title: Mitochondrial dysfunction precedes depression of AMPK/AKT signaling in insulin resistance induced by high glucose in primary cortical neurons.
abstract: Recent studies have demonstrated brain insulin signaling impairment and mitochondrial dysfunction in diabetes. Hyperinsulinemia and hyperlipidemia arising from diabetes have been linked to neuronal insulin resistance, and hyperglycemia induces peripheral sensory neuronal impairment and mitochondrial dysfunction. However, how brain glucose at diabetic conditions elicits cortical neuronal insulin signaling impairment and mitochondrial dysfunction remains unknown. In the present study, we cultured primary cortical neurons with high glucose levels and investigated the neuronal mitochondrial function and insulin response. We found that mitochondrial function was declined in presence of 10 mmol/L glucose, prior to the depression of AKT signaling in primary cortical neurons. We further demonstrated that the cerebral cortex of db/db mice exhibited both insulin resistance and loss of mitochondrial complex components. Moreover, we found that adenosine monophosphate-activated protein kinase (AMPK) inactivation is involved in high glucose-induced mitochondrial dysfunction and insulin resistance in primary cortical neurons and neuroblastoma cells, as well as in cerebral cortex of db/db mice, and all these impairments can be rescued by mitochondrial activator, resveratrol. Taken together, our results extend the finding that high glucose (≥10 mmol/L) comparable to diabetic brain extracellular glucose level leads to neuronal mitochondrial dysfunction and resultant insulin resistance, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. We found that high glucose (≥10 mmol/L), comparable to diabetic brain extracellular glucose level, leads to neuronal mitochondrial dysfunction and resultant insulin resistance in an AMPK-dependent manner, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system.
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology and The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology and The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology and The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China.
authors.forename: Le
authors.initials: L
authors.lastname: Shi
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology and The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology and The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology and The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Long
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology and The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D051058:Oncogene Protein v-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; hyperglycemia; insulin resistance; mitochondria; neuron