Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with huge goitrous Hashimoto's thyroiditis.

PURPOSE: The serum free triiodothyronine (FT3)/free thyroxine (FT4) ratio in patients with huge goitrous Hashimoto's thyroiditis (HG-HT) is relatively high. We investigated the cause of high FT3/FT4 ratios. METHODS: We measured the serum FT3, FT4, and thyrotropin (TSH) levels of seven patients with HG-HT who had undergone a total thyroidectomy. Eleven patients with papillary thyroid carcinoma served as controls. The activities and mRNA levels of type 1 and type 2 iodothyronine deiodinases (D1 and D2, respectively) were measured in the thyroid tissues of HG-HT and perinodular thyroid tissues of papillary thyroid carcinoma. RESULTS: The TSH levels in the HG-HT group were not significantly different from those of the controls. The FT4 levels in the HG-HT group were significantly lower than those of the controls, whereas the FT3 levels and FT3/FT4 ratios were significantly higher in the HG-HT group. The FT3/FT4 ratios in the HG-HT group who had undergone total thyroidectomy and received levothyroxine therapy decreased significantly to normal values. Both the D1 and D2 activities in the thyroid tissues of the HG-HT patients were significantly higher than those of the controls. However, the mRNA levels of both D1 and D2 in the HG-HT patients' thyroid tissues were comparable to those of the controls. Interestingly, there were significant correlations between the HG-HT patients' D1 and D2 activities, and their thyroid gland volume or their FT3/FT4 ratios. CONCLUSIONS: Our results indicate that increased thyroidal D1 and D2 activities may be responsible for the higher serum FT3/FT4 ratio in patients with HG-HT.

Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.

A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1), tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results indicate that irbesartan improves stress-induced adipose tissue inflammation and insulin resistance. Our results suggests that irbesartan treatment exerts additive benefits for glucose metabolism in hypertensive patients with mental stress.

[Drug-induced thyroid dysfunction].

Various drugs may cause thyroid dysfunction. The drugs which may cause thyrotoxicosis include interferon, molecular-targeted agents, amiodarone, thyroid hormone itself and so on. Those which cause hypothyroidism include anti-thyroid drugs, lithium and iodine etc. which inhibit thyroid hormone synthesis and secretion, and dopamine etc. which block TSH secretion. Those drugs which alter the thyroid hormone metabolism or the binding to TBG or those inhibit thyroid hormone absorption may cause hypothyroidism or deteriorate it in patients with hypothyroidism treated with thyroid hormone or those with diminished reserved capacity. When thyroid dysfunction occurred, it is better to discontinue the causative drug, but in many cases, the patients are forced to be treated with the drug being continued.

Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment.

Resveratrol is known to improve endothelial function in animals, but little is known about its effect on human subjects. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors underlying endothelial dysfunction. We hypothesized that the modified resveratrol, Longevinex, improves endothelial function in patients with MetS. Thirty-four patients who had been treated for MetS and lifestyle-related disease were randomly assigned to group A, in which Longevinex was administered for 3 months and then discontinued for 3 months, whereas in the time-matched group B, Longevinex was administered between 3 and 6 months. These 2 groups of patients received similar drugs at baseline for diabetes mellitus, dyslipidemia, or hypertension. Flow-mediated dilatation significantly increased during the administration of Longevinex but decreased to baseline 3 months after the discontinuation of Longevinex in the group A patients. Conversely, in the group B patients, flow-mediated dilatation remained unchanged for the first 3 months without Longevinex but was significantly increased 3 months after the treatment with Longevinex. Longevinex did not significantly affect blood pressure, insulin resistance, the lipid profile or inflammatory markers during 6-month follow-up. These results demonstrate that Longevinex specifically improves endothelial function in subjects with MetS who were receiving standard therapy for lifestyle-related disease.

Comparison of metabolic profile and adiponectin level with pioglitazone versus voglibose in patients with type-2 diabetes mellitus associated with metabolic syndrome.

Type 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versus voglibose on physical and metabolic profiles and serum adiponectin level in patients with T2DM associated with MetS. Sixty patients who were diagnosed for the first time as T2DM associated with MetS were analyzed for insulin sensitivity, lipid profile, serum adiponectin and systemic inflammation. Those patients were randomly assigned to oral pioglitazone group (n = 30) or voglibose group (n = 30) in addition to conventional diet and exercise training. Body mass index and waist circumference did not change in the pioglitazone group, whereas these physical parameters significantly decreased in the voglibose group during a 6-month follow-up period. However, glycosylated hemoglobin, fasting plasma glucose, and HOMA-IR more significantly decreased in the pioglitazone group. The level of serum adiponectin especially high-molecular weight adiponectin markedly increased in the pioglitazone group. Moreover, high sensitive CRP significantly decreased only in the pioglitazone group. These results suggest that voglibose is superior in improving obesity, while pioglitazone is superior in ameliorating insulin sensitivity and increasing serum adiponectin in patients with an early stage of T2DM associated with MetS.

Type 2 iodothyronine deiodinase is expressed in human preadipocytes.

BACKGROUND: Type 2 iodothyronine deiodinase (D2) is an enzyme that catalyzes the production of triiodothyronine (T3) from thyroxine (T4) and plays a critical role in providing the local intracellular T3. Although D2 is highly expressed in brown adipose tissue, it was thought that D2 is hardly expressed in white adipose tissue. In the present study, we examined whether D2 is expressed in human preadipocytes, using human mesenteric and subcutaneous preadipocytes (HMPA and HSCPA, respectively). METHODS: HMPA and HSCPA were purchased and cultured in the preadipocyte medium containing 10% fetal bovine serum. We measured D2 activity and mRNA level in HMPA and HSCPA incubated with or without dibutyryl cyclic adenosine monophosphate [(Bu)2cAMP]. RESULTS: D2 activity and mRNA were detectable in human HMPA and HSCPA. The apparent Michaelis-Menten constant (K(m)) value for T4 in HMPA was 2.1 ± 0.2 nM, and the maximum velocity (V(max)) value was 333.3 ± 28.0 femtomols of I⁻ released/mg protein/hour, respectively. On the other hand, the apparent K(m) value for T4 in HSCPA was 2.0 ± 0.2 nM and the V(max) value was 91.2 ± 8.7 femtomols of I⁻ released/mg protein/hour, respectively. D2 activities in HMPA and HSCPA incubated with 1 mM (Bu)2cAMP for 24 hours were 7-fold (HMPA) and 3-fold (HSCPA) higher than those without (Bu)2cAMP, respectively. D2 mRNA levels in HMPA and HSCPA incubated with 1 mM (Bu)2cAMP for 3 hours were 10-fold (HMPA) and 5-fold (HSCPA) higher than those without (Bu)2cAMP, respectively. CONCLUSIONS: In the present study, we have clearly demonstrated that D2 activity and mRNA are present in the human preadipocytes from both mesenteric and subcutaneous adipose tissue. Our experiments are the first ones that identify human preadipocytes as one of the sources of T3 production.

Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with 3,5,3'-triiodothyronine-predominant Graves' disease.

OBJECTIVE: 3,5,3'-triiodothyronine-predominant Graves' disease (T(3)-P-GD) is characterized by a persistently high serum T(3) level and normal or even lower serum thyroxine (T(4)) level during antithyroid drug therapy. The source of this high serum T(3) level has not been clarified. Our objective was to evaluate the contribution of type 1 and type 2 iodothyronine deiodinase (D1 (or DIO1) and D2 (or DIO2) respectively) in the thyroid gland to the high serum T(3) level in T(3)-P-GD. METHODS: We measured the activity and mRNA level of both D1 and D2 in the thyroid tissues of patients with T(3)-P-GD (n=13) and common-type GD (CT-GD) (n=18) who had been treated with methimazole up until thyroidectomy. RESULTS: Thyroidal D1 activity in patients with T(3)-P-GD (492.7±201.3 pmol/mg prot per h) was significantly higher (P<0.05) than that in patients with CT-GD (320.7±151.9 pmol/mg prot per h). On the other hand, thyroidal D2 activity in patients with T(3)-P-GD (823.9±596.4 fmol/mg prot per h) was markedly higher (P<0.005) than that in patients with CT-GD (194.8±131.6 fmol/mg prot per h). There was a significant correlation between the thyroidal D1 activity in patients with T(3)-P-GD and CT-GD and the serum FT(3)-to-FT(4) ratio (r=0.370, P<0.05). Moreover, there was a strong correlation between the thyroidal D2 activity in those patients and the serum FT(3)-to-FT(4) ratio (r=0.676, P<0.001). CONCLUSIONS: Our results suggest that the increment of thyroidal deiodinase activity, namely D1 and especially D2 activities, may be responsible for the higher serum FT(3)-to-FT(4) ratio in T(3)-P-GD.

Thyroid hormone activation in vascular smooth muscle cells is negatively regulated by glucocorticoid.

BACKGROUND: Type 2 iodothyronine deiodinase (D2) catalyzes the production of triiodothyronine from thyroxine. D2 is present in rat aorta media, and there is a circadian variation in the D2 expression. In rat aorta media, the D2 activity exhibited the maximal value at 1200 hour and low value between 1800 and 2400 hour. To understand the mechanisms that induce the circadian variation in the D2 expression, we examined the effects of glucocorticoid on the D2 activity and mRNA in rat aorta media and cultured vascular smooth muscle cells (VSMCs). METHODS: The effects of intrinsic and extrinsic glucocorticoid on the D2 activity and mRNA in rat aorta media were studied using metyrapone, a corticosterone synthesis inhibitor, and dexamethasone (DEX). Further, the effects of DEX on D2 expression were studied using the cultured rat VSMCs. RESULTS: The trough values of D2 activity and mRNA at 2100 hour were increased by the treatment with metyrapone. On the other hand, the peak values of D2 activity and mRNA were decreased by the treatment with DEX. D2 activity and mRNA in cultured rat VSMCs were increased by the addition of 10(-3) M dibutyryl cyclic adenosine monophosphate [(Bu)(2)cAMP]. The increments were reduced by coincubation with 10(-6) M DEX. CONCLUSIONS: These results suggest that glucocorticoids might directly suppress the D2 expression in rat VSMCs induced by a cAMP-dependent mechanism.

3,5,3'-Triiodothyronine thyrotoxicosis due to increased conversion of administered levothyroxine in patients with massive metastatic follicular thyroid carcinoma.

OBJECTIVE: Some patients with massive metastatic thyroid carcinoma exhibit T(3) thyrotoxicosis. We investigated the prevalence and cause of T(3) thyrotoxicosis and the clues to the diagnosis. DESIGN: Serum free T(3) (FT(3)), free T(4) (FT(4)), and TSH were measured in patients with massive metastases from papillary, follicular, or medullary thyroid carcinomas (31, 20, and seven patients, respectively). Patients without recurrence served as controls. Thyrotoxic patients were reexamined 1 wk after withdrawal of levothyroxine. Type 1 and type 2 iodothyronine deiodinase (D1 and D2) activities were measured in three tumor tissues from thyrotoxic patients. MAIN OUTCOME: The serum FT(3) level and FT(3)/FT(4) ratio in the follicular carcinoma (FC) group were significantly higher than those in the papillary carcinoma group or patients without recurrence. Four patients (20%) in the FC group but none in the other groups demonstrated T(3) thyrotoxicosis or a FT(3)/FT(4) ratio greater than 3.5. One week after withdrawal of levothyroxine, both FT(3) and FT(4) levels decreased. Retrospective measurements of FT(3) in frozen stored sera demonstrated that FT(3) exceeded the upper normal limit when FT(4) began to decrease but remained within the normal range. Tumor tissues showed high D1 and D2 activities. CONCLUSIONS: Twenty percent of patients with massive metastatic FC exhibited T(3) thyrotoxicosis, most likely due to increased conversion of T(4) to T(3) by tumor expressing high D1 and D2 activities. Occasional measurement of serum FT(3) in addition to FT(4) and TSH is recommended in patients with massive metastatic FC, especially when serum FT(4) decreases on fixed doses of levothyroxine.