Underlying Metabolic Abnormalities In Type And Type

Several hyperglycemia-induced pathways have been invoked as the pathogenetic basis for DPN, such as

1. Activation of the polyol-pathway resulting in redox imbalances and perturbation of myoinositol and organic osmolyte imbalances (17-19).

2. Nonenzymatic glycation yielding advanced glycation end products (20).

3. Perturbations of neurotrophic homeostasis affecting particularly the nerve growth factor (NGF) and insulin-like growth factor (IGF) systems (Fig. 1) (21-24).

Growth And Metabolic Abnormalities

Fig. 1. Scheme of pathogenetic pathways involved in type 1 and type 2 DPN. Note that some of the early key metabolic abnormalities such as Na+/K+-ATPase and NO activities as well as oxidative stress are influenced both by hyperglycemia and insulin/C-peptide deficiencies. This is also true for some of the mechanisms involved in the "structural phase" with the exception of nodal/paranodal degeneration, which appears to be a direct consequence of impaired insulin action.

Fig. 1. Scheme of pathogenetic pathways involved in type 1 and type 2 DPN. Note that some of the early key metabolic abnormalities such as Na+/K+-ATPase and NO activities as well as oxidative stress are influenced both by hyperglycemia and insulin/C-peptide deficiencies. This is also true for some of the mechanisms involved in the "structural phase" with the exception of nodal/paranodal degeneration, which appears to be a direct consequence of impaired insulin action.

Several investigators have suggested that these factors eventually come together, causing mitochondrial dysfunction, superoxide overproduction, and oxidative and nitrosative stress, leading to NO depletion, impaired nerve perfusion, which would provide a common mechanism underlying the genesis of DPN (25-27).

Recently, it was shown that endoneurial blood flow is decreased and oxidative stress increased in type 1 BB/Wor-rats. Insulinomimetic C-peptide replacement did not effect oxidative stress, but prevented nerve conduction velocity (NCV) and neurovascular deficits by NO-sensitive and -insensitive mechanisms, respectively. On the other hand, in type 2 BBZDR/Wor-rats, neurovascular deficits and increased oxidative stress were unaccompanied by sensory NCV slowing. These data suggest that sensory nerve deficits are not inevitably the consequence of oxidative stress and decreased endoneurial perfusion (28). The vascular hypothesis of DPN therefore remains controversial.

Impaired neural Na+/K+-ATPase activity consequent to perturbed redox imbalances from an activated polyol-pathway has been implied as a major contributing factor to the acute nerve conduction defect (Fig. 1) (17,29,30). Interestingly, despite exposure to the same levels of cumulative hyperglycemia, type 1 BB/Wor-rats exhibit a greater flux through the polyol-pathway in comparison with type 2 BBZDR/Wor-rats, and more severe defects in Na+/K+-ATPase activity and myoinositol depletion (31), suggesting that additional factors must contribute to the Na+/K+-ATPase defect. Recent studies have demonstrated significant dose-dependent protective effects by proinsulin C-peptide on Na+/K+-ATPase activity in neural and other tissues, in the absence of an effect on hyperglycemia and polyol-pathway activity (32-35). Therefore, it appears that both perturbed redox balances through the polyol-pathway (36) and direct effects of insulin/C-peptide deficiencies mediated through a putative G protein-linked receptor or through the insulin receptor itself (37-39) to contribute to the more severe Na+/K+-ATPase defect in type 1 diabetes (Fig. 1).

Neurotrophic factors are essential for the maintenance of neurons and their regenerative capacity and for the protection against apoptosis (23,24,40). The major groups of neurotrophic factors are NGF and its receptors, other neurotrophins as well as the IGF family of neurotrophic factors. The latter consist of IGF-I, IGF-II, insulin, and their respective receptors, as well as the IGF binding proteins (22). Various neurotrophic factors are responsible for the gene regulation of neuroskeletal proteins such as neurofilaments and neurotubules, and for the integrity of neuropeptide specific neuronal populations such as substance P (SP) and calcitonin-gene-related peptide (CGRP) dorsal root ganglion cells. Several lines of investigations have in the last number of years demonstrated that insulin and synergistically acting proinsulin C-peptide have direct gene-regulatory effects on both IGF-I and NGF family members of neurotrophic factors (Fig. 1), besides their own neurotrophic actions they also act as facilitators of ligand binding to TrkA, the high affinity NGF receptor (41-44).

These regulatory functions by insulin/C-peptide are reflected in a more severe suppression of IGF's IGF-IR, insulin receptor and NGF and TrkA receptor expression in dorsal root ganglia and peripheral nerve in the type 1 BB/Wor-rat as in comparison with the type 2 counterpart (45,46). Such differences therefore will have consequences such as regenerative capacities, survival of neuropeptide specific neuronal populations, and maintenance of axonal integrity (41,45,46).

It is therefore clear that the metabolic and molecular insults in type 1 and type 2 DPN differ in magnitude and the predominant inciting defects (Fig. 1). Hyperglycemia common to both types of diabetes is a major contributing factor as demonstrated by large-scale clinical studies as well as experimentally. However, in recent years insulin and C-peptide deficiencies have emerged as perhaps equally important in the development of type 1 late complications including DPN (32,47-51).

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