Liraglutide Activates Type 2 Deiodinase and Enhances ß3-Adrenergic-Induced Thermogenesis in Mouse Adipose Tissue.

Aims: Liraglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist used as an anti-hyperglycemic agent in type 2 diabetes treatment and recently approved for obesity management. Weight loss is attributed to appetite suppression, but therapy may also increase energy expenditure. To further investigate the effect of GLP-1 signaling in thermogenic fat, we assessed adipose tissue oxygen consumption and type 2 deiodinase (D2) activity in mice treated with liraglutide, both basally and after ß3-adrenergic treatment. Methods: Male C57BL/6J mice were randomly assigned to receive liraglutide (400 µg/kg, n=12) or vehicle (n=12). After 16 days, mice in each group were co-treated with the selective ß3-adrenergic agonist CL316,243 (1 mg/kg, n=6) or vehicle (n=6) for 5 days. Adipose tissue depots were assessed for gene and protein expression, oxygen consumption, and D2 activity. Results: Liraglutide increased interscapular brown adipose tissue (iBAT) oxygen consumption and enhanced ß3-adrenergic-induced oxygen consumption in iBAT and inguinal white adipose tissue (ingWAT). These effects were accompanied by upregulation of UCP-1 protein levels in iBAT and ingWAT. Notably, liraglutide increased D2 activity without significantly upregulating its mRNA levels in iBAT and exhibited additive effects to ß3-adrenergic stimulation in inducing D2 activity in ingWAT. Conclusions: Liraglutide exhibits additive effects to those of ß3-adrenergic stimulation in thermogenic fat and increases D2 activity in BAT, implying that it may activate this adipose tissue depot by increasing intracellular thyroid activation, adding to the currently known mechanisms of GLP-1A-induced weight loss.

The impact of selective serotonin reuptake inhibitors on the thyroid function among patients with major depressive disorder: A systematic review and meta-analysis.

Selective serotonin reuptake inhibitors (SSRI) have been claimed to negatively affect the thyroid function, albeit the evidence is controversial. We searched for studies that measured parameters of thyroid function (TSH, T4, Free T4, or T3) before and after a course of SSRI treatment in euthyroid patients with major depressive disorder. Electronic searches were conducted on MEDLINE, Embase and Web of Science databases from inception through April 4th, 2018. We performed random-effects meta-analyses to estimate the effect of SSRIs on each hormone. A total 1791 records were identified in the electronic search, and 14 observational clinical studies were included in the analyses. All studies had at least moderate risk of bias and were considered of low quality. A course of SSRI treatment was associated with a decrease in T4 of -6.58 nmol/L (95% Confidence Interval [CI], -12.17 to -.99, p = .005, I2=97%; Cohen's d = .50), a decrease in Free T4 of -.91 pmol/L (95% CI, -1.65 to -.16, p = .017, I2=96%; Cohen's d = .66), and a decrease in T3 of -.10 nmol/L (95% CI, -.18 to -.03, p = .007, I2=96%; Cohen's d = .45), and no effect on TSH (0.06 microIU/L, 95% CI, -.05 to .17, p = .285, I2=98%; Cohen's d = .17). We did not detect publication bias in any of the four meta-analyses. We conclude that there is preliminary evidence that SSRIs slightly decrease thyroid function, but quality of evidence is low. Clinical magnitude of such effect is yet unclear.

Abnormal Thyroid Hormone Status Differentially Affects Bone Mass Accrual and Bone Strength in C3H/HeJ Mice: A Mouse Model of Type I Deiodinase Deficiency.

C3H/HeJ (C3H) mice are deficient of type I deiodinase (D1), an enzyme that activates thyroid hormone (TH), converting thyroxine (T4) to triiodothyronine (T3). Nevertheless, C3H mice present normal serum T3 and a gross euthyroid phenotype. To investigate if a global D1 deficiency interferes in the TH effects on bone, we compared bone growth, bone mass accrual and bone strength of C3H and C57BL/6J (B6) mice under abnormal TH status. Four-week-old female mice of both strains were grouped as Euthyroid, Hypothyroid (pharmacologically-induced), 1xT4 and 10xT4 (hypothyroid animals receiving 1- or 10-fold the physiological dose of T4 /day/16 weeks). Hypothyroidism and TH excess similarly impaired body weight (BW) gain and body growth in both mice strains. In contrast, whereas hypothyroidism only slightly impaired bone mineral density (BMD) accrual in B6 mice, it severely impaired BMD accrual in C3H mice. No differences were observed in serum and bone concentrations of T3 between hypothyroid animals of both strains. Interestingly, treatment with 10xT4 was less deleterious to BMD accrual in C3H than in B6 mice and resulted in less elevated T3 serum levels in B6 than in C3H mice, which is probably explained by the lower D1 activity in C3H mice. In addition, hypothyroidism decreased bone strength only in C3H but not in B6 mice, while TH excess decreased this parameter in both strains. These findings indicate that D1 deficiency contributes to the TH excess-induced differences in bone mass accrual in C3H vs. B6 mice and suggest that deiodinase-unrelated genetic factors might account for the different skeleton responses to hypothyroidism between strains.

Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Dissecting thyroid hormone transport and metabolism in dendritic cells.

We reported thyroid hormone (TH) receptor expression in murine dendritic cells (DCs) and 3,5,3'-triiodothyronine (T3)-dependent stimulation of DC maturation and ability to develop a Th1-type adaptive response. Moreover, an increased DC capacity to promote antigen-specific cytotoxic T-cell activity, exploited in a DC-based antitumor vaccination protocol, was revealed. However, putative effects of the main circulating TH, l-thyroxine (T4) and the mechanisms of TH transport and metabolism at DC level, crucial events for TH action at target cell level, were not known. Herein, we show that T4 did not reproduce those registered T3-dependent effects, finding that may reflect a homoeostatic control to prevent unspecific systemic activation of DCs. Besides, DCs express MCT10 and LAT2 TH transporters, and these cells mainly transport T3 with a favored involvement of MCT10 as its inhibition almost prevented T3 saturable uptake mechanism and reduced T3-induced IL-12 production. In turn, DCs express iodothyronine deiodonases type 2 and 3 (D2, D3) and exhibit both enzymatic activities with a prevalence towards TH inactivation. Moreover, T3 increased MCT10 and LAT2 expression and T3 efflux from DCs but not T3 uptake, whereas it induced a robust induction of D3 with a parallel slight reduction in D2. These findings disclose pivotal events involved in the mechanism of action of THs on DCs, providing valuable tools for manipulating the immunogenic potential of these cells. Furthermore, they broaden the knowledge of the TH mechanism of action at the immune system network.

Effect of an Outreach Programme on Vandetanib Safety in Medullary Thyroid Cancer.

OBJECTIVES: Effective management of adverse events (AEs) following vandetanib treatment is important to maximize clinical benefits. We examined whether more frequent contact with vandetanib-treated patients reduced AEs of CTCAE grade 2 or higher. STUDY DESIGN: In this open-label, multicentre, phase III study, patients with locally advanced or metastatic medullary thyroid cancer were randomized to a patient outreach programme (outreach) or a standard AE monitoring schedule (vandetanib control) for 52 weeks. In addition to standard AE monitoring, patients in the outreach arm were contacted every 2 weeks by telephone/during their clinic visit for specific AE questioning related to diarrhoea, nausea, vomiting, fatigue, headache and rash. Patients received vandetanib at 200 or 300 mg/day, depending on the creatinine levels at screening. RESULTS: Altogether, 205 patients were randomized (outreach, n = 103; vandetanib control, n = 102). This study did not meet its primary objective; the mean percentage of time patients experienced at least one AE of grade 2 or higher was higher for the outreach group (51.65%) than for the vandetanib control group (45.19%); the difference was not statistically significant (t statistic: 1.29; 95% CI -3.44 to 16.37%; p = 0.199). The most frequently reported AEs were diarrhoea (56.9% for the outreach group vs. 46.6% for the vandetanib controls), hypertension (36.3 vs. 31.1%), rash (25.5 vs. 24.3%) and nausea (25.5% vs. 18.4%), and the most frequently reported AEs of grade 2 or higher were hypertension (33.3 vs. 23.3%), diarrhoea (26.5 vs. 24.3%) and dermatitis acneiform (11.8 vs. 9.7%). CONCLUSIONS: Additional outreach to patients treated with vandetanib had no impact on the rate or severity of AEs compared to the standard AE monitoring schedule. AEs were consistent with the known safety profile of vandetanib.

Fatty acid composition of serum lipid fractions in type 2 diabetic patients with microalbuminuria.

OBJECTIVE: To determine the fatty acid composition of serum phospholipid, triglyceride, and cholesterol ester fractions and to analyze the lipid profile of microalbuminuric type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A case-control study was conducted with 72 patients: 37 were normoalbuminuric (urinary albumin excretion rate [UAER] <20 microg/min), and 35 were microalbuminuric (UAER 20-200 microg/min). After 4 weeks of a standardized diet, the fatty acid composition of phospholipid, triglyceride, and cholesterol ester fractions was determined by gas chromatography. Total cholesterol and triglycerides were measured by enzymatic-colorimetric methods; cholesterol HDL by double precipitation with heparin, MnCl(2), and dextran sulfate; and apolipoprotein B by immunoturbidimetry. RESULTS: Microalbuminuric patients showed a lower proportion of polyunsaturated fatty acids (24.8 +/- 11.0%), especially of the n-6 family (21.7 +/- 10.5%), in triglyceride fraction than normoalbuminuric patients (34.1 +/- 11.3%, P = 0.001 and 31.4 +/- 11.5%, P < 0.001, respectively). Patients with microalbuminuria also presented higher levels of saturated fatty acids in triglyceride fraction (43.4 +/- 18.0% vs. 34.7 +/- 13.1%, P = 0.022). In the logistic regression analysis, only the proportion of polyunsaturated fatty acids in triglyceride fraction remained significantly associated with microalbuminuria (odds ratio [OR] 0.92, 95% CI 0.85-0.98, P = 0.019). Total cholesterol, HDL cholesterol, triglyceride, and apolipoprotein B levels were similar in normo- and microalbuminuric patients. CONCLUSION: Microalbuminuria in type 2 diabetic patients is associated with low polyunsaturated fatty acid contents in serum triglyceride fraction. This association may represent a risk factor for cardiovascular disease and may contribute to the progression of renal disease.

ACE and PC-1 gene polymorphisms in normoalbuminuric Type 1 diabetic patients: a 10-year prospective study.

The aim of this study was to analyze the role of ACE gene insertion/deletion (I/D) and PC-1 gene K121Q polymorphisms in the changes of glomerular filtration rate (GFR), urinary albumin excretion rate (UAER), and blood pressure (BP) levels in a cohort of normoalbuminuric Type 1 diabetic patients. This is a 10.2+/-2.0-year prospective study of 30 normotensive normoalbuminuric Type 1 diabetic patients. UAER (immunoturbidimetry), GFR ((51)Cr-EDTA single injection technique), GHb (ion exchange chromatography), and BP levels were measured at baseline and at 1.7+/-0.6-year intervals. The presence of ACE gene I/D and PC-1 gene K121Q polymorphisms was determined by polymerase chain reaction (PCR) and restriction enzyme techniques. Three patients developed diabetic nephropathy (DN), all carriers of allele D. The presence of allele D was the only predictor (R(2)=.15, F=4.92, P=.035) of the observed GFR decline (-0.29+/-0.34 ml/min/month, P<.05). UAER increased during the study (log UAER=0.0275+/-0.042 microg/min/month, P=.002) and was associated with baseline UAER levels only (R(2)=.17, F=5.72, P=.024). A significant increase (P<.05) in cases of hypertension and retinopathy were observed in ID/DD (n=19) and not in II patients (n=11). Patients with the KQ/QQ genotype (n=8) presented a significant increase (P=.045) in new cases of retinopathy. In conclusion, the presence of the ACE gene D allele in this sample of normoalbuminuric normotensive Type 1 diabetic patients was associated with a higher proportion of microvascular complications and hypertension.

D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients.

Type 2 deiodinase (D2) converts T4 into its active metabolite T3, an essential step in thyroid metabolism. A Thr92Ala polymorphism in the gene encoding D2 has been inconsistently associated with insulin resistance (IR). Recently, it was reported that the D2 Thr92Ala (rs225014) and the peroxisome proliferator-activated receptor (PPAR) γ2 Pro12Ala (rs1801282) polymorphisms interact in the modulation of metabolic syndrome in nondiabetic subjects. Here, we investigated the effect of both polymorphisms, isolated or in combination, on IR in patients with type 2 diabetes mellitus (DM2). The D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms were genotyped in 721 DM2 patients. IR was evaluated using the homeostasis model assessment-IR (HOMA(IR)) index in a subgroup of 246 DM2 subjects. The frequencies of D2 Ala92 and PPARγ2 Ala12 variants were 0.390 and 0.074, respectively. Patients carrying D2 Ala/Ala genotype had a higher fasting plasma insulin and HOMA(IR) index as compared to patients carrying Thr/Ala or Thr/Thr genotypes (P = 0.022 and P = 0.001, respectively). A significant synergistic effect was observed between D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms on HOMA(IR) index, with carriers of both D2 Ala/Ala genotype and PPARγ2 Ala12 allele showing the highest HOMA(IR) values, after adjusting for age, gender, BMI, and use of medication for DM2 (P = 0.010). In conclusion, DM2 patients harboring both D2 Ala/Ala genotype and PPARγ2 Ala12 allele seem to present more severe IR than those with other D2/PPARγ2 genotype combinations. These findings suggest that these polymorphisms interact in the IR modulation, which may constitute a potential therapeutic target.

Pneumocystis jiroveci thyroiditis: report of 15 cases in the literature.

The authors review the epidemiology, clinical manifestations, diagnosis and treatment of Pneumocystis jiroveci thyroiditis of 15 cases reported in the medical literature. Patients with acquired immunodeficiency disease syndrome were particularly at risk. P. jiroveci thyroiditis was diagnosed at autopsy as a part of disseminated infection in a substantial number of patients without clinical manifestations and laboratory evidence of thyroid dysfunction. Local signs and symptoms of infection were indistinguishable from other infectious thyroiditis and included neck enlargement with or without cervical pain, sometimes associated with dysphagia and dysphonia, and clinical and laboratory features of hypothyroidism. Antemortem diagnosis of fungal thyroiditis was made by direct microscopy and culture of a fine-needle aspirate in most cases. As most patients with P. jiroveci thyroiditis had disseminated Pneumocystis infection with a delay in diagnosis and treatment, the overall mortality was high. Pneumocystis jiroveci thyroiditis is rare but should be suspected in HIV-infected patients with CD4 count lower than 200 cells micro(-1) on prophylatic inhalatory pentamidine who present with neck enlargement with or without pain, and clinical and laboratory evidence of hypothyroidism.