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  • Diabetes induced damage results in peripheral nerve patholog


    Diabetes-induced damage results in peripheral nerve pathology that PHA 543613 hydrochloride synthesis correlates with clinical signs and symptoms. Nerve injury that results in structural changes can be measured through clinical neurological assessment, quantitative sensory testing, nerve conduction studies, and peripheral nerve biopsies that are often used in combination to diagnose diabetic neuropathy.16, 17, 18, 19, 20 The clinical features of diabetic neuropathy can be divided based on the type of fibers that are damaged and lost. Impairment of small, myelinated Aδ fibers and unmyelinated C-fibers results in altered mechanical, thermal, and pain sensation. Deficits in vibration, proprioception, and balance are often a consequence of large myelinated Aβ fiber damage. Sensory symptoms usually predominate in diabetic peripheral neuropathy, although with progression of the disease, motor dysfunction may also be present. Most diabetic patients experience insensate neuropathy characterized by painless symptoms including reduced vibratory perception, numbness, and insensitivity to touch and pain.23, 24 However, others have painful diabetic neuropathy that manifests as positive symptoms of hyperalgesia, tactile allodynia, paresthesias, abnormal sensitivity to temperature, and unremitting pain.23, 25 Data on the prevalence of painful diabetic have varied widely with some reporting a prevalence rate of 7% to 20%26 and others reporting 40% to 50% of those with diabetic neuropathy having neuropathic complications. The European Diabetes (EURODIAB) Prospective Complications Study found approximately 25% of type 1 diabetic patients developed painful symptoms throughout the course of the 7-year investigation. Although there is a considerable understanding of the molecular and pathological process responsible for damage to the peripheral nervous system, the mechanisms that produce painful versus insensate signs and symptoms are not known. Furthermore, neurophysiological and histological findings do not distinguish between patients suffering with positive and negative symptoms. The mechanisms underlying the development of these dichotomous symptoms remain a significant question that must be addressed to enable the development of improved and targeted therapies for diabetic neuropathy.
    Hyperglycemia as a Risk Factor for Diabetic Neuropathy Several large studies have clearly identified hyperglycemia as a key feature involved in the pathogenesis of diabetic neuropathy.9, 28, 29, 30 Similarly, poor glycemic control has also been recognized as an important risk factor for the development and progression of neurological complications. The Diabetes Control and Complications Trial (DCCT) followed 1,441 patients with type 1 diabetes mellitus and no history of neuropathy that were randomly assigned to either conventional therapy (1 or 2 insulin injections daily) or intensive therapy (3 or 4 daily insulin injections or continuous subcutaneous insulin infusion). The DCCT study found that intensive therapy reduced the risk of developing confirmed clinical neuropathy by 64% compared with conventional therapy after an average follow-up of 6.5 years. The Epidemiology of Diabetes Interventions and Complications (EDIC) study, the follow-up study to the DCCT, enrolled 93% of the former intensive therapy group and 91% of the former conventional therapy group to assess peripheral neuropathy for 13–14 years after the DCCT study commenced; however, as a result of the clear beneficial effects, the conventional treatment group was encouraged to begin and maintain intensive treatment. Throughout the study period, the prevalence of clinical neuropathy and nerve conduction abnormalities continued to increase in both former treatment groups; however, the group assigned to the former intensive therapy during the DCCT study had a significantly lower prevalence of indices of neuropathy despite similar glycemic control between the treatment groups.29, 32 Similarly, the EURODIAB study found both duration of diabetes and quality of glycemic control as risk factors for the development of diabetic neuropathy. Thus, prior exposure to hyperglycemia predisposed to greater risk of developing diabetic peripheral neuropathy.