Structuralfunctional Correlations

Myelinated Fibers

From the above it is clear that the early defects in NCV are caused by metabolic abnormalities, most noticeably the early Na+/K+-ATPase defect. The type 1 diabetes model shows a more severe defect, which is likely to cause subthreshold initial Na+ currents at the node resulting in a conduction block of large fast conducting myelinated fibers (52,53). This would explain the early steep decline in NCV in this model. The early reversible NCV defect is associated with reversible paranodal and nodal axonal swellings induced by the increase in intra-axonal [Na+] concentration (53). In contrast, the type 2 rat shows a significantly milder initial decline in NCV, which most likely reflects the

0 5 10 15 20 25 30 35 40 Axo-glial dysjunction (%)

Fig. 7. Correlation between NCV and extent of axoglial dysjunction in control and type 1 diabetic BB/Wor-rats at different stages of DPN. Each data point represents one animal.

0 5 10 15 20 25 30 35 40 Axo-glial dysjunction (%)

Fig. 7. Correlation between NCV and extent of axoglial dysjunction in control and type 1 diabetic BB/Wor-rats at different stages of DPN. Each data point represents one animal.

milder Na+/K+-ATPase defect (31), which may not be sufficient to cause the same extent of large fiber conduction block, although this has not been specifically examined.

Following the initial defect in the BB/Wor-rat the NCV plateaus at a 25% deficit up to 4 to 5 months duration of diabetes, followed by a further progressive decline (Fig. 2). This second phase coincides with the progressive nodal and paranodal changes such as axoglial dysjunction and emerging axonal atrophy and loss of myelinated fibers. It is obvious that the molecular and structural changes of the node of Ranvier leading to the escape of nodal Na+ channels (60,61) has a profound effect on NCV. Indeed there is a highly significant correlation between the extent of axoglial dysjunction and NCV (Fig. 7) (55). In addition, it is well known that axonal caliber correlates with NCV (100,101), hence adding to and propagating the NCV deficits.

As described earlier, the BBZDR/Wor-rat develops nodal pathologies only at a late stage, detectable only after 14 months of diabetes, at which point it shows an accelerated decrease in NCV (31). Moreover, the magnitude and progression of axonal atrophy is substantially milder, resulting in a smoother and slower decline of NCV over time in comparison with the type 1 counterpart (Figs. 2 and 3).

Unmyelinated Fibers

The progressive degeneration of unmyelinated fibers in the sural nerve of BB/Wor-rats correlates with the increasing thermal hyperalgesia of the hind paw, reflecting the hyperexcitability of these fibers (66,67). The degenerative changes are followed by progressive loss of fibers, including high frequency firing fibers (47,48), which is reflected in a reversal of hyperalgesia (Figs. 4 and 6) and is likely to eventually result in progressive analgesia with duration of diabetes.

The involvement of C-fiber pathology is substantially milder in the BBZDR/Wor-rat and is reflected in a significantly milder increase in hyperalgesia, both of which are similar to those demonstrated by C-peptide replaced BB/Wor-rats with the same duration of diabetes.

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