Comparable myelinated nerve pathology in feline and human diabetes mellitus.

The occurrence of diabetic neuropathy in cats provides an opportunity to study the development and treatment of neurological complications not present in diabetic rodent models, where few pathological alterations are evident. The present study further defines pathological alterations in nerve biopsies from 12 cats with spontaneously occurring diabetes mellitus. Peroneal nerve biopsies displayed concurrent injury to both Schwann cells and axons of myelinated fibers that was remarkably similar to that present in human diabetic neuropathy. In addition to demyelination, remyelination (constituting 20-84% of the total myelinated fiber population) was indicated by fibers with inappropriately thin myelin sheaths. Unlike our previous investigations, striking axonal injury was apparent, and consisted of dystrophic accumulations of membranous debris or neurofilaments, as well as degenerative fiber loss resulting in a 50% decrease in myelinated fiber density. In spite of extensive fiber loss, regenerative clusters were apparent, suggesting that axonal regeneration was not completely frustrated. These data highlight the potential utility of feline diabetic neuropathy as a model that faithfully replicates the nerve injury in human diabetes mellitus.

Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy.

Hedgehog proteins modulate development and patterning of the embryonic nervous system. As expression of desert hedgehog and the hedgehog receptor, patched-1, persist in the postnatal and adult peripheral nerves, the hedgehog pathway may have a role in maturation and maintenance of the peripheral nervous system in normal and disease states. We measured desert hedgehog expression in the peripheral nerve of maturing diabetic rats and found that diabetes caused a significant reduction in desert hedgehog mRNA. Treating diabetic rats with a sonic hedgehog-IgG fusion protein fully restored motor- and sensory-nerve conduction velocities and maintained the axonal caliber of large myelinated fibers. Diabetes-induced deficits in retrograde transport of nerve growth factor and sciatic-nerve levels of calcitonin gene-related product and neuropeptide Y were also ameliorated by treatment with the sonic hedgehog-IgG fusion protein, as was thermal hypoalgesia in the paw. These studies implicate disruption of normal hedgehog function in the etiology of diabetes-induced peripheral-nerve dysfunction and indicate that delivery of exogenous hedgehog proteins may have therapeutic potential for the treatment of diabetic neuropathy.

Neurological complications associated with spontaneously occurring feline diabetes mellitus.

In this study, neurological complications associated with spontaneously occurring feline diabetes were comprehensively evaluated. Physical and neurological examinations, electrophysiological assessment, and biochemical and histological analysis of nerve and muscle biopsy specimens were performed in 19 diabetic cats and referenced to similar data from 28 nondiabetic cats without evidence of neuropathy. Compared to nondiabetic cats, diabetic cats exhibited a range of functional, structural, and biochemical defects that, depending on severity, manifested as striking neurological dysfunction. A broad spectrum of clinical signs was apparent with the most notable and severe impairment being a plantigrade posture when standing or walking. A sensorimotor neuropathy, characterized by conduction deficits and increased F wave and cord dorsum potential latencies, was present in both pelvic and thoracic limbs and, except in the most severely affected animals, occurred with little or no electromyographic abnormality. As for nerve structural abnormalities, Schwann cell injury was prevalent and included myelin defects, such as splitting and ballooning, and demyelination, although axonal degeneration was noted in biopsies from severely affected cats. Evidence of polyol pathway activity consisted of marked increases in nerve fructose without appreciable sorbitol accumulation. The occurrence of diabetic neuropathy in the cat, a relatively large animal with a long life span and long nerves, provides unique opportunities to study the development and treatment of this debilitating complication.