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Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death.

Authors
Choi, SE; Lee, YJ; Hwang, GS; Chung, JH; Lee, SJ; Lee, JH; Han, SJ; Kim, HJ; Lee, KW; Kim, Y; Jun, HS; Kang, Y
Citation
Archives of biochemistry and biophysics, 505(2):231-241, 2011
Journal Title
Archives of biochemistry and biophysics
ISSN
0003-98611096-0384
Abstract
The aim of this study is to investigate the effect of mitochondrial metabolism on high glucose/palmitate (HG/PA)-induced INS-1 beta cell death. Long-term treatment of INS-1 cells with HG/PA impaired energy-producing metabolism accompanying with depletion of TCA cycle intermediates. Whereas an inhibitor of carnitine palmitoyl transferase 1 augmented HG/PA-induced INS-1 cell death, stimulators of fatty acid oxidation protected the cells against the HG/PA-induced death. Furthermore, whereas mitochondrial pyruvate carboxylase inhibitor phenylacetic acid augmented HG/PA-induced INS-1 cell death, supplementation of TCA cycle metabolites including leucine/glutamine, methyl succinate/α-ketoisocaproic acid, dimethyl malate, and valeric acid or treatment with a glutamate dehydrogenase activator, aminobicyclo-heptane-2-carboxylic acid (BCH), significantly protected the cells against the HG/PA-induced death. In particular, the mitochondrial tricarboxylate carrier inhibitor, benzene tricarboxylate (BTA), also showed a strong protective effect on the HG/PA-induced INS-1 cell death. Knockdown of glutamate dehydrogenase or tricarboxylate carrier augmented or reduced the HG/PA-induced INS-1 cell death, respectively. Both BCH and BTA restored HG/PA-induced reduction of energy metabolism as well as depletion of TCA intermediates. These data suggest that depletion of the TCA cycle intermediate pool and impaired energy-producing metabolism may play a role in HG/PA-induced cytotoxicity to beta cells and thus, HG/PA-induced beta cell glucolipotoxicity can be protected by nutritional or pharmacological maneuver enhancing anaplerosis or reducing cataplerosis.
MeSH terms
Adenosine Triphosphate/metabolismAnimalsBenzene Derivatives/pharmacologyCarboxylic Acids/pharmacologyCarrier Proteins/geneticsCell Death/*drug effectsCell Line, Tumor*Citric Acid Cycle/drug effectsDose-Response Relationship, DrugDrug InteractionsEnergy Metabolism/drug effectsGene Knockdown TechniquesGlucose/metabolism/*toxicityGlutamate Dehydrogenase/deficiency/geneticsInsulin-Secreting Cells/*cytology/*drug effects/metabolismMitochondria/drug effects/metabolismOxidation-Reduction/drug effectsPalmitates/metabolism/*toxicityRatsTricarboxylic Acids/pharmacology
DOI
10.1016/j.abb.2010.10.011
PMID
20965146
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Endocrinology & Metabolism
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
한, 승진김, 혜진이, 관우강, 엽
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