Alterations in hepatic monodeiodination of iodothyronines in the diabetic rat.

Streptozotocin (65 mg/kg body weight) or vehicle was administered intravenously to rats on day 1 and thyroid function and monodeiodination of iodothyronines by liver homogenates were examined on day 7. Serum glucose concentration was markedly elevated in streptozotocin-treated animals (mean ± SEM, 476 ± 21 vs. 144 ± 5.6, mg/dl, p <0.001). The mean serum concentration of free T3 in streptozotocin-treated diabetic animals was significantly less than that in vehicle-injected control rats, the mean serum concentration of free T4 and TSH in diabetic rats did not differ significantly from the corresponding values in control rats. Outer ring monodeiodination of T4 by liver homogenates was much lower in diabetic rats than in control rats. This was the case in the presence as well as in the absence of 4 nM dithiothreitol (DTT), a potent doner of thiol (SH) groups. That a reduction in available SH groups is not a major factor responsible for reduced hepatic T4 to T3 converting activity in diabetes mellitus was also suggested by the finding of a similar concentration of nonprotein SH groups in the liver of diabetic and control rats. These findings suggest that observed reduction in hepatic T4 to T3 converting activity is probably due to a reduction in the T4 5′-monodeiodinase. Like T4 to T3 conversion, hepatic outer ring monodeiodination of reverse T3 (rT3) (to 3,3′-diiodothyronine, 3,3′-T2) and 3′,5′-T2 (to 3′-monoiodothyronine, 3′-1) were also reduced in the diabetic rat. These data support previous findings suggesting that there is just one outer ring monodeiodinase that acts on various iodothyronines. There was also a reduction in hepatic inner ring monodeiodination of T3 (to 3,3′-T2) and 3,5-T2 (to 3-T1). The various monodeiodinations were also compared in liver homogenates of control and diabetic rats given exogenous T4 (1 μg/100 g.b.w./day) throughout the experiment. There was no reduction or only a modest reduction (that was not significant statistically) in the various monodeiodinations by liver homogenates of T4 treated diabetic rats. Serum T4 was significantly higher and serum T3 moderately higher in diabetic animals that received exogenous T4 than in those that did not. Similarly, hepatic monodeiodination of various iodothyronines was generally greater in diabetic rats given T4 than in those not given T4. These findings suggest that the reduction in the circulating thyroid hormones, described already, may have an important role in sustaining the reduction in hepatic monodeiodination of iodothyronines in diabetes mellitus. It is clear now that extrathyroidal monodeiodination of thyroxine (T4) is the major source of 3,5,3′-triiodothyronine (T3) in man and experimental animals (1–7). There are a number of clinical conditions in which the contribution of the extrathyroidal source of T3 to the total daily production of T3 is markedly reduced (7). These situations, which are often referred to as the low T3 syndrome, are characterized by a subnormal serum T3 concentration in combination with a normal or low serum T4 and a normal of high reverse T3 (rT3) concentrations (5,7). When the nature of T4 to T3 converting activity in tissues of experimental animals is examined, the data suggest that the activity is enzymic in nature (8,9), that thiol (SH) groups constitute a vital cofactor for the activity (10,11), and that the activity is located predominantly in microsomal and/or plasma membrane fractions of liver and kidney homogenates (12–14). Other studies in fetuses of various experimental species (11,15–17) and in the fasted rat (9,17–19) have revealed that there may be more than one mechanism of reduced hepatic conversion of T4 to T3. For example, it appears that diminished T4 to T3 avtivity in sheep fetal liver is due mainly to a reduction in hepatic concentration of SH groups (11) whereas the reduction of the activity in the liver of fasted rat is due to a combination of the reduction in the concentration of the 5′-monodeiodinase and SH groups (19). Insulin dependent diabetes mellitus has been recently described as another example of the low T3 syndrome (20–22). In addition, reduction in T4 to T3 converting activity has been described in liver slices of diabetic rats (18). However, there is little information on the mechanism of this reduction. The present study was undertaken to gather insight ito this amtter. We also examined the alterations of outer ring monodeiodination of some other iodothyronines, i.e., 3,3′5′-T3 and of 3′,5′-diiodothyronine (3′,5′-T2) in diabetes mellitus. This was of interest because recent studies have indicated marked similarities in many characteristics of the process of outer ring monodeiodination of several iodothyronines. This in turn has raised the possibility that there is only one 5′-monodeiodinase enzyme responsible for outer ring monodeiodination of various iodothyronines (23). Hence, it was important to determine whether the alterations in 5′-monodeiodination of iodothyronines observed in diabetes mellitus supported this concept. There is also a paucity of information on the changes in inner ring monodeiodination od iodothyronines in the low T3 syndrome. Therefore, we have also included in this report the results of our studies of inner ring monodeiodination of T3 to 3,3′ -T2 and of 3,5-T2 to 3-T1. These studies show that diabetes mellitus in the rat is associated with reduction in inner ring as well as outer ring monodeiodination of iodothyronines.