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.
Choi
Sung-E
SE
Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea.
Lee
Youn-Jung
YJ
Hwang
Geum-Sook
GS
Chung
Joo Hee
JH
Lee
Soo-Jin
SJ
Lee
Ji-Hyun
JH
Han
Seung Jin
SJ
Kim
Hae Jin
HJ
Lee
Kwan-Woo
KW
Kim
Youngsoo
Y
Jun
Hee-Sook
HS
Kang
Yup
Y
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