Resistance to trophic neurite outgrowth of sensory neurons exposed to insulin

Abstract

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.

Impairment of insulin receptor substrate 1 signaling by insulin resistance inhibits neurite outgrowth and aggravates neuronal cell death

“…In the present study, we show that IRS-1-stimulated N-Myc expression may trigger the apoptosis of neuronal cells and the inhibition of neurite outgrowth in brains with HFD-induced I/R. One study demonstrated that the I/R leads to the neurite outgrowth's inhibition of sensory neuron in vitro Resistance to trophic neurite outgrowth of sensory neurons exposed to insulin (Singh et al, 2012). In the present study, we confirmed the morphological changes including reduced neurite length in N2A cells under I/R condition.…”

“…Several in vivo studies using HFDfed animal models have found that disruption of insulin action in the brain results in impaired memory function and cognitive decline (McNeilly et al, 2011;Arnold et al, 2014). Neurite outgrowth, which is involved in cognitive function (Singh et al, 2012), is also impaired in the brains of HFD-fed animals (Hashikawa-Hobara et al, 2012). Moreover, it is known that insulin signaling is related both to impaired memory function in diabetic dementia (Grote et al, 2011) and to neuronal apoptosis (Wilk et al, 2011).…”

Gender differences in nerve regeneration after sciatic nerve injury and repair in healthy and in type 2 diabetic Goto-Kakizaki rats

“…Not only is the blood glucose level per se relevant, but also the level of insulin, which may have a trophic support [37] making the use of different models relevant. In STZ-induced diabetes, the beta cells are destroyed by the toxic effect of STZ and in the BB rats autoimmune mechanisms that destroy beta cells are in action [38].…”

Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats

“…Insulin receptors (IRs) and receptor substrate scaffolds (IRS1, IRS2) are expressed by sensory neurons and activate signal transduction pathways that modulate neurite outgrowth and axonal plasticity (Fernyhough et al, 1993; Grote et al, 2013; Huang et al, 2005; Singh et al, 2012). In neurons, the insulin receptor pathway activates several messengers that include the important survival kinase, phosphatidylinositide 3-kinase (PI3-K), that is directly associated with, and activated by, IRS-1 and induces Akt activation (Grote, et al, 2013; Huang, et al, 2005; Kim et al, 2011).…”