Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death.
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.
Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea.
Sung-E
SE
Choi
Youn-Jung
YJ
Lee
Geum-Sook
GS
Hwang
Joo Hee
JH
Chung
Soo-Jin
SJ
Lee
Ji-Hyun
JH
Lee
Seung Jin
SJ
Han
Hae Jin
HJ
Kim
Kwan-Woo
KW
Lee
Youngsoo
Y
Kim
Hee-Sook
HS
Jun
Yup
Y
Kang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004734:Energy Metabolism / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism / Q000633:toxicity*; D005969:Glutamate Dehydrogenase / Q000172:deficiency / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D014233:Tricarboxylic Acids / Q000494:pharmacology
D001555:Benzene Derivatives; D002264:Carboxylic Acids; D002352:Carrier Proteins; D010168:Palmitates; D014233:Tricarboxylic Acids; C020723:citrate-binding transport protein; C004288:benzene 1,2,3-tricarboxylic acid; D000255:Adenosine Triphosphate; D005969:Glutamate Dehydrogenase; D005947:Glucose