Small- and Large-Fiber Neuropathy After 40 Years of Type 1 Diabetes

Associations with glycemic control and advanced protein glycation: The Oslo Study

  1. Kristian F. Hanssen, MD, PHD1,2
  1. 1Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
  2. 2Institute of Clinical Medicine, Faculty of Medicine University of Oslo, Oslo, Norway
  3. 3Section of Clinical Neurophysiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  4. 4Neuromuscular Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway
  5. 5Unit of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
  6. 6Departments of Pathology and Biochemistry, Case Western Reserve University, Cleveland, Ohio
  7. 7Pediatric Department Ullevaal, Oslo University Hospital, Oslo, Norway
  1. Corresponding author: Kari Anne Sveen, k.a.sveen{at}


OBJECTIVE To study large- and small-nerve fiber function in type 1 diabetes of long duration and associations with HbA1c 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. HbA1c 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 HbA1c. 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 HbA1c 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. 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.

  • Received April 2, 2013.
  • Accepted June 13, 2013.

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