We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Insulin Protection Against Carbonyl and Hyperglycemic Stress-induced Neuronal Cell Apoptosis.
- Authors
Okouchi, Masahiro; Okayama, Naotsuka; Kimura, Ryosuke; Mizuno, Tatsuo; Wakami, Kazuko; Yamada, Kazuhiro; Imaeda, Kenro; Kamiya, Yoshinobu; Joh, Takashi
- Abstract
Patients with long-standing diabetes commonly develop cognitive impairment and dementia, recognized as primary diabetic encephalopathy. Brain insulin deficiency, the impairment of brain insulin signaling, and oxidative stress in the brain have been thought as the contributing factors. Additionally, multiple lines of evidence suggest that reactive carbonyl compounds, which are products of oxidative damage to sugar, lipids, and amino acids, are closely involved in the pathogenesis of various neurodegenerative disorders including diabetic encephalopathy. Therefore, in the current study, we investigated the oxidative susceptibility of neuronal cells to methylglyoxal (MG), a model of carbonyl stress, under chronic high glucose, and its protection by insulin. Human brain endothelial cells (IHEC) and rat pheochromocytoma cells (PC 12), both of which are used commonly as neuronal cell models, were exposed to 25 mM glucose for 7 days with or without 500 µM MG and/or 100 nM insulin. Cell apoptosis, cellular redox status, protein expressions of PI3K/Akt/mTOR/glutamate-L-cysteine ligase (GCL) and S-glutathionylation were determined. Carbonyl and hyperglycemic stress exacerbated IHEC and PC12 apoptosis, as well as redox shifts, mitochondrial cytochrome c release, caspase-9 and -3 activation, and PARP cleavage. Insulin protected against carbonyl and hyperglycemic stress-induced apoptosis through the improvement of redox status via PI3K/Akt/mTOR/Nrf2/GCL signaling. MG potentiated insulin-induced GCL expression through Nrf2 nuclear translocation independent of PI3/Akt/mTOR pathway. Additionally, MG and chronic high glucose induced Keap1-glutathionylation. In summary, human brain endothelial cells and neurons exhibit vulnerability to carbonyl and hyperglycemic stress in conjunction with cellular redox shifts and mitochondrial apoptotic signaling. Insulin treatment affords neuroprotection by reversing redox shifts through activating PI3K/Akt/mTOR/Nrf2/GCL signaling. MG potentiates the anti-apoptotic effect of insulin as a compensatory response. Keap1 glutathionylation induced by MG and chronic high glucose seems to act as inducers of Nrf2/GCL signaling as an adaptive response. Thus, the enhanced vulnerability of neuronal cells to carbonyl and hyperglycemic stress, and its neuroprotective mechanisms of insulin will have important implications for understanding primary diabetic encephalopathy.
- Subjects
COGNITION disorders; DIABETES complications; DEMENTIA; BRAIN diseases; OXIDATIVE stress; CARBONYL compounds; NEURONS; INSULIN
- Publication
Diabetes, 2007, Vol 56, pA345
- ISSN
0012-1797
- Publication type
Article