Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington’s Disease Cells

Perturbations in insulin/IGF signaling and manganese (Mn²⁺) uptake and signaling have been separately reported in Huntington’s disease (HD) models. Insulin/IGF supplementation ameliorates HD phenotypes via upregulation of AKT, a known Mn²⁺-responsive kinase. Limited evidence both in vivo and in purified biochemical systems suggest Mn²⁺ enhances insulin/IGF receptor (IR/IGFR), an upstream tyrosine kinase of AKT. Conversely, Mn²⁺ deficiency impairs insulin release and associated glucose tolerance in vivo. Here, we test the hypothesis that Mn²⁺-dependent AKT signaling is predominantly mediated by direct Mn²⁺ activation of the insulin/IGF receptors, and HD-related impairments in insulin/IGF signaling are due to HD genotype-associated deficits in Mn²⁺ bioavailability. We examined the combined effects of IGF-1 and/or Mn²⁺ treatments on AKT signaling in multiple HD cellular models. Mn²⁺ treatment potentiates p-IGFR/IR-dependent AKT phosphorylation under physiological (1 nM) or saturating (10 nM) concentrations of IGF-1 directly at the level of intracellular activation of IGFR/IR. Using a multi-pharmacological approach, we find that > 70–80% of Mn²⁺-associated AKT signaling across rodent and human neuronal cell models is specifically dependent on IR/IGFR, versus other signaling pathways upstream of AKT activation. Mn²⁺-induced p-IGFR and p-AKT were diminished in HD cell models, and, consistent with our hypothesis, were rescued by co-treatment of Mn²⁺ and IGF-1. Lastly, Mn²⁺-induced IGF signaling can modulate HD-relevant biological processes, as the reduced glucose uptake in HD STHdh cells was partially reversed by Mn²⁺ supplementation. Our data demonstrate that Mn²⁺ supplementation increases peak IGFR/IR-induced p-AKT likely via direct effects on IGFR/IR, consistent with its role as a cofactor, and suggests reduced Mn²⁺ bioavailability contributes to impaired IGF signaling and glucose uptake in HD models.