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The role of insulin in the development of nociceptive dysfunctions in impaired glucose tolerance, the condition preceding type 2 diabetes

Final Activity Report Summary - INSULIN AND PAIN (The role of insulin in the development of nociceptive dysfunctions in impaired glucose tolerance, the condition preceding type 2 diabetes)

Unpleasant sensory experiences and burning pain are frequent complications of diabetes mellitus (DM). Degenerative changes of primary sensory neurones (PSNs) caused by metabolic alterations and absence of insulin-mediated neurotrophic effects contribute to the development of these symptoms. The impairment of the nociceptive neurons results not only in a disturbance of the pain processing but also a decline in their local regulatory 'sensory efferent' functions. In type 2 DM these alterations are preceded by a compensatory hyperinsulinaemia due to the decreased glucose utilisation where dysfunctions of the thermo-nociception might also be present.

These observations suggest a functional link between the altered availability of insulin and the activity of pain sensitive PSNs. Recently, we found that insulin activate a subpopulation of PSNs expressing the noxious heat transducer molecule Transient receptor potential vanilloid 1 (TRPV1) ion channel.

Therefore, we studied the long term effects of insulin on the neurochemical phenotype and sensory functions of these chemo- and heat-sensitive PSNs. Using morphological analysis of the expression of selective neurochemical marker molecules and functional assays in cultured PSNs, we found that insulin and insulin like growth factor I (IGF-I) exert a long term trophic influence on this specific population of sensory neurons which are intimately involved in the detection and transmission of noxius heat and chemogenic (inflammatory) pain.

The analysis of the target specificity of the insulin receptor expressing sensory neurons suggested that especially the function of visceral afferent nerves might be regulated by insulin. Indeed, we demonstrated the deleterious effects of insulin deficiency on the 'sensory efferent' vasoregulatory functions of meningeal afferent nerves in vivo.

Our results emphasise the importance of insulin and some related hormones in the maintenance of the neurochemical phenotype and sensory functions of the primary nociceptors and suggest their involvement in the pathogenesis of the DM related painful sensory disturbances such as neuropathic pain, headache and visceral dysreflexia.