuropathy of autonomic nerves experience one or more symptoms of autonomic failure which can include dehabilitating loss of cardiac, gastrointestinal and/or genitourinary function. Despite the morbidity of diabetic neuropathy, there are no approved treatments for the disease itself other than glucose control. In the last 25 years, animal and in vitro experiments have implicated multiple pathways of tissue damage which can result in the onset and progression of diabetic neuropathy. The first contribution by Sullivan and colleagues discusses the development of mouse models of diabetic neuropathy to provide a tool to screen the therapeutic efficacy of drugs. The authors point out that a murine model of diabetic neuropathy should mimic the human disorder and suggest phenotyping parameters for evaluating diabetic neuropathy in mouse models. The remaining contributions focus on mechanism based drug development in diabetic neuropathy. While not all the pathways underlying the pathogenesis of diabetic neuropathy are presented in Fig. (1), pivotal pathways that serve as a framework for mechanism based drug design are presented in Fig. (1) and addressed in this special issue of Current Drug Targets. Oates begins with a review of the aldose reductase pathway. Excess glucose is converted to sorbitol by aldose reductase, leading to sorbitol and fructose accumulation, NAD(P)H-redox imbalance, and changes in multiple intracellular signaling cascades. The NAD(P)H-redox imbalance leads to depletion of necessary cellular antioxidants, such as glutathione, promoting accumulation of reactive oxygen species and oxidative damage. Previous trials of aldose reductase inhibitors have not proven efficacious, in part due to dose-related toxicity and accessibility to the nervous system. Newer aldose reductase inhibitors with a lower toxicity profile and improved nerve penetration may prove effective in the treatment of diabetic neuropathy. In the next contribution, Sima and Kamiya explore the evolving concept that the combined effects of insulin and C-peptide regulate essential metabolic processes in the nervous system, including key enzyme activity, nitric oxide release, and the production and activity of essential transcription factors, trophic factors and their receptors. Replacing C peptide can prevent and/or reverse diabetic neuropathy, supporting the essential role of C peptide in the pathogenesis of the disorder and identifying C peptide replacement as a new, promising therapy. The idea that altered neurotrophic support underlies the development of diabetic neuropathy is highlighted in the review by Calcutt and colleagues. Potential blunting of normal neurotrophic responses in the presence of persistent hyperglycemia may: 1) decrease growth factor synthesis by target organs; 2) disrupt retrograde transport of growth factors to the neuronal cell body; 3) affect the signal transduction mechanism of growth factors in neurons, or 4) alter the ability of neurons or Schwann cells to produce growth factors required for normal cell maintenance. Calcutt and colleagues discuss these ideas in the context of potential neurotrophic therapies. When deficits are identified, exogenous neurotrophic factors can represent a replacement therapy in diabetic neuropathy. The pivotal role of inflammation in the development of diabetic neuropathy is discussed by both Cameron and Cotter with a focus on nuclear factor κ B (NFκB) and Pop-Busui and coworkers with a focus on glucose-mediated alteration of cyclooxygenase (COX) pathway activity with subsequent impaired production and function of prostaglandins (PGs).........