| Peripheral nerve regeneration is impaired in diabetes mellitus, but the underlying mechanisms are obscure. The first objective was to validate neuropathy in an streptozotocin (STZ)-diabetic mouse model. STZ-mice were found to have a reduced conduction velocity and fiber loss in distal sural nerves. As duration of diabetes increased, tibial fiber caliber became smaller, dorsal root ganglion (DRG) neurons were lost, and there was a reduction in epidermal nerve fiber density. Animals that unexpectedly reverted to euglycemia 6 months following STZ injection did not reconstitute their sensory neuron pool.; Serial studies of nerve regeneration in diabetic mice demonstrated delays in motor and sensory fiber reinnervation with substantial retardation in regrowth of myelinated fibers in tibial and sural branches. There was also an associated delay in macrophage invasion and later resorption. Early outgrowth studies indicated that regenerating diabetic neurites immunoreactive for galanin did not elongate as far as nondiabetics.; Nerve injury induced upregulation of blood flow was attenuated in diabetic proximal and distal stumps as assessed by Laser Doppler flowmetry and hydrogen clearance polarography. These reductions were associated with comparatively smaller vessels and less angiogenesis. Nitric oxide synthase (NOS) activity was also influenced by diabetes. NOS activity was enhanced in intact diabetic nerve. Following axotomy, NOS activity increased in diabetic proximal stumps but proportionately more so in nondiabetics. Distal stump NOS activity was significantly reduced by diabetes indicating poor NO available for degeneration. Protein expression of iNOS appeared to be higher in diabetic proximal and distal stumps but may have been post-translationally modified. Diabetic neurons in intact rat L4 DRG were smaller with numbers comparable to nondiabetics. However, diabetics lost significantly more sensory neurons by 14 days post-axotomy. Diabetics tended to lose predominantly small diameter neurons (<30 mum) while nondiabetics lost more large diameter neurons (>30 mum). Injury-induced hyperalgesia was absent in diabetic rats 14 days following axotomy, perhaps related to greater neurological damage.; Diabetic neuropathy may be more appropriately studied in mouse models such as the STZ-induced mouse. Diabetes impairs peripheral nerve regeneration by preventing injury-induced upregulation of blood flow, altering NOS activity, and making neurons more susceptible to cell death. |
