Small- and large-fiber neuropathy after 40 years of type 1 diabetes associations with glycemic control and advanced protein glycation: the Oslo Study

Abstract

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-&#949-(carboxymethyl)lysine (CML) and methylglyoxal-derived hydroimidazolone.<p> <p>RESEARCH DESIGN AND METHODS In a long-term follow-up study, 27 persons with type 1 diabetes of 40 &#177 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_1cwas 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. <p>RESULTS Sixteen patients (59%) had large-fiber neuropathy. Twenty-two (81%) had smallfiber 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 &#177 2.3 vs. 11.2 &#177 3.5 mm, P , 0.001). IENFD correlated negatively with HbA_1c over 27 years (r = 20.4, P = 0.04) and CML (r = 20.5, P = 0.01). After adjustment for age, height, and BMI in a multiple linear regression model, CML was still independently associated with IENFD. <p>CONCLUSIONS Small-fiber sensory neuropathy is a major manifestation in type 1 diabetes of 40 years duration and more prevalent than large-fiber neuropathy. HbA1c 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.