Although a causal connection between hyperglycemia and the development of the numerous complications of diabetes mellitus has been established, the detailed sequence of molecular events resulting from hyperglycemia and leading to functional deficits remains to be elucidated. Many of the proposed mechanisms have not proven to be entirely satisfactory. The extensive nonenzymatic glycation of a variety of proteins, which has been demonstrated to alter their physical, chemical, and biological properties, has been observed in diabetic patients and has been related to the vascular pathology. We have observed highly significant increases in albumin, IgG, and IgH concentrations in endoneurial, fascicular, sural nerve biopsies of diabetic patients with and without polyneuropathy. These increases for diabetics in the absence of neuropathic abnormalities suggest that the higher levels of endoneurial plasma proteins may precede the pathological alterations. We now plan to test the hypothesis that these increases in concentrations of serum constituents in the biopsies of diabetic patients may be related to the protein itself rather than to distinctive alterations in the endothelial or perineurial barrier. We hypothesize that glycated albumin and presumably other glycated serum proteins may be preferentially transported across the blood nerve barrier to account for the quantitative increases within the fascicular sural nerve biopsies. We have developed the methodologies to quantify the permeability coefficient surface area product for these proteins across the blood nerve barrier using an i.v. bolus injection technique in the catheterized brachial vein and artery of normal rats and rats with experimental diabetic neuropathy. This proposal will examine the kinetics of glycation of albumin to determine if a correlation exists betweeen the duration of glycation and its permeability, evaluate the permeability of glycated albumin in sural nerve biopsies of diabetics with and without neuropathy. In addition, the experimental animal model of diabetic neuropathy, streptozotocin, will be evaluated to determine the permeability of albumin and glycated albumin across the blood nerve barrier, as well as to determine the endoneurial concentrations of albumin and glycated albumin in the nerves of these animals. These changes will be correlated with physiological and morphometric indices of neuropathy to determine if they precede the development of the neuropathy. These observations would have important implications for furthering our understanding of human diabetic neuropathy.
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