POSSIBLE ROLE OF CORTICOSTERONE IN THE DOWN-REGULATION OF THE HYPOTHALAMO-HYPOPHYSEAL-THYROID AXIS IN STREPTOZOTOCIN-INDUCED DIABETES-MELLITUS IN RATS

We investigated the effects of diabetes mellitus on the hypothalamo-hy pophysial-thyroid axis in male (RxU) F-1 and R-Amsterdam rats, which w ere found to respond to streptozotocin (STZ)-induced diabetes mellitus with no or marked increases, respectively, in plasma corticosterone. Males received STZ (65 mg/kg i.v.) or vehicle, and were killed 1, 2 or 3 weeks later. At all times studied, STZ-induced diabetes mellitus re sulted in reduced plasma TSH, thyroxine (T-4) and 3,5,3'-tri-iodothyro nine (T-3). Since the dialyzable T-4 fraction increased after STZ, pro bably as a result of decreased T-4-binding prealbumin, plasma free T-4 was not altered during diabetes. In contrast, both free T-3 and its d ialyzable fraction decreased during diabetes, which was associated wit h an increase in T-4-binding globulin. Hepatic activity of type I deio dinase decreased and T-4 UDP-glucuronyltransierase increased after STZ treatment. Thus, the lowered plasma T-3 during diabetes may be due to decreased hepatic T-4 to T-3 conversion. Median eminence content oi T RH increased after STZ, suggesting that hypothalamic TRH release is re duced during diabetes and that this is not caused by impaired synthesi s or axonal transport of TRH to the median eminence. Hypothalamic proT RH mRNA did not change in diabetic (RxU) F-1 rats during the period of observation, but was lower in R-Amsterdam rats 3 weeks after STZ. Sim ilarly, pituitary TSH and TSH beta mRNA had decreased in R-Amsterdam r ats by 1 week after STZ treatment, but did not change in (RxU) F-1 rat s. The difference between the responses in diabetic R-Amsterdam and (R xU) F-1 rats may be explained on the basis of plasma corticosterone le vels which increased in R-Amsterdam rats only. Hypothalamic TRH conten t was not affected by diabetes mellitus, but the hypothalami of diabet ic rats released less TRH in vitro than those of control rats. Moreove r, insulin had a positive effect on TRH release in vitro. In conclusio n, the reduced hypothalamic TRH release during diabetes is probably no t caused by decreases in TRH synthesis or transport to the median emin ence, but seems to be due to impaired TRH release from the median emin ence which may be related to the lack of insulin. Inhibition of proTRH and TSH beta gene expression in diabetic R-Amsterdam rats is not a pr imary event but appears to be secondary to enhanced adrenal activity i n these animals during diabetes.