Although the exact etiology of DPN and DAN is unknown, the Diabetes Control and Complications Trial (DCCT) confirmed the long-held concept that DPN and DAN are the result of sustained hyperglycemia in type 1 patients and not insulin deficiency and/or autoimmunity alone (7). The mechanisms underlying the metabolic and vascular changes that occur in complication-prone tissues in the presence of acute and chronic hyperglycemia are an active area of research. Multiple etiologies have been proposed to underlie the development of DPN and DAN. These include altered polyol metabolism, abnormal lipid or amino acid metabolism, protein glycation (i.e., formation of advanced glycation end productions [AGE]), blunted nitric oxide production, altered neurotrophism, and autoimmune mechanisms (8). More recently, the idea has emerged that these alterations in cellular metabolism occur in concert and as a consequence of glucose-mediated oxidative stress (8).
Early after the induction of diabetes, high glucose leads to cellular oxidative stress and accumulation of reactive oxygen species (ROS). In healthy cells, free-radical scavengers detoxify superoxide (O2~) and hydroxyl (OH) radicals, preventing mitochondrial and cellular injury and maintaining normal cellular function. Superoxide dismutase is a key enzyme in cellular detoxification. Superoxide dismutase detoxifies superoxide (O2~) into hydrogen peroxide, which is reduced in the mitochondria by glutathionine. Reduction (detoxification) of hydrogen peroxide generates an oxidized glutathione disulfide. To regenerate glutathione, glutathione disulfide is reduced by NADPH. In diabetes, conversion of glucose to sorbitol is linked to the oxidation of NADPH to NADP+. This leads to depletion of the NADPH needed for regenerating glutathione. Thus, early after the induction of diabetes, metabolic defects lead to loss of NADPH that limits the nerve's ability to scavenge ROS, leading to a vicious cycle of oxidative stress, mitochondrial dysfunction, nerve ischemia, and damage. Collectively, these insults allow ROS to injure complication-prone tissues such as nerve. Unchecked, ROS produce (1) lipid, DNA, and protein peroxidation (9-12), (2) ischemia and reduced nerve blood flow (13-16), and (3) cellular apoptosis (17,18).
These alterations in cellular metabolism result in peripheral nervous system damage and the signs and symptoms of DPN. In the diabetic rat, measures of oxidative stress and reduced levels of circulating antioxidants parallel DPN, and blocking oxidative stress in the diabetic animal prevents the development of DPN. Antioxidants restore normal blood flow and sciatic and saphenous nerve conduction velocities in streptozo-tocin (STZ) diabetic rats (9,11-14,16). Treatment with insulin decreases ROS activity in diabetes and prevents DPN (10-12). Antioxidant therapy may ameliorate DPN and DAN in man. Lipid peroxidation measured as increased serum lipid peroxides is a marker of oxidative stress and is well documented in diabetic patients with microvas-cular complications (19).
Recent interest has emerged about the role of autoimmunity in the development of DAN complicating type 1 diabetes. Risk factors for the development of DAN include age, glycemic control, duration of diabetes, and the presence of microvascular and macrovascular complications. Interestingly, a correlation has been found to hypo-glycemia (20), hyperinsulinemia, and hyperlipidema (21). Mechanistically, many of the pathologic pathways implicated in DPN are thought to be important in the development of DAN (22). A weak correlation has been found between the presence of autoan-tibodies against the sympathetic nervous system and scintigraphically detected deficits of cardiac sympathetic innervation in type 1 diabetic subjects (23). Complement-fixing autoantibodies to the vagus, sympathetic ganglia, and adrenal medulla have been identified in up to 30% of type 1 diabetic subjects (24). Others have found that antibodies against autonomic nervous system antigens are inconsistently found in diabetes and may be associated with coincidental autoimmunity against other organs (25). In a study of 64 newly diagnosed, and 142 long-duration type 1 diabetic subjects, and 57 nondia-betic neuropathic subjects, sympathetic and parasympathetic ganglia autoantibodies were found much more frequently in diabetic compared to nondiabetic neuropathic subjects. There was, however, only a trend toward an increased number of sympathetic ganglia antibodies in long-duration DAN subjects. These data confirm that autonomic ganglia autoantibodies are common in type 1 diabetes, but their role in the pathogene-sis of DAN remains uncertain (26).
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