Advanced glycation endproducts in peripheral nerve in type 2 diabetes with neuropathy.
Advanced glycation endproducts (AGE) accumulate over proteins as a consequence of diabetic hyperglycemia, and thus contribute to the pathogenesis of diabetic complications. To improve the understanding of the pathology of diabetic neuropathy, AGE accumulation was analyzed in sural and/or femoral nerves obtained under spinal anesthesia from 8 type 2 diabetic patients with both distal symmetrical polyneuropathy and proximal neuropathy. Pronounced AGE immunoreactivity was detected on axons and myelin sheaths in 90% of diabetic peripheral nerves but not in the control specimen. The intensity of axonal AGE immunopositivity significantly correlated with the severity of morphological alterations (p<0.005). AGE localization, demonstrated by immunohistochemical methods, was also present in the endoneurium, perineurium and microvessels. Morphometric analysis of the diabetic peripheral nerve showed perineurial thickening (diabetic vs. control, 15.5+/-4.9 vs. 6.6+/-2.1 microm, p<0.001), narrowing of the microvessel lumina (66.6+/-50.5 vs. 579.5+/-38.4 x10(3) microm(2), p<0.001) and significant reduction in the number of preserved axons (3.6+/-3 vs. 8.9+/-2.3 per 10(5) microm(2) per area, p<0.037). The sera of diabetic patients contained epitope(s) of AGE structure and soluble immune complexes containing AGE moiety. In conclusion, to the best of our knowledge, this is the first study providing evidence for excessive AGE formation on peripheral nerve components, primarily axons, and a significantly higher level of circulating AGE-immune complexes in patients with both distal diabetic polyneuropathy and proximal neuropathy. Humoral immune mechanisms, including the production of anti-AGE autoantibody, may potentially be involved in the development of structural abnormalities described in this report.
Misur
I
I
Clinic for Diabetes, Endocrinology and Metabolic Diseases, Vuk Vrhovac University, Dugi dol 4A, HR-10000 Zagreb, Croatia.
Zarković
K
K
Barada
A
A
Batelja
L
L
Milicević
Z
Z
Turk
Z
Z
D000368:Aged; D000936:Antigen-Antibody Complex / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005267:Femoral Nerve / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D017127:Glycation End Products, Advanced / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013497:Sural Nerve / Q000378:metabolism* / Q000473:pathology
D000936:Antigen-Antibody Complex; D017127:Glycation End Products, Advanced