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Updated: Feb 10, 2026

A Zebrafish Model of Diabetes Mellitus and Metabolic Memory
Published on: February 28, 2013
Increased susceptibility to troglitazone-induced mitochondrial permeability transition in type 2 diabetes mellitus
Masahiro Segawa1,2, Shuichi Sekine1, Tomoyuki Sato1
1Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University.
Abstract:
Troglitazone, a member of the thiazolidinedione class of antidiabetic drugs, was withdrawn from the market because it causes severe liver injury. One of the mechanisms for this adverse effect is thought to be mitochondrial toxicity. To investigate the characteristics of troglitazone-induced liver toxicity in more depth, the toxicological effects of troglitazone on hepatocytes and liver mitochondria were investigated using a rat model of type 2 diabetes mellitus (T2DM). Troglitazone was found to increase mitochondrial permeability transition (MPT) in the liver mitochondria of diabetic rats to a greater extent than in control rats, whereas mitochondrial membrane potential and oxidative phosphorylation were not affected. To identify the factors associated with this increase in susceptibility to MPT in diabetic rats, we assessed the oxidative status of the liver mitochondria and found a decrease in mitochondrial glutathione content and an increase in phospholipid peroxidation. Moreover, incorporation of oxidized cardiolipin, a mitochondrion-specific phospholipid, was involved in the troglitazone-induced alteration in susceptibility to MPT. In conclusion, liver mitochondria display disease-associated mitochondrial lipid peroxidation in T2DM, which facilitates the higher susceptibility to troglitazone-induced MPT. Thus, greater susceptibility of liver mitochondria may be a host factor leading to troglitazone-induced hepatotoxicity in T2DM.
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