title: Hyperinsulinemia induces insulin resistance in dorsal root ganglion neurons.
abstract: Insulin resistance (IR) is the major feature of metabolic syndrome, including type 2 diabetes. IR studies are mainly focused on peripheral tissues, such as muscle and liver. There is, however, little knowledge about IR in neurons. In this study, we examined whether neurons develop IR in response to hyperinsulinemia. We first examined insulin signaling using adult dorsal root ganglion neurons as a model system. Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3β. To mimic hyperinsulinemia, cells were pretreated with 20 nM insulin for 24 h and then stimulated with 20 nM insulin for 15 min. Chronic insulin treatment resulted in increased basal Akt phosphorylation. More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3β. Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. This effect was age dependent. Our results suggest that hyperinsulinemia cause IR by disrupting the Akt-mediated pathway. We also demonstrate that hyperinsulinemia increases the mitochondrial fission protein dynamin-related protein 1. Our results suggest a new theory for the etiology of diabetic neuropathy, i.e. that, similar to insulin dependent tissues, neurons develop IR and, in turn, cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury and the development of neuropathy.
authors.affiliation: University of Michigan, Department of Neurology, 109 Zina Pitcher Place, 5371 BSRB, Ann Arbor, Michigan 48109-2200, USA. bhumsoo@umich.edu
authors.forename: Bhumsoo
authors.initials: B
authors.lastname: Kim
authors.forename: Lisa L
authors.initials: LL
authors.lastname: McLean
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Philip
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases