Cortical neurons develop insulin resistance and blunted Akt signaling: a
potential mechanism contributing to enhanced ischemic injury in diabetes.
Authors Kim B, Sullivan KA, Backus C, Feldman EL
Submitted By Eva Feldman on 8/1/2012
Status Published
Journal Antioxidants & redox signaling
Year 2011
Date Published 5/15/2011
Volume : Pages 14 : 1829 - 1839
PubMed Reference 21194385
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-3ß (GSK-3ß). 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-3ß 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.

Investigators with authorship
Eva FeldmanUniversity of Michigan