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BBZDR/Wor-rats

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BB/Wor-rats + C-peptide

1 week 2 month 4 month 6 month 8 month Duration of diabetes

Fig. 4. Latencies of hind paw withdrawal after a noxious thermal stimulus reflecting C-fiber function. In type 1 BB/Wor-rats the latencies decreased significantly to less than half of that in control rats. Hyperalgesia reflects hyperexcitability of damaged C-fibers (see text). This decrease was followed by a recovery of the latencies most likely reflecting loss of hyperexcitable C-fibers (see Fig. 6). In the type 2 BBZDR/Wor-rat the decrease in latency to thermal stimuli was slower and was only significantly different from that in control rats after 6 months of diabetes consistent with the near normal morphometric parameters of C-fibers in this model (Fig. 6). C-peptide replacement in BB/Wor-rat significantly prevented hyperalgesia resulting in a profile similar to that in BBZDR/Wor-rat. The data points represent the means ± SD's of at least eight animals.

1 week 2 month 4 month 6 month 8 month Duration of diabetes

Fig. 4. Latencies of hind paw withdrawal after a noxious thermal stimulus reflecting C-fiber function. In type 1 BB/Wor-rats the latencies decreased significantly to less than half of that in control rats. Hyperalgesia reflects hyperexcitability of damaged C-fibers (see text). This decrease was followed by a recovery of the latencies most likely reflecting loss of hyperexcitable C-fibers (see Fig. 6). In the type 2 BBZDR/Wor-rat the decrease in latency to thermal stimuli was slower and was only significantly different from that in control rats after 6 months of diabetes consistent with the near normal morphometric parameters of C-fibers in this model (Fig. 6). C-peptide replacement in BB/Wor-rat significantly prevented hyperalgesia resulting in a profile similar to that in BBZDR/Wor-rat. The data points represent the means ± SD's of at least eight animals.

period (Fig. 4). However, in type 1 BB/Wor-rats, there is a rapid and progressive decline in the latencies during the first 6 months of diabetes, followed by an increase from 6 to 10 months of diabetes, representing increasing relative analgesia (47). The hyperalgesia in type 1 BB/Wor-rats can be significantly, but not completely prevented by insulinomimetic C-peptide (Fig. 4) (47). In contrast the type 2 BBZDR/Wor-rat shows a significantly slower progression of hyperalgesia (Fig. 4) (46).

Nociceptive C-fibers emanate from small nociceptive SP and CGRP dorsal root ganglion cells, which are dependent on neurotrophic support by NGF, insulin, and IGF-1 (10,44,70). In the BB/Wor-rat both systemic insulin and IGF-1 are significantly diminished as is endogenous IGF-1, abnormalities which are coupled with significantly decreased expression of the insulin and IGF-1 receptors in dorsal root ganglia (46). These changes are either milder or nonexistent even in chronically diabetic BBZDR/Wor-rat (46). Added to these deficiencies, sciatic nerve NGF as well as the expression of NGF-TrkA in dorsal root ganglion cells are more severely affected in the type 1 model (46). Hence, as would be expected, these deficiencies lead to impaired expression of SP and CGRP in type 1 but not in type 2 BB-rats (46). The underlying molecular abnormalities in the type 1 BB/Wor-rat are almost totally prevented by replenishment of insulinomimetic C-peptide that is associated with prevention of hyperalgesia (47,71), which suggests that nociceptive sensory neuropathy is mainly an insulin/C-peptide deficiency-mediated phenomenon rather than a hyperglycemia-induced entity. This is further supported by the frequent occurrence of "idiopathic" painful neuropathy in patients (72,73) and animals (70) with prediabetes or impaired glucose tolerance and P-cell dysfunction.

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