Progression And Mechanisms Of Somatic Nerve Dysfunction

Myelinated Fiber Function

Dysfunction of myelinated fiber populations is reflected in decreased NCV, reflecting particularly large myelinated fibers. Motor nerve conduction velocity (MNCV) shows after 1 week's duration of diabetes significant deficits in the type 1 BB/Wor-rat, whereas the type 2 counterpart shows a milder but significant decrease only after 1 month's duration of diabetes (Fig. 2) (31-32). These early deficits correlate with a milder degree of nodal axonal hydropic swelling in the type 2 model consistent with a milder Na+/K+-ATPase defect (31). On the other hand, the endoneurial nutritive nerve blood flow is equally diminished in type 1 and type 2 BB-rats (28), suggesting that diminished Na+/K+-ATPase activity is a stronger determinant for the acute metabolic nerve conduction defect than is endoneurial blood flow.

Earlier nodal clamp studies in the BB/Wor-rat has demonstrated decreased axolem-mal Na+ equilibrium potentials, and decreased nodal Na+ permeability and currents,

Onset 1week Imonth2month4month 5month 6month7month 8month Duration of diabetes

Hyperglycemic component

Insuiin/C-peptide deficiency

Component

Onset 1week Imonth2month4month 5month 6month7month 8month Duration of diabetes

Fig. 2. Longitudinal data on motor nerve conduction velocities (MNCV) in control-, BB/Wor-, BBZDR/Wor-, and C-peptide replaced BB/Wor-rats. Note a severe acute immediate decline in MNCV in BB/Wor-rats which is probably associated with the more severe Na+/K+-ATPase defect in comparison with BBZDR/Wor-rats. In the BB/Wor-rat the MNCV then levels off to 5 months duration followed by a further progressive decline. This coincides with the emergence of nodal and paranodal degenerative changes. The type 2 BBZDR/Wor-rat, which shows milder early metabolic abnormalities and nodal and paranodal degenerative changes, shows a significantly milder progression of the MNCV deficit. Replenishment of C-peptide in BB/Wor-rats significantly prevents the MNCV defect, although not completely as these animals are still hyperglycemic. The MNCV profile of these animals is similar to that of type 2 BBZDR/Wor-rats. These comparisons therefore allow us to separate out a hyperglycemic NCV defect and in type 1 animals an additional insulin/ C-peptide deficiency component. Each data point represents means ± SD's from at least eight animals.

resulting in a blunted initial inward Na+ current (52-54). These findings correlate with increased intra-axonal [Na+]' at the node. Hence the bioelectrical changes are in full agreement with impaired Na+/K+-ATPase activity at the nodal membrane and intra-axonal nodal swelling. This series of interrelated changes is correctable with insulin treatment (53,55), aldose reductase inhibition (56), acetyl-L-carnitine treatment (57), or C-peptide replenishment (32), all of which simultaneously correct the neural Na+/K+-ATPase defect. Recently Kitano et al. (58) using the threshold tracking technique, demonstrated reduced transaxolemmal Na+ gradients in patients with mild DPN, changes which improved along with NCV after 4 weeks of intensive insulin treatment.

After this initial, so called metabolic and reversible NCV-defect, the MNCV starts to show a further progressive decline at 4-5 months duration of diabetes in the BB/Wor-rat (Fig. 2) and becomes increasingly uncorrectable by metabolic means. This is the initiation of the socalled structural and irreversible NCV defect. At this time, there are early axonal atrophy and the emergence of nodal and paranodal molecular and structural changes in the BB/Wor-rat.

Table 1

Progression of Axonal Atrophy and Fiber Loss in Sensory Myelinated Fibers in Sural Nerve

Table 1

Progression of Axonal Atrophy and Fiber Loss in Sensory Myelinated Fibers in Sural Nerve

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