Koji Mukasa

Dehydroepiandrosterone (DHEA) ameliorates the insulin sensitivity in older rats

To evaluate whether dehydroepiandrosterone (DHEA) ameliorates the decreased insulin sensitivity in older rats, hyperinsulinemic euglycemic clamp studies were performed in rats of various age groups previously treated with DHEA. The glucose metabolic clearance rate (MCR) of the control rats showed a gradual decline with the advancing ages (MCR = 13.05 - 0.027*age (days), r2=0.683, p < 0.01, n = 18). The glucose MCR of the DHEA-treated rats also showed a gradual decline with the aging process (MCR = 12.67 - 0.011*age (days), r2=0.429, p < 0.01, n = 18). However, the MCR of the DHEA-treated rats were significantly higher than that of control rats. As glucose MCR is a parameter which indicates the insulin sensitivity in various tissues, especially in muscles and body composition, was not changed after the injection of DHEA, DHEA is considered to work on muscles to increase insulin sensitivity.

Prevention of diabetes, hepatic injury, and colon cancer with dehydroepiandrosterone.

The levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) peak in human in their twenties, then decrease gradually with age. The physiological importance of DHEA was not clear until recent research reports showing that DHEA has beneficial effects on preventing diabetes, malignancy, inflammation, osteoporosis, and collagen disease. We summarize our results concerning diabetes, hepatitis, and colon cancer. In 1982, Coleman et al. [Diabetes 31 (1982) 830] reported that DHEA decreased hyperglycemia in diabetic db/db mice, which become insulin resistant. We measured hepatic gluconeogenic enzymes in an attempt to elucidate the mechanical mechanism of DHEA action. The activity and gene expression of hepatic gluconeogenic enzyme such as glucose-6-phosphatase (G6Pase) was increased in db/db mice despite hyperinsulinemia compared to control db/+m mice. DHEA, like troglitazone, decreased these levels in db/db mice. We also showed that DHEA improved the insulin resistance caused by aging or obesity using the glucose clamp technique in another animal model. In humans, the serum DHEA concentration was shown to be associated with hyperinsulinemia in diabetes. It also became clear that DHEA increased insulin secretion in old-aged db/db mice. DHEA increases not only insulin sensitivity due to the effects in the liver and muscle, but also insulin secretion. As an effect of DHEA on T-cell mediated hepatitis induced by concanavalin A (ConA), DHEA reduced hepatic injury by inhibiting several inflammatory mediators and apoptosis. As an effect of DHEA on carcinogenesis, DHEA would be a potential chemopreventative agent against colon cancer because it decreases the number of azoxymethane (AOM) induced aberrant crypt foci, which is a possible precursor to adenoma and cancer in a murine model.Thus, since DHEA has many beneficial effects experimentally, we should consider administration of DHEA in the future, and common mechanisms among these actions of DHEA should be elucidated in further studies.

Hepatotoxicity and cutaneous reactions after antithyroid drug administration

Use of the antithyroid drugs (ATDs) thiamazole (MMI) and propylthiouracil (PTU) is associated with a high frequency of side effects. When patients experience side effects with one (the 1st) ATD, it is usually discontinued and another is administered (the 2nd ATD). We investigated side effects associated with the 1st and 2nd ATDs.

mRNA and enzyme activity of hepatic 11β-hydroxysteroid dehydrogenase type 1 are elevated in C57BL/KsJ-db/db mice

To evaluate the importance of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in insulin resistant diabetic C57BL/KsJ-db/db mice, we measured the activity and mRNA level of 11beta-HSD1 in the liver of db/db mice and their heterozygote litter mates, db/+m mice. The blood glucose, plasma insulin, and corticosterone levels of db/db mice were significantly higher than those of db/+m mice. Despite hyperinsulinemia, the activity level of this enzyme was significantly higher in db/db mice, and the mRNA level of hepatic 11beta-HSD1 was also significantly higher in db/db mice. Since hepatic 11beta-HSD1 in vivo mainly functions as 11-keto-reductase and does not work as 11beta-oxidase, these results suggest that the rate of hepatic conversion of 11-dehydrocorticosterone to corticosterone is increased in db/db mice, resulting in higher glucocorticoid activity in the liver. The increased hepatic corticosterone concentration due to the elevation of 11beta-HSD1 and high plasma corticosterone concentration may antagonize the action of insulin and cause insulin resistance. These findings have a potentially important implication for relationships between increased hepatic 11beta-HSD1 and insulin resistance in db/db mice. The present paper is the first to demonstrate the increased activities and mRNA level of hepatic 11beta-HSD1 in db/db mice.

Lower incidence of postpartum thyrotoxicosis in women with Graves disease treated by radioiodine therapy than by subtotal thyroidectomy or with antithyroid drugs.

Purpose of the Report The incidence of postpartum thyrotoxicosis (PT) in Graves disease (GD) patients treated with antithyroid drugs (ATDs) is higher than in the general population, but the incidence of PT among GD patients who had been treated with radioiodine (RI) or by subtotal thyroidectomy before their pregnancy is not well known. Subjects and Methods We reviewed the cases of women with GD who had become pregnant, and we selected the 188 women who had undergone RI therapy before the pregnancy and the 148 women who had undergone subtotal thyroidectomy for GD before the pregnancy as the subjects of this study. The ATD subjects were 107 women with GD who had become pregnant after being treated with ATDs alone before their pregnancy and were in remission before and throughout the pregnancy. Results The overall incidence of PT was 2.1% (4/188) in the RI group, 23.6% (35/148) in the subtotal thyroidectomy group, and 55.1% (59/107) in the ATD group. There were no cases of permanent thyrotoxicosis in the RI group. Conclusions The incidence of PT among women with GD who have undergone RI therapy before their pregnancy was significantly low compared to thyroidectomy group and ATD group. This finding is interesting because the incidence of PT in the RI group was lower than subtotal thyroidectomy group even though thyroid volume had been greatly reduced by thyroidectomy. RI treatment is recommended in the choice of treatment for childbearing-age women as regards the risk of postpartum recurrence.

Inhibitory effect of low-dose inorganic iodine on thyroidal radioactive iodine uptake in healthy Japanese adults.

In the event of a nuclear power plant accident, prophylactic administration of potassium iodide (KI) is recommended to prevent thyroid damage due to uptake of radioiodine. To assess the inhibitory effect of low-dose inorganic iodine on thyroidal radioactive iodine uptake (RAIU) in healthy adults without dietary iodine restriction, single or repeated doses of 10 mg inorganic iodine solution were given to 22 Japanese volunteers, 18 men and 4 women with the mean age of 35.7 years, between 2011 and 2013. Changes in urinary iodine excretion, thyroid function and 24-hour RAIU were also evaluated. The median 24-hour RAIU without iodine restriction was 13% (range, 5-26%). A single-dose of 10 mg inorganic iodine suppressed the median 24-hour RAIU measured one hour after iodine administration to 3% (range, 1-7 %) and, in 90.9% of 22 participants their 24-hour RAIU was < 5%. For seven participants given 10 mg of inorganic iodine daily for 14 days, the median 24-hour RAIU measured at 24 hours after the last administration of iodine was 6% (range, 2-12%), although the inhibitory effect was diminished in two participants. Serum thyroid stimulating hormone concentration was slightly elevated in three participants without decreased serum FT3 and FT4 levels. We conclude that a single-dose of 10 mg inorganic iodine is sufficient to inhibit RAIU in adults, although the inhibitory effect of repeated-dose on RAIU is diminished when KI is given once daily. The dose, duration or interval of iodine administration should be evaluated in iodine-sufficient regions in a future.

Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves’ disease

Background Euthyroid Graves’ disease (EGD) is a rare condition defined as the presence of thyroid-associated ophthalmopathy (TAO) in patients with normal thyroid function. Due to the rarity of this disease, only a limited number of studies and case reports are available for further evaluation of the characteristics of the disease. The aim of this study was to examine the changes in the thyroid function, thyrotropin receptor antibodies (TRAb) and eye symptoms, and then determine whether TRAb is related to TAO in EGD patients. TRAb in this study was defined as including both thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSAb). Patients and methods Medical records of patients diagnosed with EGD were reviewed. Ophthalmologists specializing in TAO examined the eyes of all subjects. Results Of the 58 patients diagnosed with EGD, 24.1% developed hyperthyroidism, while 3.4% developed hypothyroidism. A total of 72.4% of the 58 patients remained euthyroid throughout the entire follow-up period. At the initial presentation, TBII and TSAb were positive in 74.5% and 70.5%, respectively. Ophthalmic treatments were administered to 30 (51.7%) out of the 58 patients. A significant spontaneous improvement of the eye symptoms was found in 28 of the EGD patients who did not require eye treatments. EGD patients exhibited positive rates for both TBII and TSAb, with the number of the TRAb-positive patients gradually decreasing while the eye symptoms spontaneously improved over time. There were no correlations found between TRAb at initial presentation and the eye symptoms. Conclusion TBII and TSAb were positive in about 70% of EGD patients at their initial visit. Thyroid functions of EGD patients who have been euthyroid for more than 6.7 years may continue to remain euthyroid in the future.