Insulin-Like Growth Factors
A deficiency of insulin like growth factors (IGF's) has been proposed to lead to cell death. Neuroaxonal dystrophy occurs in the nerve terminals of the prevertebral sympathetic ganglia and ileal mesenteric nerves of the streptozotocin (STZ)-diabetic and biobreeding/Worcester rat, and has been related to hyperglycemia and a deficiency of circulating IGF-I levels. In contrast, although the Zucker diabetic fatty rat is hyperglycemic it does not develop neuroaxonal dystrophy because it is claimed it has normal levels of plasma IGF-I (65). In cultured Schwann cells and the STZ-diabetic rat, IGF-1 administration prevents apoptosis through PI 3-kinase (66). However, again transla-tional studies in man have failed to show any differences in the expression of Insulinlike growth factor I and IGF-I receptor mRNA levels in the sural nerve of patients with diabetes compared with control subjects (67).
C-peptide deficiency has emerged as a prominent factor in the pathogenesis of the microvascular complications in type 1 diabetes (68). In neuropathy it has been shown to have effects on Na(+)/K(+)-ATPase activity, expression of neurotrophical factors, regulation of molecular species underlying the degeneration of the nodal apparatus as well as DNA binding of transcription factors leading to apoptosis (69). Administration of C-pep-tide in the STZ rat improves NCV through enhanced activity of endothelial nitric oxide synthase and an improvement in nerve blood flow (70). In a small randomized doubleblind placebo-controlled study of 46 patients with type 1 diabetes and excellent glycemic control (HbA1c-7%), a significant improvement in sural sensory NCV and vibration perception, without a benefit in either cold or heat perception was observed after 12 weeks of daily subcutaneous C-peptide treatment (71). More recently, a larger randomized double-blind placebo-controlled study of 139 patients has also demonstrated a significant improvement in sensory NCV and a clinical score of neurological deficits after 6 months of daily C-peptide (72).
VEGF was originally discovered as an endothelial-specific growth factor with a predominant role in angiogenesis and retinopathy (73). However, recent observations indicate that VEGF also has direct effects on neurons and glial cells stimulating their growth, survival, and axonal outgrowth (74). Thus with its potential for a dual impact on both the vasculature and neurones it could represent an important therapeutic intervention in diabetic neuropathy (75). A transient increase in the transcriptional regulator hypoxia-inducible factor-1a and a number of its target genes including VEGF and erythropoietin has been demonstrated recently in diabetic rats (76). Similarly in the STZ-diabetic rat intense VEGF staining has been shown in cell bodies and nerve fibers compared with no or very little VEGF in controls and animals treated with insulin orNGF (77). After 4-week intramuscular gene transfer of plasmid DNA encoding VEGF-1/2 nerve vascularity, blood flow, and both large and small fiber dysfunction were restored in the STZ-diabetic rat and the alloxan-induced diabetic rabbit (78). Thus, although there is an intrinsic capacity to upregulate hypoxia-inducible factor-1a and hence VEGF, this appears insufficient and may require exogenous delivery possibly through gene therapy. In 29 patients with angiographically proven critical leg ischemia (six patients with diabetes), injections of phVEGF165 in the muscles of the ischemic limb resulted in a significant improvement in the sensory examination score, peroneal nerve motor amplitude, and vibration perception threshold (79). The improvement in the vascular ankle-brachial index corresponded to the improvement in neuropathy and four of six patients with diabetes also showed an improvement in neurological deficits.
A phase I/II double-blind, placebo-controlled study evaluating the impact of VEGF165 gene transfer on diabetic sensory neuropathy is currently underway (80).
Neurotrophins promote neuronal survival by inducing morphological differentiation, enhancing nerve regeneration, and stimulating neurotransmitter expression (81). Although the data implicating deranged neurotrophical support is compelling in animal models, in diabetic patients results are somewhat contradictory. Thus, although dermal NGF protein levels are reduced in patients with diabetes, sensory fiber dysfunction (82), skin mRNA NGF (83), and NT-3 (84) are increased and sciatic nerve ciliary neurotrophic factor levels remain unchanged (85). Furthermore, in situ hybridization studies demonstrate increased expression of TrkA (NGF-receptor) and trkC (NT-3 receptor) in the skin of patients with diabetes (86), whereas a phase II clinical trial of recombinant human nerve growth factor demonstrated a significant improvement in neuropathy (87), a phase III trial failed to demonstrate a significant benefit (88). More recently brain-derived neurotrophic factor has demonstrated no significant improvement in nerve conduction, quantitative sensory, and autonomic function tests, including the cutaneous axon-reflex (89).
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