Abstract
The aim of this study was to characterize the early alterations of the liver mitochondrial function in ZDF (fa/fa) rats that develop diabetes compared to that of their lean counterparts ZDF (fa/+). Liver mitochondrial function was examined in 11- and 14-week-old ZDF (fa/fa) and ZDF lean (fa/+) rats. Oxygen consumption, H2O2 release, calcium retention capacity (CRC), membrane potential, membrane fluidity, and fatty acid composition were analyzed. State 3 oxygen consumption with palmitoyl-carnitine increases between 11 and 14weeks of age in lean but not in diabetic animals. This response was not seen with other substrates, suggesting that the use of fatty acids is impaired in diabetic rats. H2O2 release was lower in 14-week-old ZDF (fa/fa) rats as compared to ZDF lean (fa/+). These changes were not associated with differences in enzymatic activities of the respiratory complexes, suggesting regulatory mechanisms independent of their expression levels. Membrane fluidity and composition analyses show only slight effects linked to diabetes progression. The most salient feature was a reduction in CRC in the presence of CsA, an effect reflecting PTP dysregulation. Our data suggest few changes of mitochondrial function in ZDF fa/fa rats. At the age of 11weeks, liver mitochondria have mainly a reduced effect of CsA on CRC.
Highlights
Factors underlying the establishment of type 2 diabetes (T2D) have not been fully elucidated despite a large number of investigations in the field; the relationship between insulin resistance, hyperglycemia and mitochondrial function is increasingly gaining interest and remains a new therapeutic approach
H2O2 release and calcium retention capacity (CRC) as well as mitochondrial membrane potential, composition, and specifications to determine whether mitochondrial dysfunction is involved in the early events after establishment of hyperglycemia
Mitochondrial state-3 oxygen consumption was identical in ZDF fa/fa rats compared to ZDF lean, when glutamate/malate or succinate substrates were used (Fig. 1A and B)
Summary
Factors underlying the establishment of type 2 diabetes (T2D) have not been fully elucidated despite a large number of investigations in the field; the relationship between insulin resistance, hyperglycemia and mitochondrial function is increasingly gaining interest and remains a new therapeutic approach More than 10 years later, Ramsey et al presented a study reporting an increase in mitochondrial proton leak in ZDF obese rat (Ramsey et al 1996). A large study performed by Brookes demonstrated that the proton leak at 37°C was similar in obese and control Zucker rats, causing doubt (Brookes et al 1998). These results were reinforced as there is no dysfunction in liver mitochondria extracted from ZDF rats at the age of 11 weeks (Flamment et al 2008). H2O2 release and calcium retention capacity (CRC) as well as mitochondrial membrane potential, composition, and specifications to determine whether mitochondrial dysfunction is involved in the early events after establishment of hyperglycemia
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