Development of sensory neuropathy in streptozotocin-induced diabetic mice

Abstract

Diabetic polyneuropathy is a major complication of diabetes and the most common cause of peripheral neuropathy. Sensory-dominant neuropathy is the most common type. We previously used streptozotocin (STZ)-induced diabetic ddY mice with sensory neuropathy to evaluate the therapeutic effects of vascular endothelial growth factor and placental growth factor isoforms. In this study, to characterize the development of diabetic sensory neuropathy, electrophysiological, behavioral, and histopathological studies were performed in these diabetic mice. A significant difference in sensory conduction velocity in the tail nerve was observed between healthy and diabetic mice at 1 week after STZ injection. Diabetic mice developed hypoalgesia at 5 weeks after STZ injection. Axon area and myelin thickness of the myelinated fibers were increased in 17-week-old healthy mice compared with those in 8-week-old healthy mice. However, these increases were retarded in 17-week-old diabetic mice. In unmyelinated fibers, axon area was significantly reduced in 17-week-old diabetic mice compared with 8- and 17-week-old healthy mice. These findings suggest that both impaired maturation of myelinated fibers and atrophy of unmyelinated fibers simultaneously occur in the early stage of diabetes in these mice. Our mouse model may be useful for studying the pathogenesis of and therapies for diabetic sensory neuropathy.

Keywords: Diabetic sensory neuropathy; STZ-induced diabetic mice; impaired maturation; sensory conduction velocity; unmyelinated fiber atrophy.

Figure 1

Sensory nerve conduction velocity of tail nerves in healthy and diabetic mice. Diabetic mice (DM) (filled circles) (n = 13), healthy mice (control) (open circles) (n = 7). DM versus control: *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student's t-test.

Figure 2

Nociceptive threshold of the hindpaw in healthy and diabetic mice. Diabetic mice (DM) (filled circles) (n = 13), healthy ddY mice (control) (open circles) (n = 7). DM versus control: *P < 0.05, **P < 0.01, unpaired Student's t-test.

Figure 3

Correlation between sensory conduction velocity (SCV) of the tail nerve and the nociceptive threshold of the hindpaw in healthy and diabetic mice; n = 114, r = −0.516, P < 0.001, Pearson's correlation coefficient test.

Figure 4

Insulin treatment increased sensory conduction velocity (SCV) of the tail nerve (A) and prevented the elevation of the nociceptive threshold (B) in diabetic mice. Blood glucose levels (C) and body weight (D) were measured at the indicated time points. Nontreated diabetic mice (NT) (filled circles) (n = 8), treated diabetic mice (T) (filled squares) (n = 8), healthy mice (control) (open circles) (n = 8). T versus NT: *P < 0.05, **P < 0.01, ***P < 0.001 (analysis of variance [ANOVA] followed by Bonferroni's modified t-test).

Figure 5

Axon size distribution of myelinated fibers in the sciatic nerves. Eight-week-old healthy mice (H8) (open bars; n = 6), 17-week-old healthy mice (H17) (stippled bars; n = 5), 17-week-old diabetic mice (DM17) (shaded bars; n = 5). H17, DM17 versus H8: ***P < 0.001, H17 versus DM17: *P < 0.05 (analysis of variance [ANOVA] followed by Bonferroni's modified t-test).

Figure 6

Axon size distribution of unmyelinated fibers in the sciatic nerves. Eight-week-old healthy mice (H8) (open bars; n = 5), 17-week-old healthy mice (H17) (stippled bars; n = 5), 17-week-old diabetic mice (DM17) (shaded bars; n = 5). H8, DM17 versus H17: *P < 0.05, **P < 0.01 (analysis of variance [ANOVA] followed by Bonferroni's modified t-test).