Advanced Diabetic Neuropathy: A Point of no Return?

Abstract

■ AbstractDiabetic peripheral neuropathy is the most common complication of long-standing diabetes mellitus which frequently results in clinically significant morbidities e.g. pain, foot ulcers and amputations. During its natural course it progresses from initial functional changes to late, poorly reversible, structural changes. Various interconnected pathogenetic concepts of diabetic neuropathy have been proposed based on metabolic and vascular factors, mostly derived from long-term hyperglycemia. These pathogenetic mechanisms have been targeted in several experimental and clinical trials. This review summarizes available, mainly morphological data from interventions designed to halt the progression or achieve the reversal of established diabetic neuropathy, which include the recovery of normoglycemia by pancreas or islet transplantation, polyol pathway blockade by aldose reductase inhibitors, mitigation of oxidative stress by the use of antioxidants or correction of abnormalities in essential fatty acid metabolism. Unfortunately, to date, no treatment based on pathogenic considerations has shown clear positive effects and thus early institution of optimal glycemic control remains the only available measure with proven efficacy in preventing or halting progression of diabetic neuropathy. Further experimental and clinical research employing objective reproducible parameters is clearly needed. Novel noninvasive or minimally invasive methods e.g. corneal confocal microscopy or epidermal nerve fiber counts may represent potentially useful instruments for the objective assessment of nerve damage and monitoring of treatment effects.

Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain

“…Second, in studies showing absence of abnormal heat sensitivity, it is possible that unmyelinated C-fiber afferents, which carry thermal nociceptive information, remain unaffected; whereas in studies that demonstrate thermal hyperalgesia, C-fibers may become more excitable in this rat model of diabetic pain (Ahlgren and Levine, 1994). This latter interpretation is in agreement with evidence supporting multiple pathological mechanisms originating in the periphery (i.e., peripheral neuropathy, vascular dysfunction, hypoxic tissue damage, and altered sodium channel expression, each of which can contribute to diabetic neuropathic pain) (Benbow et al, 1994;Craner et al, 2002b;Boucek, 2006;Jain, 2008;Veves et al, 2008).…”

Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia

“…The discrepancy between these findings might be explained by the multiple pathological mechanisms that contribute to the development of diabetic neuropathic pain (for example, peripheral nerve damage, secondary vascular disease, hypoxia), such that even small changes in the pathogenesis of diabetes could produce large variations in specific sensory modalities, such as heat detection (16,33,34). For example, in studies that report normal thermal sensitivity, small DRG neurons with thinly myelinated Aδ fibers or unmyelinated C-fiber afferents, which carry thermal nociceptive information, may have been minimally unaffected, whereas in other cases of diabetes, C fibers may have become more substantially affected (35). Alternatively, the instrumentation and assessment used to detect the noxious heat threshold (for example, a radiant heat stimuli was used in this study) might have limited sensitivity in this assay.…”

Prophylactic L-arginine and ibuprofen delay the development of tactile allodynia and suppress spinal miR-155 in a rat model of diabetic neuropathy

“…Given that the late stages of DN are hardly reversible and that nerve regeneration in diabetics is impaired, 13 a prophylactic measure would be useful. Therefore, the purpose of the present study was to investigate a possible prophylactic effect of ibuprofen and L-arginine and their combination against the development of tactile allodynia in a rat model of streptozotocin (STZ) induced DN.…”