Update on the pathogenesis of diabetic neuropathy

Abstract

Peripheral diabetic neuropathy (PDN) affects up to 60% to 70% of diabetic patients, and is the leading cause of foot amputation. The pathogenesis of PDN involves multiple mechanisms. The findings obtained in 1999 to 2003 support the role of previously established mechanisms such as increased aldose reductase activity, nonenzymatic glycation or glyco-oxidation, activation of protein kinase C, enhanced oxidative stress, impaired neurotrophic support, and reveal the importance of new downstream effectors of oxidative injury. Those include mitogen-activated protein kinases and poly (ADP-ribose) polymerase that are activated by diabetes, and contribute to such neuropathic changes as motor and sensory nerve conduction deficits, decreased nerve blood flow, and energy failure. Further studies are needed to understand the role of other signaling pathways as well as interactions among previously discovered mechanisms in the pathogenesis of PDN.

Effects of U83836E on nerve functions, hyperalgesia and oxidative stress in experimental diabetic neuropathy

“…This deficit in composite NBF was improved significantly but not completely reversed upon U83836E treatment. It has been reported that complete normalization of NBF is not required for correction of MNCV in diabetic rats (Obrosova, 2003).…”

“…In addition to vascular mechanisms, nonvascular mechanisms have also been reported to cause conduction deficits (Li et al, 2004;Obrosova, 2003). Enhancement of neurotrophic factors by prosaposin-derived peptide has shown to preserve nerve conduction, but not NBF by reversible modification of the metabolic and neurotrophic state of the neuron and Schwann cells in the peripheral nervous system (Mizisin et al, 2001).…”

“…Diabetes-induced deficits in motor and sensory nerve conduction velocities and other manifestations of peripheral diabetic neuropathy (PDN) have been well correlated with chronic hyperglycemia. Hyperglycemia has been reported to result in increased polyol pathway activity, oxidative stress, advanced glycation end product formation (AGE), nerve hypoxia/ ischemia, increased activation of protein kinase C and impaired nerve growth factor support (Sima and Sugimoto, 1999;van Dam, 2002;Feldman, 2003;Obrosova, 2003;Vincent et al, 2004). All these pathways contribute to the development of diabetic neuropathy.…”

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

“…It is important to re-emphasize that, at least in part, diabetic retinopathy, neuropathy and nephropathy all develop on the basis of endothelial dysfunction (Nitenberg 2002, Obrosova 2003 and it is conceivable that improvements in endothelial function may underlie some of the improvements seen in neuronal conduction in diabetes in response to PARP inhibition.…”

Dioscorea Extract (DA-9801) Modulates Markers of Peripheral Neuropathy in Type 2 Diabetic db/db Mice

“…However, possible etiologic factors have been suggested. They include long-standing hyperglycemia, increased flux of the polyol pathway, enhanced non-enzymatic advanced glycation end-product formation, free radical and oxidative stress, and impaired nerve growth factor (NGF) support (Zorrilla Hernandez et al, 1994;Sima and Sugimoto, 1999;van Dam, 2002;Obrosova, 2003;Vincent et al, 2004). Several studies suggest that NGF deficiency may be one of the major risk factors for the development of diabetic neuropathy (Hellweg and Hartung, 1990;Apfel et al, 1994;Hellweg et al, 1994;Ordonez et al, 1994;Anand et al, 1996).…”