| Authors |
Kim B, McLean LL, Philip SS, Feldman EL
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| Submitted By |
Eva Feldman on 2/22/2012 |
| Status |
Published |
| Journal |
Endocrinology |
| Year |
2011 |
| Date Published |
10/1/2011 |
| Volume : Pages |
152 : 3638 - 3647 |
| PubMed Reference |
21810948 |
| 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-3ß. 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-3ß. 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.
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