Small- and Large-Fiber Neuropathy After 40 Years of Type 1 Diabetes: Associations with glycemic control and advanced protein glycation: the Oslo Study

OBJECTIVE: To study large- and small-nerve fiber function in type 1 diabetes of long duration and associations with HbA(1c) and the advanced glycation end products (AGEs) N-ε-(carboxymethyl)lysine (CML) and methylglyoxal-derived hydroimidazolone. RESEARCH DESIGN AND METHODS: In a long-term follow-up study, 27 persons with type 1 diabetes of 40 ± 3 years duration underwent large-nerve fiber examinations, with nerve conduction studies at baseline and years 8, 17, and 27. Small-fiber functions were assessed by quantitative sensory thresholds (QST) and intraepidermal nerve fiber density (IENFD) at year 27. HbA(1c) was measured prospectively through 27 years. Serum CML was measured at year 17 by immunoassay. Serum hydroimidazolone was measured at year 27 with liquid chromatography–mass spectrometry. RESULTS: Sixteen patients (59%) had large-fiber neuropathy. Twenty-two (81%) had small-fiber dysfunction by QST. Heat pain thresholds in the foot were associated with hydroimidazolone and HbA(1c). IENFD was abnormal in 19 (70%) and significantly lower in diabetic patients than in age-matched control subjects (4.3 ± 2.3 vs. 11.2 ± 3.5 mm, P < 0.001). IENFD correlated negatively with HbA(1c) over 27 years (r = −0.4, P = 0.04) and CML (r = −0.5, P = 0.01). After adjustment for age, height, and BMI in a multiple linear regression model, CML was still independently associated with IENFD. CONCLUSIONS: Small-fiber sensory neuropathy is a major manifestation in type 1 diabetes of 40 years duration and more prevalent than large-fiber neuropathy. HbA(1c) and the AGEs CML and hydroimidazolone are important risk factors in the development of large- and small-fiber dysfunction in long-term type 1 diabetes.