title: Does the prevailing hypothesis that small-fiber dysfunction precedes large-fiber dysfunction apply to type 1 diabetic patients?
abstract: OBJECTIVE
  The prevailing hypothesis that early subclinical small-fiber injury precedes large-fiber damage in diabetic sensorimotor polyneuropathy (DSP) is based on lower intraepithelial nerve fiber density in type 2 prediabetic patients despite normal nerve conduction studies (NCSs). We aimed to confirm the same hypothesis in type 1 diabetic patients by examining whether: (1) subjects without DSP include a spectrum with both normal and abnormal small-fiber measures and (2) subjects with DSP have concurrent evidence of abnormal small-fiber measures.
  
  
  METHODS
  A healthy control population (n = 53) was used to generate threshold values for four small-fiber tests: cooling detection thresholds (CDTs), laser Doppler imaging of heat-evoked flare (LDIflare), heart rate variability (HRV), and corneal confocal microscopy. Based on NCS results, type 1 diabetic patients (n = 131) were dichotomized according to the presence or absence of DSP.
  
  
  RESULTS
  Threshold values derived from healthy control subjects were 26.5 °C, 1.4 cm2, 13%, and 12.9 mm/mm2 for CDT, LDIflare, HRV, and corneal nerve fiber length, respectively. Among type 1 diabetic patients, 57 of 131 had evidence of DSP, and 74 of 133 did not. Using abnormality of any small-fiber test to define small-fiber dysfunction, 55 of 57 (96.5%) DSP patients and 39 of 74 (52.7%) control subjects without DSP had concurrent small-fiber damage. The severity of small-fiber abnormalities worsened with an increasing number of NCS abnormalities (ANOVA, P < 0.01).
  
  
  CONCLUSIONS
  Our findings in type 1 diabetes support the prevailing hypothesis that small-fiber dysfunction occurs early in DSP. However, further research is required to determine which combination of small-fiber tests is most suitable as a surrogate marker in clinical trials.
authors.affiliation: Corresponding author: Ari Breiner, ari.breiner@mail.utoronto.ca.
authors.forename: Ari
authors.initials: A
authors.lastname: Breiner
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Lovblom
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Perkins
authors.forename: Vera
authors.initials: V
authors.lastname: Bril
mesh_terms: D000328:Adult; D003315:Cornea / Q000294:innervation; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D005260:Female; D006339:Heart Rate; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009412:Nerve Fibers / Q000502:physiology*; D011236:Prediabetic State; D055815:Young Adult