Cortical neurons develop insulin resistance and blunted Akt signaling: a potential mechanism contributing to enhanced ischemic injury in diabetes

Antioxid Redox Signal. 2011 May 15;14(10):1829-39. doi: 10.1089/ars.2010.3816. Epub 2011 Mar 8.

Abstract

Patients with diabetes are at higher risk of stroke and experience increased morbidity and mortality after stroke. We hypothesized that cortical neurons develop insulin resistance, which decreases neuroprotection via circulating insulin and insulin-like growth factor-I (IGF-I). Acute insulin treatment of primary embryonic cortical neurons activated insulin signaling including phosphorylation of the insulin receptor, extracellular signal-regulated kinase (ERK), Akt, p70S6K, and glycogen synthase kinase-3β (GSK-3β). To mimic insulin resistance, cortical neurons were chronically treated with 25 mM glucose, 0.2 mM palmitic acid (PA), or 20 nM insulin before acute exposure to 20 nM insulin. Cortical neurons pretreated with insulin, but not glucose or PA, exhibited blunted phosphorylation of Akt, p70S6K, and GSK-3β with no change detected in ERK. Inhibition of the phosphatidylinositol 3-kinase (PI3-K) pathway during insulin pretreatment restored acute insulin-mediated Akt phosphorylation. Cortical neurons in adult BKS-db/db mice exhibited higher basal Akt phosphorylation than BKS-db(+) mice and did not respond to insulin. Our results indicate that prolonged hyperinsulinemia leads to insulin resistance in cortical neurons. Decreased sensitivity to neuroprotective ligands may explain the increased neuronal damage reported in both experimental models of diabetes and diabetic patients after ischemia-reperfusion injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Butadienes / pharmacology
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Chromones / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Immunohistochemistry
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Insulin-Like Growth Factor I
  • Morpholines / pharmacology
  • Neurons / cytology
  • Neurons / metabolism*
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Pregnancy
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Insulin
  • Morpholines
  • Nitriles
  • U 0126
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Insulin-Like Growth Factor I
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Gsk3b protein, rat
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Glycogen Synthase Kinase 3