The Mechanism of Impaired T3 Production from T4 in Diabetes

Abstract

Uncontrolled diabetes in man is associated with low serum T3 values and impaired production of T3 from T4. Because the thiol-dependent enzyme T4-5′-deiodinase catalyzes T4-deiodination to T3, the present study was conducted to determine whether these alterations in iodothyronine metabolism consequent to diabetes were due to a reduction in the tissue content of active enzyme or thiol cofactor availability. T4-5′- deiodinase activity and nonprotein sulfhydryl (NP-SH) groups were examined in liver homogenate preparations from groups of rats (T4-treated) diabetic (streptozotocin, 100 mg/kg i.p.) for 48-96 h and compared with controls. The mean hepatic T4-5′-deiodinase activity in the control group was 4.8 ± 0.4 pmol/min/100 mg protein (mean ± SEM). In each of the diabetic groups (48, 72, and 96 h), the mean enzyme activity was significantly less (P < 0.005) than the control mean. Homogenate enrichment with the thiol reagent dithiothreitol (DTT) (5 mM) failed to reverse this diabetic effect. Moreover, although the hepatic content of NP-SH groups was significantly less than the controls after 48 and 72 h of hyperglycemia, it had spontaneously reverted to normal by 96 h. Thus, the impaired enzyme activity could not be attributed to a deficiency of thiol cofactors. The dissociation between enzyme activity and tissue sulfhydryl groups was further illustrated by the response to insulin treatment. Insulin was given by continuous s.c. infusion to 48-h diabetic rats for 48-96 h. Although insulin therapy normalized both enzyme activity and the hepatic thiol content, the temporal profile of each response was different. Insulin therapy rapidly (48 h) corrected the hepatic content of NP-SH groups, whereas the normalization of T4-5′-deiodinase activity required 72-96 h of insulin treatment. There was a positive correlation (r = + 0.69, P < 0.025) between the serum T3 values and hepatic T4-5′-deiodinase activity. The mean serum T3 concentration was significantly reduced (P < 0.001) by the diabetes after 48 h and remained low at 72 and 96 h. Insulin treatment reversed this defect but, as in the case of enzyme activity, the normalization was delayed until 72-96 h of insulin therapy. These results indicate that (1) diabetes reduces serum T3 levels and hepatic T4-5′-deiodinase activity in T4-treated rats, (2) T4-5′-deiodinase is probably the major regulator of serum T3 levels under these conditions, and (3) the reduced T4 -5′-deiodinase activity is independent of changes in the hepatic content of NPSH groups and probably reflects a reduction in the hepatic content of active enzyme.

Somatostatin inhibits rat hepatic T4-5'-deiodinase. The effect is independent of the associated hypoinsulinemia.

“…Somatostatin is known to influence nutriment absorption and carbohydrate metabolism (10,25,26). However, the demonstrated absence of weight loss and the normal hepatic glycogen content in the somatostatin-treated glucose-fed and -refed animals in the present study suggest that there was no impairment of glucose absorption.…”

“…These somatostatin effects on T3 metabolism may have been mediated through a reduction in the activity of tissue T4-5'-deiodinase, the enzyme that regulates extrathyroidal production of T3 from T4 (8). Such a somatostatin effect seems possible as dietary modulation and diabetes significantly alter both T3 metabolism and somatostatin kinetics (9)(10)(11). Fasting and diabetes are associated with an increased pancreatic content of somatostatin and impaired T3 production from T4 (9-11).…”

Effects of nutrients and hormones on transcriptional and post‐transcriptional regulation of fatty acid synthase in rat liver

“…We found that the plasma levels of triiodothyronine of diabetic rats (0.35 f 0.03 ng/ml, mean f SD, n = 3) were much lower than those in normal rats (0.99 f 0.06 ng/ml) [36]. Subsequent treatment with insulin was reported to restore the plasma triiodothyronine level to normal [5]. On the other hand, the plasma triiodothyronine level was not decreased in diabetic rats after fructose feeding [36].…”

“…In the present work, following the cloning of fatty acid synthase cDNA of rat liver, we have investigated the effects of insulin and triiodothyronine on diabetic rats, in which the plasma triiodothyronine level is low [5]. Moreover, individual effects of dietary nutrients on the transcriptional regulation of fatty acid synthase were investigated in detail.…”

Maternal Diabetes Mellitus, a Rat Model for Nonthyroidal Illness: Correction of Hypothyroxinemia with Thyroxine Treatment Does Not Improve Fetal Thyroid Hormone Status

“…Such a decrease was also previously described for both nonpregnant (9,35,36) and pregnant (11) Although treatment with T3 has been recently found to be beneficial after coronary artery bypass surgery (38,39), it is suspected that treatment with T4 is of no benefit to patients with nonthyroidal illness (40,41 …”