UC San Diego

The assessment of epidermal innervation is emerging as a valuable means of diagnosing and staging clinical diabetic neuropathy. In order to address whether or not rodent models of diabetes develop a similar loss of cutaneous innervation, we quantified epidermal nerve fiber density in various strains of diabetic rats and mice. After confirming that each of these strains developed epidermal nerve fiber loss, as well as epidermal thinning, we examined the relationship between changes in epidermal nerve fiber density and changes in heat sensitivity. After 2 weeks of diabetes, Swiss Webster mice developed significant thermal hypoalgesia. However, a significant reduction in epidermal innervation did not develop until after 4 weeks of diabetes, indicating that loss of heat sensitivity precedes a detectable reduction in epidermal innervation. Next we attempted to examine the mechanisms of thermal hypoalgesia by examining the effects of an aldose reductase inhibitor and exogenous neurotrophic support in type 1 diabetic Swiss Webster mice. The aldose reductase inhibitor IDD 676 and the NGF-enhancing compound Neotrofin partially ameliorated motor nerve conduction velocity slowing, but were unable to prevent thermal hypoalgesia. CNTF and the prosaposin-like peptide TX14(A) prevented the development of thermal hypoalgesia, but none of these compounds were able to reverse established deficits. Next we examined the neurotrophic properties of insulin by comparing the severity of neuropathy in type 1 and type 2 diabetic mouse models. Both models developed thermal hypoalgesia and IENF deficits, indicating that insulin does not protect against the development of these deficits. To further explore insulin's neurotrophic properties, we examined the effects of insulin supplementation in a type 1 diabetic mouse model. Low doses of insulin prevented epidermal thinning after 4 weeks of diabetes and high doses of insulin prevented thermal hypoalgesia after 4 and 8 weeks of diabetes, indicating neurotrophic effects of insulin. Together, these results demonstrate that rodent models develop the epidermal nerve fiber loss observed in humans with diabetes. However, a loss of thermal sensitivity precedes reductions in epidermal innervation. Loss of neurotrophic support may be involved in the development of these deficits