Pilot--Central Synaptic Function in Diabetic Rat

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In diabetic polyneuropathy large diameter sensory and motor axons innervating the lower limb and hands demonstrate dysfunctional responses that result in positive (gain of function) and negative (loss of function) symptoms. These functional changes are assumed to be caused by morphological alterations in peripheral nerve including axonal degeneration, demyelination, and ultimately neuronal death, yet may initially be independent of such changes. The goal of this project is to explain the loss of sensorimotor function in locomotor pathways of diabetics. Specifically, data will determine whether there is an early and preceding loss of function at central sensorimotor synapses caused by a decline in trophic support. Data will help determine the early changes in motoneuron and proprioceptor function and synaptic efficacy in diabetes. Loss of sensorimotor function in diabetic patients show that movement disorders may be due to functional losses in proprioceptors synapsing on the motor neurons subserving the behavior, in the motoneurons themselves, or in the processing of information at the synapse between primary afferents and motoneurons. Loss of trophic support may aid in producing the neuropathy experienced by many diabetics. In adult rats made diabetic, direct intra-axonal or intrasomatic records of neuronal function will be made followed by morphological study of those neurons. Data will show the extent of damage, if any, that occurs at early time points following induction of disease, whether dysfunction is due to central or peripheral changes in structure or function, and whether neurons in the peripheral or central nervous system can be rescued by direct local delivery of low doses of insulin or its associated growth factors, IGF-I or -II. Of the approximately 18 million people in the United States that are diabetic, 12% will have neuropathy, and after 25 years of disease 50% will have it. Although many treatments have been attempted, no therapy has completely reversed neuropathy. The results will help to elaborate on the neurons involved in locomotor dysfunction in diabetes, and aid in directing effective therapeutic regimens using novel drug delivery systems with an appropriate time course when treatment is likely to be more effective.