Vanilloid Receptors in Diabetic Peripheral Neuropathy

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DESCRIPTION (provided by applicant): Peripheral neuropathy is one of the most common complications of diabetes, yet the mechanisms responsible for abnormal sensory perception are poorly understood. In individuals with type 1 diabetes (T1D), insulin and insulin-like growth factor-1 (IGF1) levels are reduced. Elevated blood glucose is implicated in diabetic peripheral neuropathy (DPN), however, lack of an absolute correlation between neuropathy and hyperglycemia suggests that other mechanisms likely contribute to the pathogenesis of DPN. Insulin and IGF1 have established neuroendocrine functions that include maintenance of synaptic integrity and neurotrophic effects on sensory neurons. Our studies demonstrate that vanilloid receptor-1 (VR1), an ion channel that functions to transmit thermal and inflammatory pain, is potentiated by insulin and IGF1. We hypothesize that insulin and IGF1 are required for proper VR1 function, thereby maintaining the integrity, of sensory nerve terminals. By extension, a lack of insulin and/or IGF1 is expected to reduce nociception resulting in neuropathy as observed in T1D. In this study we will explore the molecular mechanisms that allow insulin and IGF 1 to potentiate membrane current and intracellular calcium levels through VR1. Insulin and IGF 1 bind the insulin (IR) and IGF (IGFR) receptors, respectively. However, each hormone can also bind the opposing receptor albeit with lower affinity and both receptors use similar second messengers. Our studies show that protein kinase C (PKC)- mediated phosphorylation of VR1 induces an increase in membrane current and calcium flux. We hypothesize that insulin and IGF 1 as a short-term effect cause PKC-mediated phosphorylation of VR1 and promotes translocation of VR1 from cytosol to plasma membrane. As a long-term effect by activating second messenger molecules, particularly p38 MAPK, insulin/IGF1 alter VR1 expression levels,. Thus, we will identify signal transduction molecules that link IR_GFR signaling with VR1 phosphorylation. To confirm these hypotheses in vivo, we will compare VR1 function in normal and T1D mice. This will include testing the ability of exogenous insulin and IGF1 to restore the otherwise abnormal thermal nociception observed in TID mice to near normal values. To confirm the involvement of VR1 we will measure changes in VR-dependent CGRP release and nerve function in these animals. We hypothesize that VR1 function is down regulated in diabetic animals due to insulin/IGF1 deficiency. Information gained here will provide a mechanistic link between T1D and peripheral neuropathy that includes VR1 as a central player in peripheral pain perception and insulin/IGF1 as modifiers that help to maintain normal nerve function, but when absent contribute to neuropathy.