Simultaneous Measurement of Oxygen Consumption and 13C16O2 Production From 13C-Pyruvate in Diabetic Rat Heart Mitochondria

Several investigators have shown defects in energy production in hearts from animal models of diabetes mellitus (DM). These defects generally involve changes in oxidative phosphorylation (ox-phos) or in Krebs cycle functions. Abnormalities in ox-phos have been observed in heart mitochondria isolated from streptozotocin-diabetic (Pierce and Dhalla, 1985) and alloxan-diabetic (Puckett and Reddy, 1979) models as well as in genetic diabetic models (Kuo et al., 1983). In DM mitochondria, State 3 is decreased when a variety of substrates are used: Pyr plus malate and palmitylcarnitine plus malate (Kuo et al., 1983), a-ketoglutarate (Taegtmeyer et al, 1987), glutamate (Mokhtar et al., 1993), 3-hy-droxybutyrate and malate, and acetoacetate plus malate (Grinblat et al., 1986). The RCI also decreased in mitochondria from DM animals. The ADP/O ratio is depressed only in the early stages of chemically induced DM, returning to normal ranges later on, indicating that mitochondria from DM hearts have normal ability to transfer electrons from NADH to O2 or to couple oxidation to phosphorylation. This suggests that the deficiency of energy production is related to a decrease in substrate oxidation through the Krebs cycle. Two important cellular functions which may contribute to abnormal ox-phos are alterations in mi-tochondrial transporter systems (Kazmi et al., 1985; Paulson et al., 1984) and decrease in substrate supply. One possible mechanism of impaired substrate oxidation in the DM heart is abnormal mitochondrial Ca2+ uptake (Baba and Kako, 1991). It is well known that Ca2+ plays an important role in regulation of several matrix dehydrogenases (including PDH