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Resistance to trophic neurite outgrowth of sensory neurons exposed to insulin
Author(s) -
Singh Bhagat,
Xu Yongqin,
McLaughlin Todd,
Singh Vandana,
Martinez Jose A.,
Krishnan Anand,
Zochodne Douglas W.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07681.x
Subject(s) - neurite , insulin , insulin resistance , insulin receptor , endocrinology , medicine , receptor , biology , neuron , diabetes mellitus , neuroscience , biochemistry , in vitro
J. Neurochem. (2012) 121 , 263–276. Abstract Insulin offers trophic support through receptors expressed widely on peripheral neurons. In this work, we studied whether peripheral sensory neurons demonstrate resistance to its trophic properties, a property relevant during type 2 diabetes mellitus or following supraphysiological therapy. Insulin receptors were not only localized to neuronal membranes and cytoplasm but also had a unique, previously unrecognized localization to neuronal nuclei. We confirmed that nanomolar doses increased neurite outgrowth of adult sensory neurons, but in response to micromolar doses of insulin, even following a brief 2‐h exposure, survival and outgrowth of neurites were blunted. Neurons exposed to picomolar insulin concentrations in their media for 5 days had resistance to the impact of later nanomolar doses of insulin. Using a stripe assay seeded with insulin, neurites were more likely to reject higher doses of insulin. Insulin down‐regulated mRNAs of the insulin receptor β subunit and up‐regulated levels of GSK‐3β, both potential mechanisms of insulin resistance, while down‐regulating the protein expression of pAkt and pGSK‐3β. Overall, these studies identify neuronal nuclear targeting of insulin and evidence for insulin‐induced resistance to its trophic properties. The findings have implications for the understanding of the actions of insulin in the treatment of diabetes and neurological disorders.