Abnormal function of C-fibers in patients with diabetic neuropathy

Abstract

The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36-67 years old), and these were compared with 77 C-fibers from healthy controls (41-64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was approximately 2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechano-responsive nociceptors.

Figures

Figure 1.

Percentages of characterized C-fibers in the three subject groups. The distribution of fibers characterized within the groups of HC, DNP, and DN was significantly different. This difference was most apparent regarding the CM, symp, and Cxi fibers. The absolute numbers of the different fiber types found within each group are given below the bars. CM and CMi fibers include fibers responding to heating (CMH and CH, respectively). Cxi are fibers with axonal properties resembling CM fibers but with no afferent or efferent response. Cdes are fibers with axonal properties resembling CM but with only an afferent response to heat or with a rudimentary response to mechanical stimulation. Cspont/sens represents afferent fibers with either mechanical sensitization or spontaneous activity.

Figure 2.

CV and total slowing of three fiber types in healthy controls and patients. CV and total slowing of CM, CMi, and abnormal fibers with axonal properties of CM but no response to afferent or efferent stimuli and no spontaneous activity (Cxi) identified as follows: A, healthy controls (CM, 27; CMi, 12; Cxi, 2); B, patients with nonpainful diabetic neuropathy (CM, 9; CMi, 15; Cxi, 5); and C, patients with painful diabetic neuropathy (CM, 10; CMi, 24; Cxi, 14). The CV and relative total slowing (to the increasing electrical stimulus frequency protocol) of the Cxi fibers were in the range of the CM fibers, although they did not respond to mechanical stimuli.

Figure 3.

Mean relative slowing at increasing stimulus frequencies in CM, Cxi, symp, and CMi fibers. Fibers from both patient groups and healthy controls are pooled to look at conductive properties of Cxi (n = 21) fibers compared with CM (n = 45), symp (n = 23), and CMi (n = 50) fibers. The relative slowing to all three frequencies was significantly different in the four groups (p < 0.001, ANOVA). There was significantly more slowing to all frequencies in CMi fibers compared with CM, symp, and Cxi fibers (p < 0.001, post hoc Dunnett's T3 test for all 3 comparisons at all 3 frequencies). There was also significantly more pronounced slowing in the Cxi fibers compared with the CM fibers at 0.125 Hz (p = 0.008, post hoc Dunnett's T3 test) and less pronounced slowing of the Cxi fibers compared with the CM fibers at 0.5 Hz (p = 0.02, ANOVA, post hoc Dunnett's T3 test). The symp fibers slowed significantly more than the Cxi at both 0.25 and 0.5 Hz (p < 0.001, post hoc Dunnett's T3 test, at both paces), whereas the relative slowing did not differ significantly between Cxi fibers and symp fibers at 0.125 Hz. The CM fibers slowed significantly less than the symps at 0.250 Hz (p < 0.001, ANOVA, post hoc Dunnett's T3 test), whereas the relative slowing at 0.125 and 05.Hz did not differ significantly between these two fiber types. *p < 0.05 and ≥0.01; **p < 0.01 and ≥0.001; ***p < 0.001.

Figure 4.

Slowing to 2 Hz, 3 min protocol. A 2 Hz, 3 min protocol was performed in some of the fibers recorded from patients (CM, 13; CMi, 14; symp, 4; Cxi, 8) and in some from healthy controls (CM, 26; CMi, 4; symp, 8; Cxi, 0). This additional protocol for testing the slowing at higher stimulus repetition rates can be used to distinguish between afferent and efferent C-fibers. In the patients, Cxi fibers slowed in a manner similar to symp fibers and significantly less than CM and CMi fibers (CM, p = 0.04; CMi, p = 0.003; ANOVA, post hoc Scheffé's test). However, the shape of the curve of the Cxi fibers (steepness of slope and no plateau or speeding after 1 min of stimulation) differed from the shape seen in sympathetic fibers with a significantly longer half-maximum time in Cxi compared with symp (p = 0.04, ANOVA post hoc Scheffé's test). In contrast to the relative total slowing parameter in the low repetition rate protocol, in this protocol, Cxi fibers showed less slowing than CM in healthy and diseased nerves.