Prevalence and Treatment Outcomes of Marine-Lenhart Syndrome in Japan.

INTRODUCTION: Marine-Lenhart syndrome (MLS) is now understood to be a combination of Graves' disease and autonomously functioning thyroid nodule(s) (AFTNs). The prevalence of the syndrome and suitable treatments for those living in iodine-sufficient areas are uncertain. OBJECTIVES: We aimed to investigate the prevalence, treatment, and prognosis of MLS in Japan, an iodine-sufficient area. METHODS: This study involved patients who visited our hospital between February 2005 and August 2019. Among patients with both thyrotoxicosis and thyroid nodule(s) larger than 10 mm, MLS and isolated AFTNs were diagnosed based on serum thyroid-stimulating hormone receptor antibody levels and scintigraphy using radioiodine or technetium-99m and thyroid uptake. RESULTS: Twenty-two patients were found to have MLS, compared to 372 with isolated AFTNs and 8,343 with Graves' disease, during the period. Therefore, the rate of MLS cases was 0.26% among all patients with Graves' disease (22/8,343). Treatments and outcomes were assessed for cases of MLS (n = 18) and isolated AFTNs (n = 269). Antithyroid drugs (ATDs) were withdrawn in 27.8% of cases in the MLS group and 10.3% in the isolated AFTN group. There was no significant difference in the clinical outcome after ATD withdrawal between the 2 groups. However, the rate of hypothyroidism after radioactive iodine (RAI) administration was significantly higher in the MLS group than in the isolated AFTN group (42.9 vs. 9.0%, p = 0.005) despite similar doses of RAI. CONCLUSIONS: The prevalence of MLS among patients with Graves' disease was 0.26% in Japan. RAI therapy induces hypothyroidism more frequently than in those with AFTNs probably because RAI is taken up in the surrounding Graves' tissues.

Serum Thyroid Hormone Balance in Levothyroxine Monotherapy-Treated Patients with Atrophic Thyroid After Radioiodine Treatment for Graves' Disease.

Background: Some studies reported that among athyreotic patients on levothyroxine (LT4) after total thyroidectomy, patients with normal serum thyrotropin (TSH) levels had mildly low serum free triiodothyronine (fT3) levels, whereas patients with mildly suppressed serum TSH levels had normal serum fT3 levels. The reduction of the thyroid volume (TV) after radioiodine treatment for Graves' disease is well known; however, a few studies evaluated thyroidal function including serum triiodothyronine (T3) levels of hypothyroid patients on LT4 after radioiodine treatment in detail. Methods: We retrospectively studied 446 patients treated with LT4 for radioiodine-induced hypothyroidism and who had undergone ultrasonography. We compared serum fT4 and fT3 levels in hypothyroid patients on LT4 who presented an atrophic thyroid change after radioiodine treatment, with those in the euthyroid matched control group with intact thyroids. We also stratified patients with normal TSH levels according to TV and evaluated serum thyroid hormone levels. Results: In 356 of 446 (80%) patients, TV was lower than the lower limit of the 95% reference range of controls. Excluding 43 patients with high serum TSH levels, we assessed thyroid function test results in 313 patients with atrophic thyroid glands. Of these cases, eight patients with strongly suppressed TSH levels had serum fT3 levels that were significantly higher than those in controls (p < 0.001). Overall, 27 patients with mildly suppressed TSH levels had serum fT3 levels equivalent to those in controls (p = 0.386), whereas 278 patients with normal TSH levels had serum fT3 levels that were significantly lower than those in controls (p < 0.001). We also assessed fT3 levels relative to TV in 326 patients with normal TSH levels. Of these cases, in 267 patients with TV less than 5 mL and in 46 patients with TV between 5 and 10 mL, serum fT3 levels were significantly lower than those in controls (p < 0.001). In 13 patients with TV more than 10 mL, serum fT3 levels were equivalent to those in controls (p = 0.844). Conclusions: Serum thyroid hormone balance in most patients on LT4 after radioiodine treatment for Graves' disease was similar to that in athyreotic patients on LT4. Mild TSH suppression with LT4 is needed to achieve normal fT3 levels in such patients.

The association between thyroid hormone balance and thyroid volume in patients with Hashimoto thyroiditis.

While patients with large goitrous thyroid diseases often have a relatively high serum free triiodothyronine (FT3)/free thyroxine (FT4) ratio, athyreotic patients have a relatively low FT3/FT4 ratio. Here we investigated the relationship between thyroid hormone status and thyroid volume (TV) among a large number of euthyroid Hashimoto thyroiditis (HT) patients. We retrospectively enrolled 2,603 untreated HT patients who visited the Kuma hospital from 2012 to 2016, and divided them into four groups as per the TV: normal TV (<20 mL), slight goiter (20 ≤ TV < 50 mL), moderate goiter (50 ≤ TV < 80 mL), and the large goiter group (≥80 mL). Baseline characteristics and laboratory data of each group were compared to those of 1,554 control subjects. The association between FT3/FT4 ratio and TV among HT patients was then analyzed. We observed a change in laboratory parameters among 13 patients in the large goiter group who were prescribed levothyroxine (LT4) for reducing TV. Compared to normal subjects, the moderate and large goiter groups exhibited significantly higher serum FT3 levels, while all HT groups exhibited lower serum FT4 levels. Serum FT3/FT4 ratios showed a positive correlation with TV (r = 0.35, p < 0.01), which was independent of age, sex, body mass index, and TgAb and TSH levels. LT4 treatment lowered serum FT3 levels and FT3/FT4 ratios significantly. Our results indicated that HT patients with increased TV tended to present with high serum FT3, low FT4, and high FT3/FT4 ratios. The elevation of deiodinase activity may be an important factor affecting thyroid hormonal balance in such patients.

Effect of Anagliptin on Glycemic and Lipid Profile in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Anagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor expected to improve the lipid profile as well as glycemic control. However, findings from large-scale prospective trials have not been obtained. METHODS: We performed a multicenter prospective trial in patients with type 2 diabetes receiving anagliptin to evaluate its effect on glycemic control and the lipid profile. A total of 95 patients received anagliptin at 200 mg twice daily. Markers of glucose and lipid metabolism were measured at baseline and after 12 and 24 weeks of administration, and the absolute changes and percent changes were determined. RESULTS: Both HbA1c and plasma glucose were significantly decreased by anagliptin therapy. Regarding the lipid profile, total cholesterol (TC) showed a significant decrease at 12 weeks, while TC, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were significantly decreased at 24 weeks. Multivariate analysis revealed that female sex was an independent predictor of greater reduction of TC, LDL-C, and HDL-C, while a baseline TC level ≥ 200 mg/dL predicted greater reduction of TC and a baseline HDL-C level ≥ 40 mg/dL predicted greater reduction of LDL-C and HDL-C. CONCLUSIONS: This study suggested that anagliptin significantly reduced TC, LDL-C, and HDL-C levels, as well as improving glycemic control, particularly in female patients.

Association of usual sleep quality and glycemic control in type 2 diabetes in Japanese: A cross sectional study. Sleep and Food Registry in Kanagawa (SOREKA).

OBJECTIVES: Excessively short and long sleep durations are associated with type 2 diabetes, but there is limited information about the association between sleep quality and diabetes. Accordingly, the present study was performed to investigate this relationship. MATERIALS AND METHODS: The subjects were 3249 patients with type 2 diabetes aged 20 years or older. Sleep quality was assessed by using the Pittsburgh Sleep Quality Index (PSQI). A higher global PSQI score indicates worse sleep quality, and a global PSQI score >5 differentiates poor sleepers from good sleepers. RESULTS: The mean global PSQI score was 5.94 ± 3.33, and 47.6% of the patients had a score of 6 or higher. Regarding the components of the PSQI, the score was highest for sleep duration, followed by subjective sleep quality and then sleep latency in decreasing order. When the patients were assigned to HbA1c quartiles (≤ 6.5%, 6.6-7.0%, 7.1-7.8%, and ≥ 7.9%), the top quartile had a significantly higher global PSQI score than the other quartiles. The top HbA1c quartile had a sleep duration of only 6.23 ± 1.42 hours, which was significantly shorter than in the other quartiles. Also, sleep latency was 25.3 ± 31.8 minutes in the top quartile, which was significantly longer (by approximately 20 minutes) than in the other quartiles. When analysis was performed with adjustment for age, gender, BMI, smoking, and other confounders, the global PSQI score was still significantly higher and sleep duration was shorter in the top HbA1c quartile (HbA1c ≥ 7.9%). CONCLUSIONS: Japanese patients with type 2 diabetes were found to have poor subjective sleep quality independently of potential confounders, especially those with inadequate glycemic control. Impairment of sleep quality was associated with both increased sleep latency and a shorter duration of sleep.

Hepatic CREB3L3 controls whole-body energy homeostasis and improves obesity and diabetes.

Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor (PPAR) α promoter in an autoloop fashion and is crucial for the ligand transactivation of PPARα by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1α. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes.

The liver-enriched transcription factor CREBH is nutritionally regulated and activated by fatty acids and PPARalpha.

To elucidate the physiological role of CREBH, the hepatic mRNA and protein levels of CREBH were estimated in various feeding states of wild and obesity mice. In the fast state, the expression of CREBH mRNA and nuclear protein were high and profoundly suppressed by refeeding in the wild-type mice. In ob/ob mice, the refeeding suppression was impaired. The diet studies suggested that CREBH expression was activated by fatty acids. CREBH mRNA levels in the mouse primary hepatocytes were elevated by addition of the palmitate, oleate and eicosapenonate. It was also induced by PPARalpha agonist and repressed by PPARalpha antagonist. Luciferase reporter gene assays indicated that the CREBH promoter activity was induced by fatty acids and co-expression of PPARalpha. Deletion studies identified the PPRE for PPARalpha activation. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) assay confirmed that PPARalpha directly binds to the PPRE. Activation of CREBH at fasting through fatty acids and PPARalpha suggest that CREBH is involved in nutritional regulation.