Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death |
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Authors: | Choi Sung-E Lee Youn-Jung Hwang Geum-Sook Chung Joo Hee Lee Soo-Jin Lee Ji-Hyun Han Seung Jin Kim Hae Jin Lee Kwan-Woo Kim Youngsoo Jun Hee-Sook Kang Yup |
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Institution: | aInstitute for Medical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea;bKorea Basic Science Institute, Seoul, Republic of Korea;cDepartment of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea;dCancer Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea;eLeegilya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon, Republic of Korea |
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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. |
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Keywords: | Anaplerosis Beta cell Glucolipotoxicity Mitochondria TCA cycle |
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