Info

Axonal size (% of normal) Fiber member (% of normal)

91.3a 89.6e

88.5b 80.6b

82.9b 76.8b

80.5b 70.7b

79.3b 67.1b

77.5b

Values are percentages of control values.

Values are percentages of control values.

Abnormalities of the nodal apparatus consist of a breach of the paranodal ion-channel barrier (axoglial dysjunction), allowing for the lateralization of nodal Na-channels, hence diminishing their concentration at the nodal axolemma (1,55,59,60). Axoglial dysjunction leads to further perturbations of nodal Na+ permeability and diminished excitability of the nodal membrane (49,59), potentially resulting in conduction block. As large myelinated fibers are more susceptible to axoglial dysjunction, it will greatly impact on the nerve conduction velocity (55), and contribute to the progressive increase in the chronic nerve conduction defect in type 1 DPN. Additional contributing factors are progressive axonal atrophy and eventually myelinated fiber loss (Table 1). These changes occur only late and to a significantly milder extent in the type 2 BBZDR/Wor-rat, explaining the milder progression of the nerve conduction defects in this model (Fig. 2).

Recently the molecular abnormalities underlying axoglial dysjunction were described and demonstrated that they are mainly caused by impaired gene regulatory mechanisms secondary to perturbed insulin signaling (61). Therefore, these findings are in keeping with insulin/C-peptide deficiencies in type 1 diabetes mellitus, which are not present in type 2 diabetes. To provide further evidence for this notion, it was demonstrated that C-peptide replacement, which does not effect hyperglycemia, prevented underlying molecular abnormalities and restored significantly MNCV to values similar to those exhibited by the type 2 BBZDR/Wor-rat. From these data it was concluded that the NCV defect in type 1 DPN consists of a hyperglycemia-induced component which it has in common with type 2 DPN, and an additional insulin/C-peptide deficiency component specific for type 1 DPN (Fig. 2), which hence shows a more severe overall NCV defect.

Sensory nerve conduction velocity (SNCV) deficits in the two models show slower progression rates with a significant deficit only after 6 weeks of diabetes in the BB/Wor-rat and only after 8 months of diabetes in the type 2 BBZDR/Wor-rat (Fig. 3). Like MNCV, SNCV shows a relatively steep decline during the first 2 months in the BB/Wor-rat, which levels off to be followed by a further progressive decline after 6 months of diabetes. The initial decline in SNCV occurs only after 6 months of diabetes in the type 2 model (Fig. 3). The more severe deficits under type 1 diabetic conditions are ameliorated with replenishment of C-peptide, analogous to the deficits in MNCV. Therefore, distinct differences exist in the progression and severity of both MNCV and SNCV between the two models despite the same exposure to hyperglycemia (Figs. 2 and 3).

Fig. 3. Sensory nerve conduction velocity (SNCV) profiles in type 1 BB/Wor-rats with and without C-peptide replacement and in type 2 BBZDR/Wor-rats. Note in BB/Wor-rats an acute significant decline in SNCV like that seen in MNCV (Fig. 2). However, this is only evident after 6 weeks of diabetes. SNCV then stabilizes to show a further decline starting at 6 months. In contrast BBZDR/Wor-rats show only a significant decline in SNCV beyond 6 months of diabetes (Fig. 3). C-peptide replacement showed a significant effect on SNCV, although this is not completely prevented, again suggesting a hyperglycemic and an insulin/C-peptide deficiency component. Data points represent means ± SEM's for clarity of at least eight animals.

Fig. 3. Sensory nerve conduction velocity (SNCV) profiles in type 1 BB/Wor-rats with and without C-peptide replacement and in type 2 BBZDR/Wor-rats. Note in BB/Wor-rats an acute significant decline in SNCV like that seen in MNCV (Fig. 2). However, this is only evident after 6 weeks of diabetes. SNCV then stabilizes to show a further decline starting at 6 months. In contrast BBZDR/Wor-rats show only a significant decline in SNCV beyond 6 months of diabetes (Fig. 3). C-peptide replacement showed a significant effect on SNCV, although this is not completely prevented, again suggesting a hyperglycemic and an insulin/C-peptide deficiency component. Data points represent means ± SEM's for clarity of at least eight animals.

As alluded to, these differences can be partly abolished by replenishment of insuli-nomimetic C-peptide, thereby confirming the role of default insulin signaling in the genesis of nerve dysfunction in type 1 diabetes.

Unmyelinated Fiber Function

Painful diabetic neuropathy is a common and often debilitating symptom in DPN (62). The underlying mechanisms are multiple and have not been fully elucidated (63). However, it is clear that damage to unmyelinated and small myelinated fibers play a prominent role (64) along with remodeling of afferent large myelinated AP fibers to secondary nociceptive neurons in the spinal cord, so-called central sensitization (65).

Perturbed nociception is associated with degenerative damage to C-fibers giving rise to an increase in Na+-channels and a-adrenergic receptors (63) lending them hyperex-citable (66), with a high-frequency spontaneous firing pattern (67-69), which also sensitizes and maximizes spinal nociceptive circuits (68).

The unmyelinated fiber populations in peripheral nerve are made up of nociceptive C-fibers and the axons of secondary sympathetic ganglia. The most common modes of measuring somatic C-fiber function is through thresholds to mechanical or thermal nociceptive stimulation.

Measurements of the latencies of hind paw withdrawal to a thermal noxious stimulus are an established technique for measurements of hyperalgesia or hyperexcitability of C-fibers. In control rats the latencies to thermal stimuli remain fairly constant over a 10-month

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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